COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

{ "type": "p", "children": [], "text": "COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC)." }

Do NOT substitute COMETRIQ capsules with cabozantinib tablets.

The recommended daily dose of COMETRIQ is 140 mg once daily without food until disease progression or unacceptable toxicity. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ.

Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules.

Do not take a missed dose within 12 hours of the next dose.

Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 while taking COMETRIQ.

Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions, intolerable Grade 2 adverse reactions, or osteonecrosis of the jaw.

Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows:

Permanently discontinue COMETRIQ for any of the following:

Reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg [see Drug Interactions (7.2), Clinical Pharmacology (12.3)].

The recommended starting dose of COMETRIQ for patients with mild to moderate hepatic impairment is 80 mg [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Capsules:

{ "type": "p", "children": [], "text": "Capsules:" }

20-mg gelatin capsules, grey with "XL184 20mg" printed in black on the body of the capsule.

{ "type": "p", "children": [], "text": "20-mg gelatin capsules, grey with \"XL184 20mg\" printed in black on the body of the capsule." }

80-mg gelatin capsules, Swedish orange with "XL184 80mg" printed in black on the body of the capsule.

{ "type": "p", "children": [], "text": "80-mg gelatin capsules, Swedish orange with \"XL184 80mg\" printed in black on the body of the capsule." }

None

{ "type": "p", "children": [], "text": "None" }

Gastrointestinal (GI) perforations and fistulas, including fatal cases, were reported in 3% and 1% of COMETRIQ-treated patients (N=214), respectively. Non-GI fistulas including tracheal/esophageal, including fatal cases, were reported in 4% of COMETRIQ-treated patients.

Monitor patients for symptoms of perforations and fistulas, including abscess and sepsis. Discontinue COMETRIQ in patients who experience a Grade 4 fistula or a GI perforation [see Dosage and Administration (2.2)].

Severe and fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥ 3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%).

Discontinue COMETRIQ for Grade 3 or 4 hemorrhage [see Dosage and Administration (2.2)]. Do not administer COMETRIQ to patients with a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

COMETRIQ increased the incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively).

Discontinue COMETRIQ in patients who develop an acute myocardial infarction or arterial or venous thromboembolic events that require medical intervention [see Dosage and Administration (2.2)].

Wound complications have been reported with COMETRIQ. Withhold COMETRIQ for at least 3 weeks prior to elective surgery. Do not administer COMETRIQ for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of COMETRIQ after resolution of wound healing complications has not been established.

COMETRIQ can cause hypertension, including hypertensive crisis. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension was identified in 61% in COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial [see Adverse Reactions (6.1)].

Do not initiate COMETRIQ in patients with uncontrolled hypertension. Monitor blood pressure regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy and for hypertensive crisis [see Dosage and Administration (2.2)].

Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. Withhold COMETRIQ treatment for at least 3 weeks prior to scheduled dental surgery, or invasive dental procedures, if possible. Withhold COMETRIQ for development of ONJ until complete resolution [see Dosage and Administration (2.2)].

Diarrhea occurred in 63% of patients treated with COMETRIQ. Grade 3-4 diarrhea occurred in 16% of patients treated with COMETRIQ [see Adverse Reactions (6.1)].

Withhold COMETRIQ until improvement to Grade 1 and resume COMETRIQ at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.

Palmar-plantar erythrodysesthesia (PPE) occurred in 50% of patients treated with COMETRIQ, including 13% Grade 3 [see Adverse Reactions (6.1)].

Withhold COMETRIQ until improvement to Grade 1 and resume COMETRIQ at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Proteinuria was observed in 2% of patients receiving COMETRIQ, including one with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS [see Dosage and Administration (2.2)].

Based on data from animal studies and its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib administration to pregnant animals during organogenesis resulted in embryolethality at exposures below those occurring clinically at the recommended dose, and in increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with COMETRIQ and for 4 months after the last dose [see Use in Specific Populations (8.1), (8.3), and Clinical Pharmacology (12.1)].

COMETRIQ can cause hypocalcemia. Based on the safety population [see Clinical Trial Experience (6.1)], hypocalcemia occurred in 52% of patients treated with COMETRIQ, including Grade 3 or 4 in 12% of patients.

Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at a reduced dose upon recovery or discontinue COMETRIQ depending on severity [see Dosage and Administration (2.2)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of COMETRIQ was evaluated in 330 patients with progressive metastatic medullary thyroid cancer randomized to receive 140 mg COMETRIQ (n = 214) or placebo (n = 109) administered daily until disease progression or intolerable toxicity in a randomized, doubleblind, controlled trial (Study 1) [see Clinical Studies (14)]. The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years.

Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration.

The COMETRIQ dose was reduced in 79% of patients receiving COMETRIQ and in 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ and in no patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ. The most frequent adverse reactions leading to permanent discontinuation of COMETRIQ were: hypocalcemia, increased lipase, PPE, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation and vomiting.

Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.

Adverse reactions which occurred in ≥ 25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia (PPE), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥25%) were increased AST, increased ALT, lymphopenia, increased ALP, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥ 5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 2% included, in order of decreasing frequency; diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (Table 1 and Table 2 summarize the adverse reactions and laboratory abnormalities reported in Study 1).

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 1. Selected Adverse Reactions Occurring at a Higher Incidence in COMETRIQ-Treated Patients (Study 1) [Between Arm Difference of ≥ 5% (All Grades)<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> or ≥ 2% (Grades 3-4)]</span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule" rowspan="2">   System Organ Class/Preferred Terms</th><th align="center" class="Botrule Lrule Rrule" colspan="2">COMETRIQ<br/> (n=214)</th><th align="center" class="Botrule Lrule Rrule" colspan="2">Placebo<br/> (n=109)</th> </tr> <tr class="Last"> <th align="center" class="Botrule Lrule Rrule">All<br/> Grades<br/>(%)</th><th align="center" class="Botrule Lrule Rrule">Grades<br/> 3-4<br/>(%)</th><th align="center" class="Botrule Lrule Rrule">All<br/> Grades<br/>(%)</th><th align="center" class="Botrule Lrule Rrule">Grades<br/> 3-4<br/>(%)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">‡</a> </dt> <dd>Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">§</a> </dt> <dd>Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain</dd> <dt> <a href="#footnote-reference-5" name="footnote-5">¶</a> </dt> <dd>Palmar-plantar erythrodysesthesia</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule" colspan="5">   GASTROINTESTINAL DISORDERS</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Diarrhea</td><td align="center" class="Botrule Rrule">63</td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">33</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Stomatitis<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a></td><td align="center" class="Botrule Rrule">51</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Nausea</td><td align="center" class="Botrule Rrule">43</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">21</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Oral pain<a class="Sup" href="#footnote-3" name="footnote-reference-3">‡</a></td><td align="center" class="Botrule Rrule">36</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Constipation</td><td align="center" class="Botrule Rrule">27</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Abdominal pain<a class="Sup" href="#footnote-4" name="footnote-reference-4">§</a></td><td align="center" class="Botrule Rrule">27</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">13</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Vomiting</td><td align="center" class="Botrule Rrule">24</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dysphagia</td><td align="center" class="Botrule Rrule">13</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dyspepsia</td><td align="center" class="Botrule Rrule">11</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hemorrhoids</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="5">   SKIN AND SUBCUTANEOUS TISSUE DISORDERS</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        PPE<a class="Sup" href="#footnote-5" name="footnote-reference-5">¶</a></td><td align="center" class="Botrule Rrule">50</td><td align="center" class="Botrule Rrule">13</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hair color changes/ depigmentation, graying</td><td align="center" class="Botrule Rrule">34</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Rash</td><td align="center" class="Botrule Rrule">19</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dry skin</td><td align="center" class="Botrule Rrule">19</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Alopecia</td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Erythema</td><td align="center" class="Botrule Rrule">11</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hyperkeratosis</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="5">   INVESTIGATIONS</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Decreased weight</td><td align="center" class="Botrule Rrule">48</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="5">   METABOLISM AND NUTRITION DISORDERS</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Decreased appetite</td><td align="center" class="Botrule Rrule">46</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dehydration</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="5">   GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Fatigue</td><td align="center" class="Botrule Rrule">41</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">28</td><td align="center" class="Botrule Rrule">3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Asthenia</td><td align="center" class="Botrule Rrule">21</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">15</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="5">   NERVOUS SYSTEM DISORDERS</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dysgeusia</td><td align="center" class="Botrule Rrule">34</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Headache</td><td align="center" class="Botrule Rrule">18</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dizziness</td><td align="center" class="Botrule Rrule">14</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Paresthesia</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Peripheral sensory neuropathy</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Peripheral neuropathy</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="5">   VASCULAR DISORDERS</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypertension</td><td align="center" class="Botrule Rrule">33</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypotension</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="5">   RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dysphonia</td><td align="center" class="Botrule Rrule">20</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="5">   MUSCULOSKELETAL AND CONNECTIVE<br/>   TISSUE DISORDERS</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Arthralgia</td><td align="center" class="Botrule Rrule">14</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Muscle spasms</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Musculoskeletal chest pain</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="5">   PSYCHIATRIC DISORDERS</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">        Anxiety</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">0</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 2 Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients (Study 1) [Between Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3-4)]</span> </caption> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="15%"/> <thead> <tr class="First"> <th align="left" class="Lrule Rrule" valign="bottom">   Test</th><td align="center" class="Botrule Lrule Rrule" colspan="2">COMETRIQ<br/> (n=214)</td><td align="center" class="Botrule Lrule Rrule" colspan="2">Placebo<br/> (N=109)</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule"> </td><td align="center" class="Botrule Lrule Rrule">All Grades<br/>(%)</td><td align="center" class="Botrule Lrule Rrule">Grade 3-4<br/>(%)</td><td align="center" class="Botrule Lrule Rrule">All Grades<br/>(%)</td><td align="center" class="Botrule Lrule Rrule">Grade 3-4<br/>(%)</td> </tr> </thead> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">   Chemistries</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased AST</td><td align="center" class="Botrule Rrule">86</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">35</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased ALT</td><td align="center" class="Botrule Rrule">86</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">41</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased ALP</td><td align="center" class="Botrule Rrule">52</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">35</td><td align="center" class="Botrule Rrule">3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypocalcemia</td><td align="center" class="Botrule Rrule">52</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">27</td><td align="center" class="Botrule Rrule">3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypoalbuminemia</td><td align="center" class="Botrule Rrule">43</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypophosphatemia</td><td align="center" class="Botrule Rrule">28</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hyperbilirubinemia</td><td align="center" class="Botrule Rrule">25</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">14</td><td align="center" class="Botrule Rrule">5</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypomagnesemia</td><td align="center" class="Botrule Rrule">19</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypokalemia</td><td align="center" class="Botrule Rrule">18</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hyponatremia</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">   Hematologic</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Lymphopenia</td><td align="center" class="Botrule Rrule">53</td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">51</td><td align="center" class="Botrule Rrule">11</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Neutropenia</td><td align="center" class="Botrule Rrule">35</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">15</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Thrombocytopenia</td><td align="center" class="Botrule Rrule">35</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">3</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"> </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" colspan="5"><span class="Sup"> ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase</span></td> </tr> </tbody> </table></div>

Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 3 Per-Patient Incidence of Hypertension (Study 1)</span> </caption> <col align="left" valign="middle" width="75%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-6" name="footnote-6">*</a> </dt> <dd>Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003: 289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged.</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">†</a> </dt> <dd>Patients classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose.</dd> <dt> <a href="#footnote-reference-8" name="footnote-8">‡</a> </dt> <dd>Patients with at least two blood pressure measurements after the first dose</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule">   Hypertension, JNC<a class="Sup" href="#footnote-6" name="footnote-reference-6">*</a> Stage<a class="Sup" href="#footnote-7" name="footnote-reference-7">†</a></td><td align="center" class="Botrule Lrule Rrule">COMETRIQ<br/> N=211<a class="Sup" href="#footnote-8" name="footnote-reference-8">‡</a>(%)</td><td align="center" class="Botrule Lrule Rrule">Placebo<br/> N=107<a class="Sup" href="#footnote-8">‡</a>(%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Normal: Grade 0: Systolic &lt; 120 mmHg and Diastolic &lt; 80 mmHg</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">15</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Pre-hypertension: Systolic ≥ 120 mmHg or Diastolic ≥ 80 mmHg</td><td align="center" class="Botrule Rrule">34</td><td align="center" class="Botrule Rrule">54</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Stage 1: Systolic ≥ 140 mmHg or Diastolic ≥ 90 mmHg</td><td align="center" class="Botrule Rrule">46</td><td align="center" class="Botrule Rrule">25</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Stage 2: Systolic ≥ 160 mmHg or Diastolic ≥ 100 mmHg</td><td align="center" class="Botrule Rrule">15</td><td align="center" class="Botrule Rrule">5</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">   Malignant: Diastolic ≥ 120 mmHg</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">0</td> </tr> </tbody> </table></div>

Other clinically important adverse reactions (all grades) that were reported in clinical trials include: hepatitis cholestatic (<1%).

The following adverse reactions have been identified during postapproval use of COMETRIQ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hematology: A case of supratherapeutic international normalized ratio (INR) and epistaxis during concomitant use of warfarin

Musculoskeletal and Connective Tissue Disorders: Extremity pain

Vascular Disorders: Arterial (including aortic) aneurysms, dissections, and rupture

Administration of a strong CYP3A4 inhibitor, ketoconazole to healthy subjects increased single-dose plasma cabozantinib exposure by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) while taking COMETRIQ or reduce the dosage of COMETRIQ if concomitant use with strong CYP3A4 inhibitors cannot be avoided [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].

Avoid ingestion of foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 while taking COMETRIQ.

Administration of a strong CYP3A4 inducer, rifampin to healthy subjects decreased single-dose plasma cabozantinib exposure by 77%. Avoid chronic co-administration of strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ or increase the dosage of COMETRIQ if concomitant use with strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].

Concomitant administration of MRP2 inhibitors may increase the exposure to cabozantinib. Monitor patients for increased toxicity when MRP2 inhibitors (e.g., abacavir, adefovir, cidofovir, furosemide, lamivudine, nevirapine, ritonavir, probenecid, saquinavir, and tenofovir) are co-administered with COMETRIQ [see Clinical Pharmacology (12.3)].

Risk Summary

Based on findings from animal studies and its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. In animal developmental and reproductive toxicology studies administration of cabozantinib to pregnant rats and rabbits during organogenesis resulted in embryofetal lethality and structural anomalies at exposures that were below those occurring clinically at the recommended dose (see Data). Advise pregnant women or women of childbearing potential of the potential hazard to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

In an embryo-fetal development study in pregnant rats, daily oral administration of cabozantinib throughout organogenesis caused increased embryo-fetal lethality compared to controls at a dose of 0.03 mg/kg (less than 1% of the human exposure by AUC at the 140 mg dose). Findings included delayed ossifications and skeletal variations at a dose of 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the 140 mg dose).

In pregnant rabbits, daily oral administration of cabozantinib throughout organogenesis resulted in findings of visceral malformations and variations including reduced spleen size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the 140 mg dose).

In a pre- and postnatal study in rats, cabozantinib was administered orally from gestation day 10 through postnatal day 20. Cabozantinib did not produce adverse maternal toxicity or affect pregnancy, parturition or lactation of female rats, and did not affect the survival, growth or postnatal development of the offspring at doses up to 0.3 mg/kg/day (approximately 0.02 times the recommended clinical dose of 140 mg based on body surface area).

Risk Summary

There is no information regarding the presence of cabozantinib or its metabolites in human milk, or their effects on the breastfed infant, or milk production. Because of the potential for serious adverse reactions in a breastfed infant from COMETRIQ, advise a lactating woman not to breastfeed during treatment with COMETRIQ and for 4 months after the final dose.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating COMETRIQ [see Use in Specific Populations (8.1)].

Contraception

COMETRIQ can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Advise females of reproductive potential to use effective contraception during treatment with COMETRIQ and for 4 months after the final dose.

Infertility

Females and Males

Based on findings in animals, COMETRIQ may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of COMETRIQ in pediatric patients have not been studied.

Juvenile Animal Toxicity Data

Juvenile rats were administered cabozantinib daily at doses of 1 or 2 mg/kg/day from Postnatal Day 12 (comparable to less than 2 years in humans) through Postnatal Day 35 or 70. Mortalities occurred at doses equal and greater than 1 mg/kg/day (approximately 0.07 times the clinical dose of 140 mg/day based on body surface area). Hypoactivity was observed at both doses tested on Postnatal Day 22. Targets were generally similar to those seen in adult animals, occurred at both doses, and included the kidney (nephropathy, glomerulonephritis), reproductive organs, gastrointestinal tract (cystic dilatation and hyperplasia in Brunner’s gland and inflammation of duodenum; and epithelial hyperplasia of colon and cecum), bone marrow (hypocellularity and lymphoid depletion), and liver. Tooth abnormalities and whitening as well as effects on bones including reduced bone mineral content and density, physeal hypertrophy, and decreased cortical bone also occurred at all dose levels. Recovery was not assessed at the 2 mg/kg dose level (approximately 0.14 times the clinical dose of 140 mg based on body surface area) due to high levels of mortality. At the low dose level, effects on bone parameters were partially resolved but effects on the kidney and epididymis/testis persisted after treatment ceased.

Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.

Increased exposure to cabozantinib has been observed in patients with mild to moderate hepatic impairment. Reduce the starting dose of COMETRIQ in patients with mild (Child-Pugh score (C-P) A) or moderate (C-P B) hepatic impairment. COMETRIQ is not recommended for use in patients with severe hepatic impairment [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

Dosage adjustment is not required in patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment [see Clinical Pharmacology (12.3)].

One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented.

{ "type": "p", "children": [], "text": "One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented." }

COMETRIQ is the (S)-malate salt of cabozantinib, a kinase inhibitor. Cabozantinib (S)-malate is described chemically as N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1,1-dicarboxamide, (2S)-hydroxybutanedioate. The molecular formula is C28H24FN3O5•C4H6O5 and the molecular weight is 635.6 Daltons as malate salt. The chemical structure of cabozantinib (S)-malate salt is:

{ "type": "p", "children": [], "text": "COMETRIQ is the (S)-malate salt of cabozantinib, a kinase inhibitor. Cabozantinib (S)-malate is described chemically as N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1,1-dicarboxamide, (2S)-hydroxybutanedioate. The molecular formula is C28H24FN3O5•C4H6O5 and the molecular weight is 635.6 Daltons as malate salt. The chemical structure of cabozantinib (S)-malate salt is:" }

Cabozantinib (S)-malate salt is a white to off-white solid that is practically insoluble in aqueous media.

{ "type": "p", "children": [], "text": "Cabozantinib (S)-malate salt is a white to off-white solid that is practically insoluble in aqueous\nmedia." }

COMETRIQ (cabozantinib) capsules for oral use are supplied as printed hard gelatin capsules containing cabozantinib (S)-malate equivalent to 20 mg or 80 mg cabozantinib and the following inactive ingredients: silicified microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate, fumed silica, and stearic acid.

{ "type": "p", "children": [], "text": "COMETRIQ (cabozantinib) capsules for oral use are supplied as printed hard gelatin capsules containing cabozantinib (S)-malate equivalent to 20 mg or 80 mg cabozantinib and the following inactive ingredients: silicified microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate, fumed silica, and stearic acid." }

The grey gelatin capsule shells contain black iron oxide and titanium dioxide and the Swedish orange gelatin capsule shells contain red iron oxide, and titanium dioxide. The printing ink contains shellac glaze, black iron oxide, N-butyl alcohol, isopropyl alcohol, propylene glycol, and ammonium hydroxide.

{ "type": "p", "children": [], "text": "The grey gelatin capsule shells contain black iron oxide and titanium dioxide and the Swedish orange gelatin capsule shells contain red iron oxide, and titanium dioxide. The printing ink contains shellac glaze, black iron oxide, N-butyl alcohol, isopropyl alcohol, propylene glycol, and ammonium hydroxide." }

In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the tyrosine kinase activity of RET, MET, VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, ROS1, TYRO3, MER, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.

Cardiac Electrophysiology

The effect of orally administered COMETRIQ 140 mg on QTc interval was evaluated in a randomized, double-blinded, placebo-controlled study in patients with MTC. A mean increase in QTcF of 10 - 15 ms was observed at 4 weeks after initiating COMETRIQ. A concentration-QTc relationship could not be definitively established. Changes in cardiac wave form morphology or new rhythms were not observed. No COMETRIQ-treated patients had a QTcF > 500 ms [see Clinical Studies (14)].

A population pharmacokinetic analysis of cabozantinib was performed using data collected from 289 patients with solid tumors including MTC following oral administration of 140 mg daily doses. Repeat daily dosing of COMETRIQ at 140 mg for 19 days resulted in 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady state was achieved by Day 15.

Absorption

Following oral administration of COMETRIQ, median time to peak cabozantinib plasma concentrations (Tmax) ranged from 2 to 5 hours post-dose.

A 19% increase in the Cmax of the tablet formulation (CABOMETYX™) compared to the capsule formulation (COMETRIQ) was observed following a single 140 mg dose. A less than 10% difference in the AUC was observed between cabozantinib tablet (CABOMETYX) and capsule (COMETRIQ) formulations [see Dosage and Administration (2.1)].

Cabozantinib Cmax and AUC values increased by 41% and 57%, respectively, following a high-fat meal relative to fasted conditions in healthy subjects administered a single 140 mg oral COMETRIQ dose.

Distribution

The oral volume of distribution (V/F) of cabozantinib is approximately 349 L. Cabozantinib is highly protein bound in human plasma (≥ 99.7%).

Elimination

The predicted effective half-life is approximately 55 hours and the clearance (CL/F) at steady-state is estimated to be 4.4 L/hr.

Metabolism

Cabozantinib is a substrate of CYP3A4 in vitro.

Excretion

Approximately 81% of the total administered radioactivity was recovered within a 48-day collection period following a single 140 mg dose of an investigational 14C-cabozantinib formulation in healthy subjects. Approximately 54% was recovered in feces and 27% in urine. Unchanged cabozantinib accounted for 43% of the total radioactivity in feces and was not detectable in urine following a 72 hour collection.

Specific Populations

The following patient characteristics did not result in a clinically relevant difference in the pharmacokinetics of cabozantinib: age (20-86 years), sex, race (Whites and non-Whites), or mild to moderate renal impairment (eGFR greater than or equal to 30 mL/min/1.73 m2 as estimated by MDRD (modification of diet in renal disease equation)). The pharmacokinetics of cabozantinib is unknown in patients with worse than moderate renal impairment (eGFR less than 29 mL/min/1.73m2) as estimated by MDRD equation or renal impairment requiring dialysis.

Patients with Hepatic Impairment

Following a single oral 60 mg COMETRIQ, mean AUC0-inf for cabozantinib increased by 81% in subjects with mild (Child-Pugh A) hepatic impairment and 63% in subjects with moderate (Child-Pugh B) hepatic impairment compared to subjects with normal hepatic function [see Dosage and Administration (2.5), Use in Specific Populations (8.6)].

The pharmacokinetics of cabozantinib has not been studied in patients with severe (Child-Pugh C) hepatic impairment [see Use in Specific Populations (8.6)].

Drug Interaction Studies

CYP3A4 Inhibition on Cabozantinib

Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%.

CYP3A4 Induction on Cabozantinib

Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%.

Cabozantinib on CYP2C8 substrates

No clinically-significant effect on single-dose rosiglitazone (a CYP2C8 substrate) plasma exposure (Cmax and AUC) was observed when co-administered with cabozantinib at steady-state plasma concentrations (≥ 100 mg/day daily for a minimum of 21 days) in patients with solid tumors.

Gastric pH modifying agents on Cabozantinib

No clinically-significant effect on plasma cabozantinib exposure (AUC) was observed following co-administration of the proton pump inhibitor (PPI) esomeprazole (40 mg daily for 6 days) with a single dose of 100 mg cabozantinib to healthy volunteers.

In vitro Studies

Metabolic Pathways:

Inhibition of CYP3A4 reduced the formation of the XL184 N-oxide metabolite by >80%. Inhibition of CYP2C9 had a minimal effect on cabozantinib metabolite formation (i.e., a <20% reduction). Inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation.

Although cabozantinib is an inhibitor of CYP2C8 in vitro, a clinical study of this potential interaction concluded that concurrent use did not result in a clinically relevant effect on CYP2C8 substrate exposure. Given this finding, other less sensitive substrates of pathways affected by cabozantinib in vitro (i.e., CYP2C9, CYP2C19, and CYP3A4) were not evaluated in a clinical study because, although a clinically relevant exposure effect cannot be ruled out, it is unlikely. Cabozantinib does not inhibit CYP1A2 and CYP2D6 isozymes in vitro.

Cabozantinib is an inducer of CYP1A1 mRNA; however, the clinical relevance of this finding is unknown. Cabozantinib does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4.

Drug Transporter Systems:

Cabozantinib is an inhibitor, but not a substrate, of P-gp transport activities and has the potential to increase plasma concentrations of co-administered substrates of P-gp. The clinical relevance of this finding is unknown.

Cabozantinib is a substrate of MRP2 in vitro and MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib. The clinical relevance of this finding is unknown.

The carcinogenic potential of cabozantinib has been evaluated in two species: rasH2 transgenic mice and Sprague-Dawley rats. In the 2-year rat carcinogenicity study, once daily oral administration of cabozantinib resulted in a statistically significant increase in the incidence of malignant/complex malignant pheochromocytoma in combination with benign pheochromocytoma or in benign pheochromocytoma alone in male rats at a dose of 1 mg/kg (approximately 0.6 times the human exposure by AUC at the recommended 140 mg dose). Cabozantinib was not carcinogenic in a 26-week carcinogenicity study in rasH2 transgenic mice at a slightly higher exposure than the intended human therapeutic exposure.

Cabozantinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Based on nonclinical findings, male and female fertility may be impaired by treatment with COMETRIQ. In a fertility study in which cabozantinib was administered to male and female rats at doses of 1, 2.5, and 5 mg/kg/day, male fertility was significantly compromised at doses equal to or greater than 2.5 mg/kg/day (approximately equal to the human exposure by AUC at the recommended dose), with a decrease in sperm counts and reproductive organ weights. In females, fertility was significantly reduced at doses equal to or greater than 1 mg/kg/day (approximately 50% of the human exposure by AUC at the 140 mg recommended dose) with a significant decrease in the number of live embryos and a significant increase in pre- and post-implantation losses.

Observations of effects on reproductive tract tissues in general toxicology studies were supportive of effects noted in the dedicated fertility study and included hypospermia and absence of corpora lutea in male and female dogs in a 6-month repeat dose study at exposures equal to 6% and 3%, respectively, the human exposure by AUC at the recommended dose. In addition, female rats administered 5 mg/kg/day for 14 days (approximately equal to the human exposure by AUC at the 140 mg recommended dose) exhibited ovarian necrosis.

The safety and efficacy of COMETRIQ was assessed in an international, multi-center, randomized, double-blind, controlled trial (Study 1) of 330 patients with metastatic medullary thyroid carcinoma (MTC). Patients were required to have evidence of actively progressive disease within 14 months prior to study entry confirmed by an Independent Radiology Review Committee (IRRC) masked to treatment assignment (89%) or the treating physician (11%). Patients were randomized (2:1) to receive COMETRIQ 140 mg (n = 219) or placebo (n = 111) orally once daily, without food, until disease progression determined by the treating physician or until intolerable toxicity. Randomization was stratified by age (≤ 65 years vs. > 65 years) and prior use of a tyrosine kinase inhibitor (TKI) (yes vs. no). No cross-over was allowed at the time of progression. The main efficacy outcome measures of progression-free survival (PFS), objective response (OR), and response duration were based on IRRC-confirmed events using modified RECIST criteria.

{ "type": "p", "children": [], "text": "The safety and efficacy of COMETRIQ was assessed in an international, multi-center, randomized, double-blind, controlled trial (Study 1) of 330 patients with metastatic medullary thyroid carcinoma (MTC). Patients were required to have evidence of actively progressive disease within 14 months prior to study entry confirmed by an Independent Radiology Review Committee (IRRC) masked to treatment assignment (89%) or the treating physician (11%). Patients were randomized (2:1) to receive COMETRIQ 140 mg (n = 219) or placebo (n = 111) orally once daily, without food, until disease progression determined by the treating physician or until intolerable toxicity. Randomization was stratified by age (≤ 65 years vs. > 65 years) and prior use of a tyrosine kinase inhibitor (TKI) (yes vs. no). No cross-over was allowed at the time of progression. The main efficacy outcome measures of progression-free survival (PFS), objective response (OR), and response duration were based on IRRC-confirmed events using modified RECIST criteria." }

Of 330 patients randomized, 67% were male, the median age was 55 years, 23% were 65 years or older, 89% were white, 54% had a baseline ECOG performance status of 0, and 92% had undergone a thyroidectomy. The RET mutation status determined by a research-use assay was positive in 51%, negative in 14%, and was unknown in 35%. Twenty-five percent (25%) had two or more prior systemic therapies and 21% had been previously treated with a TKI.

{ "type": "p", "children": [], "text": "Of 330 patients randomized, 67% were male, the median age was 55 years, 23% were 65 years or older, 89% were white, 54% had a baseline ECOG performance status of 0, and 92% had undergone a thyroidectomy. The RET mutation status determined by a research-use assay was positive in 51%, negative in 14%, and was unknown in 35%. Twenty-five percent (25%) had two or more prior systemic therapies and 21% had been previously treated with a TKI." }

A statistically significant prolongation in PFS was demonstrated among COMETRIQ-treated patients compared to those receiving placebo [HR 0.28 (95% CI: 0.19, 0.40); p<0.0001], with median PFS times of 11.2 months and 4.0 months in the COMETRIQ and placebo arms, respectively.

{ "type": "p", "children": [], "text": "A statistically significant prolongation in PFS was demonstrated among COMETRIQ-treated patients compared to those receiving placebo [HR 0.28 (95% CI: 0.19, 0.40); p<0.0001], with median PFS times of 11.2 months and 4.0 months in the COMETRIQ and placebo arms, respectively." }

Partial responses were observed only among patients in the COMETRIQ arm (27% vs. 0; p<0.0001). The median duration of objective responses was 14.7 months (95% CI: 11.1, 19.3) for patients treated with COMETRIQ. There was no statistically significant difference in overall survival (median OS: 26.6 months in the COMETRIQ arm vs. 21.1 months in the placebo arm [HR = 0.85 (95% CI: 0.64, 1.12), p = 0.2409]).

{ "type": "p", "children": [], "text": "Partial responses were observed only among patients in the COMETRIQ arm (27% vs. 0; p<0.0001). The median duration of objective responses was 14.7 months (95% CI: 11.1, 19.3) for patients treated with COMETRIQ. There was no statistically significant difference in overall survival (median OS: 26.6 months in the COMETRIQ arm vs. 21.1 months in the placebo arm [HR = 0.85 (95% CI: 0.64, 1.12), p = 0.2409])." }

Figure 1: Progression-Free Survival

{ "type": "p", "children": [], "text": "\nFigure 1: Progression-Free Survival\n" }

COMETRIQ 20 mg capsules are supplied as hard gelatin capsules with grey cap and grey body, printed with "XL184 20mg" in black ink and containing cabozantinib (S)-malate salt equivalent to 20 mg cabozantinib.

{ "type": "p", "children": [], "text": "COMETRIQ 20 mg capsules are supplied as hard gelatin capsules with grey cap and grey body, printed with \"XL184 20mg\" in black ink and containing cabozantinib (S)-malate salt equivalent to 20 mg cabozantinib." }

COMETRIQ 80 mg capsules are supplied as hard gelatin capsules with Swedish orange cap and Swedish orange body, printed with "XL184 80mg" in black ink and containing cabozantinib (S)- malate salt equivalent to 80 mg cabozantinib.

{ "type": "p", "children": [], "text": "COMETRIQ 80 mg capsules are supplied as hard gelatin capsules with Swedish orange cap and Swedish orange body, printed with \"XL184 80mg\" in black ink and containing cabozantinib (S)- malate salt equivalent to 80 mg cabozantinib." }

COMETRIQ capsules are supplied as follows:Cartons

{ "type": "p", "children": [], "text": "COMETRIQ capsules are supplied as follows:Cartons" }

{ "type": "ul", "children": [ "140 mg daily-dose carton                                                                  NDC#42388-011-14Containing four 140 mg daily-dose blister cards(each blister card contains seven 80-mg and twenty-one 20-mg capsules)", "100 mg daily-dose carton                                                                  NDC#42388-012-14Containing four 100 mg daily-dose blister cards(each blister card contains seven 80-mg and seven 20-mg capsules)", "60 mg daily-dose carton                                                                    NDC#42388-013-14Containing four 60 mg daily-dose blister cards(each blister card contains twenty-one 20-mg capsules)" ], "text": "" }

Store COMETRIQ at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store COMETRIQ at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]." }

Advise patients to read the FDA-approved patient labeling (Patient Information).

{ "type": "p", "children": [], "text": "Advise patients to read the FDA-approved patient labeling (Patient Information)." }

{ "type": "ul", "children": [ "\nPerforations and fistulas: Advise patients that gastrointestinal disorders such as diarrhea, nausea, vomiting, and constipation may develop during COMETRIQ treatment and to seek immediate medical attention if they experience persistent or severe abdominal pain because cases of gastrointestinal perforation and fistula have been reported in patients taking COMETRIQ [see Warnings and Precautions (5.1)].", "\nHemorrhage: Instruct patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual severe bleeding or hemorrhage [see Warnings and Precautions (5.2)].", "\nThrombotic events: Venous and arterial thrombotic events have been reported. Advise patients to report signs or symptoms of an arterial thrombosis. Venous thromboembolic events including pulmonary embolus have been reported. Advise patients to contact their health care provider if new onset of dyspnea, chest pain, or localized limb edema occurs [see Warnings and Precautions (5.3)].", "\nImpaired wound healing: Advise patients that COMETRIQ may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Warnings and Precautions (5.4)].", "\nHypertension and hypertensive crisis: Inform patients of the signs and symptoms of hypertension. Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if they experience signs or symptoms of hypertension [see Warnings and Precautions (5.5)].", "\nOsteonecrosis of the jaw: Advise patients regarding good oral hygiene practices. Advise patients to immediately contact their healthcare provider for signs or symptoms associated with osteonecrosis of the jaw [see Warnings and Precautions (5.6)].", "\nDiarrhea: Advise patients to notify their healthcare provider at the first signs of poorly formed or loose stool or an increased frequency of bowel movements [see Warnings and Precautions (5.7)].", "\nPalmar-plantar erythrodysesthesia: Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.8)].", "\nReversible posterior leukoencephalopathy syndrome: Advise patients to immediately contact their health care provider for new onset or worsening neurological function [see Warnings and Precautions (5.10)].", "\nEmbryo-fetal toxicity:\nAdvise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)].\nAdvise patients of reproductive potential to use effective contraception during treatment with COMETRIQ and for at least 4 months after the final dose [see Use in Specific Populations (8.3)].\n\n\n", "\nLactation: Advise women not to breastfeed during treatment with COMETRIQ and for 4 months following the last dose [see Use in Specific Populations (8.2)].", "\nDrug interactions: Advise patients to inform their healthcare provider of all prescription or nonprescription medications, vitamins or herbal products. Inform patients to avoid grapefruit, grapefruit juice, and St. John’s wort [see Drug Interactions (7.1), (7.2)].", "\nHypocalcemia: Advise patients that COMETRIQ can cause low calcium levels and that their serum calcium levels should be monitored regularly during treatment. Advise patients to immediately contact their healthcare provider for signs or symptoms of hypocalcemia [see Warnings and Precautions (5.12)].\n" ], "text": "" }

Important administration information

{ "type": "p", "children": [], "text": "\nImportant administration information\n" }

{ "type": "ul", "children": [ "Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Instruct patients that COMETRIQ capsules should not be opened or crushed and to take COMETRIQ capsules with a full glass (at least 8 ounces) of water." ], "text": "" }

Manufactured for Exelixis, Inc. Alameda, CA 94502

{ "type": "p", "children": [], "text": "Manufactured for Exelixis, Inc. Alameda, CA 94502" }

PATIENT INFORMATIONCOMETRIQ® (Ko-me-trik)cabozantinib capsules

{ "type": "p", "children": [], "text": "\nPATIENT INFORMATIONCOMETRIQ® (Ko-me-trik)cabozantinib capsules\n" }

What is COMETRIQ?

{ "type": "p", "children": [], "text": "\nWhat is COMETRIQ?\n" }

COMETRIQ is a prescription medicine used to treat people with medullary thyroid cancer that has spread to other parts of the body.

{ "type": "p", "children": [], "text": "COMETRIQ is a prescription medicine used to treat people with medullary thyroid cancer that has spread to other parts of the body." }

It is not known if COMETRIQ is safe and effective in children.

{ "type": "p", "children": [], "text": "It is not known if COMETRIQ is safe and effective in children." }

Before you take COMETRIQ, tell your healthcare provider about all of your medical conditions including if you:

{ "type": "p", "children": [], "text": "\nBefore you take COMETRIQ, tell your healthcare provider about all of your medical conditions including if you:" }

{ "type": "ul", "children": [ "have a recent history of coughing up blood or bleeding or any unusual bleeding", "have an open or healing wound", "have high blood pressure", "have a low calcium level in your blood (hypocalcemia)", "plan to have any surgery, a dental procedure, or have had a recent surgery. You should stop taking COMETRIQ at least 3 weeks before planned surgery. See \"What are the possible side effects of COMETRIQ?\"\n", "have liver problems", "are pregnant or plan to become pregnant. COMETRIQ can harm your unborn baby.\n \nIf you are able to become pregnant, your healthcare provider will check your pregnancy status before you start treatment with COMETRIQ.\nFemales who are able to become pregnant should use effective birth control (contraception) during treatment and for 4 months after the final dose of COMETRIQ.\nTalk to your healthcare provider about birth control methods that may be right for you.\nIf you become pregnant or think you are pregnant, tell your healthcare provider right away.\n\n", "are breastfeeding or plan to breastfeed. It is not known if COMETRIQ passes into your breast milk. Do not breastfeed during treatment and for 4 months after the final dose of COMETRIQ." ], "text": "" }

Tell your healthcare provider about all the medicines you take, including prescription or over-the-counter medicines, vitamins, and herbal supplements. COMETRIQ and certain other medicines may affect each other causing side effects.

{ "type": "p", "children": [], "text": "\nTell your healthcare provider about all the medicines you take, including prescription or over-the-counter medicines, vitamins, and herbal supplements. COMETRIQ and certain other medicines may affect each other causing side effects." }

How should I take COMETRIQ?

{ "type": "p", "children": [], "text": "\nHow should I take COMETRIQ?\n" }

{ "type": "ul", "children": [ "Take COMETRIQ exactly as your healthcare provider tells you to take it.", "\nDo not take COMETRIQ with food. Do not eat for at least 2 hours before and at least 1 hour after taking COMETRIQ.", "Swallow COMETRIQ capsules whole with a full glass (at least 8 ounces) of water.", "Do not crush or open COMETRIQ capsules.", "If you miss a dose and your next dose is in less than 12 hours, take your next dose at the normal time.\nDo not make up the missed dose." ], "text": "" }

What should I avoid while taking COMETRIQ?

{ "type": "p", "children": [], "text": "\nWhat should I avoid while taking COMETRIQ?\n" }

Do not drink grapefruit juice, eat grapefruit or take supplements that contain grapefruit or St. John's wort during treatment with COMETRIQ.

{ "type": "p", "children": [], "text": "\nDo not drink grapefruit juice, eat grapefruit or take supplements that contain grapefruit or St. John's wort during treatment with COMETRIQ." }

What are the possible side effects of COMETRIQ?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of COMETRIQ?\n" }

COMETRIQ may cause serious side effects, including:

{ "type": "p", "children": [], "text": "\nCOMETRIQ may cause serious side effects, including:\n" }

{ "type": "ul", "children": [ "\na tear in your stomach or intestinal wall (perforation) or an abnormal connection between 2 parts of your body (fistula) that may lead to death. Tell your healthcare provider right away if you get tenderness or pain in your stomach-area (abdomen) that is severe or that does not go away.", "\nbleeding (hemorrhage). COMETRIQ can cause severe bleeding that may lead to death. Tell your healthcare provider right away if you get any signs of bleeding during treatment with COMETRIQ, including:\ncoughing up blood or blood clots\nvomiting blood or if your vomit looks like coffee-grounds\nred or black (looks like tar) stools\nmenstrual bleeding that is heavier than normal\nany unusual or heavy bleeding\n\n", "\nblood clots, stroke, heart attack, and chest pain. Get emergency help right away if you get:\nswelling or pain in your arms or legs\nshortness of breath\nfeel lightheaded or faint\nsweating more than usual\nnumbness or weakness of your face, arm or leg, especially on one side of your body\nsudden confusion, trouble speaking or understanding\nsudden trouble seeing in one or both eyes\nsudden trouble walking\ndizziness, loss of balance or coordination\na sudden severe headache\n\n", "\nwound healing problems. Wound healing problems have happened in some people who take COMETRIQ. Tell your healthcare provider if you plan to have any surgery before or during treatment with COMETRIQ.\nYou should stop taking COMETRIQ at least 3 weeks before planned surgery.\nYour healthcare provider should tell you when you may start taking COMETRIQ again after surgery.\n\n", "\nhigh blood pressure (hypertension). Hypertension is common with COMETRIQ and can be severe. Your healthcare provider will check your blood pressure before starting COMETRIQ and regularly during treatment with COMETRIQ. If needed, your healthcare provider may prescribe medicine to treat your high blood pressure. Tell your healthcare provider if you develop severe headaches, nose bleeds, tiredness or confusion, vision changes, chest pain, trouble breathing, irregular heartbeat, or blood in your urine.", "\nsevere jaw bone problems (osteonecrosis). Your healthcare provider should examine your mouth before you start and during treatment with COMETRIQ. Tell your dentist that you are taking COMETRIQ. It is important for you to practice good mouth care during treatment with COMETRIQ. Tell your healthcare provider right away if you develop any symptoms of jaw problems including: jaw pain, toothache, or sores on your gums.", "\ndiarrhea. Diarrhea is common with COMETRIQ and can be severe. If needed, your healthcare provider may prescribe medicine to treat your diarrhea. Tell your healthcare provider right away, if you have frequent loose, watery bowel movements.", "\na skin problem called hand-foot skin reaction. Hand-foot skin reactions are common with COMETRIQ and can be severe. Tell your healthcare provider right away if you have rashes, redness, pain, swelling, or blisters on the palms of your hands or soles of your feet.", "\nprotein in your urine and possible kidney problems. Symptoms may include swelling in your hands, arms, legs, or feet.", "\nReversible Posterior Leukoencephalopathy Syndrome (RPLS). A condition called reversible posterior leukoencephalopathy syndrome can happen during treatment with COMETRIQ. Tell your healthcare provider right away if you have headaches, seizures, confusion, changes in vision, or problems thinking.", "\ndecreased calcium level in your blood (hypocalcemia). COMETRIQ can cause you to have a decreased amount of calcium in your blood. Your healthcare provider will do blood tests to check you for this problem and give you calcium if needed. Tell your healthcare provider right away if you get any of the following signs or symptoms:\n\nmuscle stiffness or muscle spasms\nnumbness or tingling in your fingers, toes, or around your mouth\nseizures\nsudden weight gain\nswelling of your arms, hands, legs, and ankles\n\n" ], "text": "" }

Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with COMETRIQ if you have certain side effects.

{ "type": "p", "children": [], "text": "Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with COMETRIQ if you have certain side effects." }

The most common side effects of COMETRIQ include:

{ "type": "p", "children": [], "text": "\nThe most common side effects of COMETRIQ include:\n" }

{ "type": "ul", "children": [ "diarrhea", "redness, swelling or pain in your mouth or throat, or mouth sores. Tell your healthcare provider if these symptoms prevent you from eating or drinking.", "weight loss", "decreased appetite", "nausea", "tiredness", "hair color turning lighter", "change in taste", "pain in your abdomen", "constipation" ], "text": "" }

The most common abnormal blood test results with COMETRIQ include:

{ "type": "p", "children": [], "text": "\nThe most common abnormal blood test results with COMETRIQ include:\n" }

{ "type": "ul", "children": [ "increased liver function blood tests", "decreased white blood cell counts", "increased levels of enzyme called alkaline phosphatase in the blood (test for liver or bone problems)", "decreased calcium and phosphate blood le", "decreased platelet counts", "increased bilirubin blood levels" ], "text": "" }

COMETRIQ may cause fertility problems in females and males, which may affect your ability to have children. Talk to your healthcare provider if you have concerns about fertility.

{ "type": "p", "children": [], "text": "COMETRIQ may cause fertility problems in females and males, which may affect your ability to have children. Talk to your healthcare provider if you have concerns about fertility." }

These are not all the possible side effects of COMETRIQ

{ "type": "p", "children": [], "text": "These are not all the possible side effects of COMETRIQ" }

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088." }

How should I store COMETRIQ?

{ "type": "p", "children": [], "text": "\nHow should I store COMETRIQ?\n" }

{ "type": "ul", "children": [ "Store COMETRIQ at room temperature between 68°F to 77°F (20°C to 25°C)." ], "text": "" }

Keep COMETRIQ and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep COMETRIQ and all medicines out of the reach of children.\n" }

General information about the safe and effective use of COMETRIQ.

{ "type": "p", "children": [], "text": "\nGeneral information about the safe and effective use of COMETRIQ.\n" }

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use COMETRIQ for a condition for which it was not prescribed. Do not give COMETRIQ to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about COMETRIQ that is written for health professionals.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use COMETRIQ for a condition for which it was not prescribed. Do not give COMETRIQ to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about COMETRIQ that is written for health professionals." }

What are the ingredients in COMETRIQ?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in COMETRIQ?\n" }

Active ingredient: cabozantinib

{ "type": "p", "children": [], "text": "\nActive ingredient: cabozantinib" }

Inactive ingredients: silicified microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate, fumed silica, and stearic acid

{ "type": "p", "children": [], "text": "\nInactive ingredients: silicified microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate, fumed silica, and stearic acid" }

Capsule shells: Grey gelatin capsule shells contain black iron oxide and titanium dioxide. Swedish orange gelatin capsule shells contain red iron oxide, and titanium dioxide.

{ "type": "p", "children": [], "text": "Capsule shells: Grey gelatin capsule shells contain black iron oxide and titanium dioxide. Swedish orange gelatin capsule shells contain red iron oxide, and titanium dioxide." }

The printing ink contains shellac glaze, black iron oxide, N-butyl alcohol, isopropyl alcohol, propylene glycol, and ammonium hydroxide.

{ "type": "p", "children": [], "text": "The printing ink contains shellac glaze, black iron oxide, N-butyl alcohol, isopropyl alcohol, propylene glycol, and ammonium hydroxide." }

Manufactured for Exelixis, Inc. Alameda, CA 94502

{ "type": "p", "children": [], "text": "Manufactured for Exelixis, Inc. Alameda, CA 94502" }

For more information, go to www.cometriq.com or call 1-855-292-3935.

{ "type": "p", "children": [], "text": "For more information, go to www.cometriq.com or call 1-855-292-3935." }

This Patient Information has been approved by the U.S. Food and Drug Administration.                                                            Revised 08/2023

{ "type": "p", "children": [], "text": "This Patient Information has been approved by the U.S. Food and Drug Administration.                                                            Revised 08/2023" }

Package Label - CARTON - 140 mg Daily Dose of COMETRIQ

{ "type": "p", "children": [], "text": "\n\nPackage Label - CARTON - 140 mg Daily Dose of COMETRIQ\n" }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n\n\n" }

Cometriq® (cabozantinib) capsules 140 mg Daily Dose Blister Cards Each 140 mg daily dose contains a combination of one Swedish orange 80 mg and three grey 20 mg capsules. Each capsule contains cabozantinib (S)-malate equivalent to 80 mg or 20 mg of cabozantinib. EXELIXIS® NDC 42388-011-14 Carton containing 4 blister cards: The blister cards in this carton are for patients prescribed a 140 mg daily dose. Rx Only

{ "type": "p", "children": [], "text": "\nCometriq®\n(cabozantinib) capsules\n140 mg Daily Dose Blister Cards\n\nEach 140 mg daily dose contains a combination of one Swedish orange 80 mg and three grey 20 mg\ncapsules. Each capsule contains cabozantinib (S)-malate equivalent to 80 mg or 20 mg of\ncabozantinib. \n\nEXELIXIS®\n\n NDC 42388-011-14\nCarton containing 4 blister cards: The blister cards in this carton are for patients prescribed a 140 mg daily dose.\nRx Only\n\n\n" }

Package Label - CARTON - 100 mg Daily Dose of COMETRIQ

{ "type": "p", "children": [], "text": "\n\nPackage Label - CARTON - 100 mg Daily Dose of COMETRIQ\n" }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n\n\n" }

Cometriq® (cabozantinib) capsules 100 mg Daily Dose Blister Cards Each 100 mg daily dose contains a combination of one Swedish orange 80 mg and one grey 20 mg capsule. Each capsule contains cabozantinib (S)-malate equivalent to 80 mg or 20 mg of cabozantinib. EXELIXIS® NDC 42388-012-14 Carton containing 4 blister cards: The blister cards in this carton are for patients prescribed a 100 mg daily dose. Rx Only

{ "type": "p", "children": [], "text": "\nCometriq®\n(cabozantinib) capsules\n100 mg Daily Dose Blister Cards\n\nEach 100 mg daily dose contains a combination of one Swedish orange 80 mg and one grey 20 mg capsule. Each capsule contains cabozantinib (S)-malate equivalent to 80 mg or 20 mg of cabozantinib.\n\nEXELIXIS®\n\nNDC 42388-012-14\nCarton containing 4 blister cards: The blister cards in this carton are for patients prescribed a 100 mg daily dose.\nRx Only\n\n\n" }

Package Label - CARTON - 60 mg Daily Dose of COMETRIQ

{ "type": "p", "children": [], "text": "\n\nPackage Label - CARTON - 60 mg Daily Dose of COMETRIQ\n" }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n\n\n" }

Cometriq® (cabozantinib) capsules 60 mg Daily Dose Blister Cards Each 60 mg daily dose contains three grey 20 mg capsules. Each capsule contains cabozantinib(S)-malate equivalent to 20 mg of cabozantinib. EXELIXIS® NDC 42388-013-14 Carton containing 4 blister cards: The blister cards in this carton are for patients prescribed a 60 mg daily dose. Rx Only

{ "type": "p", "children": [], "text": "\nCometriq®\n(cabozantinib) capsules\n60 mg Daily Dose Blister Cards\n\nEach 60 mg daily dose contains three grey 20 mg capsules. Each capsule contains cabozantinib(S)-malate equivalent to 20 mg of cabozantinib.\n\nEXELIXIS®\n\nNDC 42388-013-14\nCarton containing 4 blister cards: The blister cards in this carton are for patients prescribed a 60 mg daily dose.\nRx Only\n\n\n" }

CABOMETYX is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

CABOMETYX, in combination with nivolumab, is indicated for the first-line treatment of patients with advanced RCC.

CABOMETYX is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible.

CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic neuroendocrine tumors (pNET).

CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated extra-pancreatic neuroendocrine tumors (epNET).

The recommended dosage of CABOMETYX as a single agent is 60 mg orally once daily until disease progression or unacceptable toxicity [see Dosage and Administration (2.9)].

The recommended dosage of CABOMETYX in combination with nivolumab is provided in the following table:

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 1. Recommended Dosage of CABOMETYX in Combination with Nivolumab</span> </caption> <col align="left" valign="top" width="50%"/> <col align="left" valign="top" width="50%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule">Recommended Dosage</th><th align="left" class="Botrule Rrule">Duration of Therapy</th> </tr> </thead> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule">CABOMETYX 40 mg orally once daily</td><td align="left" class="Botrule Rrule">Until disease progression or unacceptable toxicity</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">Nivolumab 240 mg every 2 weeks (30-minute intravenous infusion) or 480 mg every 4 weeks (30- minute intravenous infusion)</td><td align="left" class="Botrule Rrule">Until disease progression or unacceptable toxicity for up to 2 years</td> </tr> </tbody> </table></div>

The recommended dosage of CABOMETYX as a single agent is 60 mg orally once daily until disease progression or unacceptable toxicity [see Dosage and Administration (2.9)].

Table 2 provides the recommended dosage of CABOMETYX for differentiated thyroid cancer (DTC) and neuroendocrine tumors (NET).

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 2: Recommended Dosages for DTC and NET</span> </caption> <col align="left" valign="top" width="50%"/> <col align="left" valign="top" width="50%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule">Adult and pediatric patients 12 years of age and older with bodyweight greater than or equal to 40 kg</td><td align="left" class="Botrule Rrule">60 mg orally once daily until disease progression or unacceptable toxicity</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">Pediatric patients 12 years of age and older with bodyweight less than 40 kg</td><td align="left" class="Botrule Rrule">40 mg orally once daily until disease progression or unacceptable toxicity</td> </tr> </tbody> </table></div>

Withhold CABOMETYX for:

Upon resolution/improvement (i.e., return to baseline or resolution to Grade 1) of an adverse reaction, reduce the dose as follows:

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 3. Recommended Dosage Reductions for CABOMETYX for Adverse Reactions</span> </caption> <col align="left" valign="top" width="33.34%"/> <col align="left" valign="top" width="33.33%"/> <col align="left" valign="top" width="33.33%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule">Recommended Dosage</th><th align="left" class="Botrule Rrule">First Dosage Reduction To</th><th align="left" class="Botrule Rrule">Second Dosage Reduction To</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>If previously receiving lowest dose, resume at same dose. If lowest dose not tolerated, discontinue CABOMETYX.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule">CABOMETYX 60 mg daily in adult and pediatric patients 12 years of age and older with bodyweight greater than or equal to 40 kg </td><td align="left" class="Botrule Rrule">40 mg daily</td><td align="left" class="Botrule Rrule">20 mg daily<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">CABOMETYX 40 mg daily in pediatric patients 12 years of age and older with bodyweight less than 40 kg </td><td align="left" class="Botrule Rrule">20 mg daily</td><td align="left" class="Botrule Rrule">20 mg every other day<a class="Sup" href="#footnote-1">*</a></td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">CABOMETYX 40 mg daily in combination with nivolumab</td><td align="left" class="Botrule Rrule">20 mg daily</td><td align="left" class="Botrule Rrule">20 mg every other day<a class="Sup" href="#footnote-1">*</a></td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 4. Recommended Dosage Modifications for CABOMETYX Adverse Reactions</span> </caption> <col align="left" valign="top" width="33.34%"/> <col align="left" valign="top" width="33.33%"/> <col align="left" valign="top" width="33.33%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule">Adverse Reaction</th><th align="left" class="Botrule Rrule">Severity<a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a></th><th align="left" class="Botrule Rrule">CABOMETYX Dosage Modification</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0)</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule">Hemorrhage <span class="Italics">[see <a href="#s5.1">Warnings and Precautions (5.1)</a>]</span></td><td align="left" class="Botrule Rrule">Grade 3 or 4</td><td align="left" class="Botrule Rrule"> <ul> <li>Permanently discontinue CABOMETYX</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Perforations and Fistulas <span class="Italics">[see <a href="#s5.2">Warnings and Precautions (5.2)</a>]</span></td><td align="left" class="Botrule Rrule">Any grade gastrointestinal perforation or<br/> <br/>Grade 4 fistula</td><td align="left" class="Botrule Rrule"> <ul> <li>Permanently discontinue CABOMETYX</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Thrombotic Events <span class="Italics">[see <a href="#s5.3">Warnings and Precautions (5.3)</a>]</span></td><td align="left" class="Botrule Rrule">Any grade acute myocardial infarction or<br/> <br/>Grade 2 or higher cerebral infarction or<br/> <br/>Grade 3 or 4 arterial thromboembolic events or<br/> <br/>Grade 4 venous thromboembolic events</td><td align="left" class="Botrule Rrule"> <ul> <li>Permanently discontinue CABOMETYX</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="2">Hypertension and Hypertensive Crisis <span class="Italics">[see <a href="#s5.4">Warnings and Precautions (5.4)</a>]</span></td><td align="left" class="Botrule Rrule">Grade 3</td><td align="left" class="Botrule Rrule"> <ul> <li>Withhold CABOMETYX until hypertension is adequately controlled to ≤Grade 2</li> <li>Resume at reduced dose</li> <li>Permanently discontinue CABOMETYX for hypertension that cannot be controlled</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Rrule">Grade 4</td><td align="left" class="Botrule Rrule"> <ul> <li>Permanently discontinue CABOMETYX</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Diarrhea <span class="Italics">[see <a href="#s5.5">Warnings and Precautions (5.5)</a>]</span></td><td align="left" class="Botrule Rrule">Grade 2, Grade 3, or Grade 4</td><td align="left" class="Botrule Rrule"> <ul> <li>Withhold CABOMETYX until ≤Grade 1</li> <li>Resume at reduced dose</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Palmar-Plantar Erythrodysesthesia <span class="Italics">[see <a href="#s5.6">Warnings and Precautions (5.6)</a>]</span></td><td align="left" class="Botrule Rrule">Intolerable Grade 2 or Grade 3</td><td align="left" class="Botrule Rrule"> <ul> <li>Withhold CABOMETYX until ≤Grade 1</li> <li>Resume at reduced dose</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Proteinuria <span class="Italics">[see <a href="#s5.9">Warnings and Precautions (5.9)</a>]</span></td><td align="left" class="Botrule Rrule">Grade 2 or 3</td><td align="left" class="Botrule Rrule"> <ul> <li>Withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria</li> <li>Resume at a reduced dose</li> <li>Permanently discontinue CABOMETYX for nephrotic syndrome</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Osteonecrosis of the jaw (ONJ) <span class="Italics">[see <a href="#s5.10">Warnings and Precautions (5.10)</a>]</span></td><td align="left" class="Botrule Rrule">Any grade</td><td align="left" class="Botrule Rrule"> <ul> <li>Withhold CABOMETYX for development of ONJ until complete resolution</li> <li>Resume at reduced dose</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Reversible Posterior Leukoencephalopathy Syndrome <span class="Italics">[see <a href="#s5.12">Warnings and Precautions (5.12)</a>]</span></td><td align="left" class="Botrule Rrule">Any grade</td><td align="left" class="Botrule Rrule"> <ul> <li>Permanently discontinue CABOMETYX</li> </ul> </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">Other Adverse Reactions <span class="Italics">[see <a href="#s6.1">Adverse Reactions (6.1)</a>]</span></td><td align="left" class="Botrule Rrule">Intolerable Grade 2,<br/> <br/> or Grade 3,<br/> <br/> or Grade 4</td><td align="left" class="Botrule Rrule"> <ul> <li>Withhold CABOMETYX until improvement to baseline or ≤Grade 1</li> <li>Resume at reduced dose</li> </ul> </td> </tr> </tbody> </table></div>

The following table represents dosage modifications for the drug administered in combination that are different from those described above for CABOMETYX or in the Full Prescribing Information:

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 5. Recommended Specific Dosage Modifications for Hepatic Adverse Reactions for Combination</span> </caption> <col align="left" valign="top" width="33.34%"/> <col align="left" valign="top" width="33.33%"/> <col align="left" valign="top" width="33.33%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>Consider corticosteroid therapy for hepatic adverse reactions if CABOMETYX is withheld or discontinued when administered in combination with nivolumab</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">†</a> </dt> <dd>After recovery, rechallenge with one or both of CABOMETYX and nivolumab may be considered. If rechallenging with nivolumab with or without CABOMETYX, refer to nivolumab Prescribing Information.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Lrule Rrule"><span class="Bold">CABOMETYX in combination with nivolumab</span></td><td align="left" class="Botrule Rrule">ALT or AST &gt;3 times ULN but ≤10 times ULN with concurrent total bilirubin &lt;2 times ULN</td><td align="left" class="Botrule Rrule">Withhold<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a> both CABOMETYX and nivolumab until adverse reactions recover<a class="Sup" href="#footnote-4" name="footnote-reference-4">†</a> to Grades 0 or 1</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"></td><td align="left" class="Botrule Lrule Rrule">ALT or AST &gt;10 times ULN or &gt;3 times ULN with concurrent total bilirubin ≥2 times ULN</td><td align="left" class="Botrule Rrule">Permanently discontinue both CABOMETYX and nivolumab</td> </tr> </tbody> </table></div>

When administering CABOMETYX in combination with nivolumab for the treatment of advanced RCC, refer to the nivolumab prescribing information.

Reduce the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 40 mg daily or from 40 mg to 20 mg daily or from 20 mg daily to 20 mg every other day in pediatric patients 12 years of age and older with bodyweight less than 40 kg). Resume the dose that was used prior to initiating the strong CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Increase the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 80 mg daily or from 40 mg to 60 mg daily) as tolerated. Resume the dose that was used prior to initiating the strong or moderate CYP3A4 inducer 2 to 3 days after discontinuation of the inducer. Do not exceed a daily dose of 80 mg [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Reduce the starting dose of CABOMETYX 60 mg daily to 40 mg daily or 40 mg daily to 20 mg daily (for pediatric patients 12 years of age and older with bodyweight less than 40 kg) in patients with moderate hepatic impairment (Child-Pugh B) [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Administer CABOMETYX on an empty stomach. Administer at least 1 hour before or at least 2 hours after eating [see Clinical Pharmacology (12.3)].

Tablets:

{ "type": "p", "children": [], "text": "Tablets:" }

{ "type": "ul", "children": [ "60 mg: yellow film-coated, oval shaped with no score, and debossed with \"XL\" on one side and \"60\" on the other side.", "40 mg: yellow film-coated, triangle shaped with no score, and debossed with \"XL\" on one side and \"40\" on the other side.", "20 mg: yellow film-coated, round with no score, and debossed with \"XL\" on one side and \"20\" on the other side." ], "text": "" }

None.

{ "type": "p", "children": [], "text": "None." }

CABOMETYX can cause severe and fatal hemorrhages. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX-treated patients in RCC, HCC, and DTC studies [see Adverse Reactions (6.1)].

Withhold CABOMETYX for 3 weeks prior to scheduled surgery, including dental surgery to reduce the risk of hemorrhage. Permanently discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended [see Dosage and Administration (2.5), Warnings and Precautions (5.10, 5.11)].

CABOMETYX can cause gastrointestinal (GI) perforations and fistulas.

Fistulas, including fatal cases, occurred in 1% of CABOMETYX-treated patients [see [see Adverse Reactions (6.1)]. GI perforations, including fatal cases, occurred in 1% of CABOMETYX- treated patients.

Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation [see Dosage and Administration (2.5)].

CABOMETYX can cause arterial or venous thromboembolic events.

Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism occurred in 2% of CABOMETYX-treated patients. Fatal thrombotic events occurred in CABOMETYX-treated patients [see Adverse Reactions (6.1)].

Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention [see Dosage and Administration (2.5)].

CABOMETYX can cause hypertension, including hypertensive crisis [see Adverse Reactions (6.1)]. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX- treated patients. In CABINET (n=195) [see Clinical Studies (14.4)], hypertension was reported in 65% (26% Grade 3) of CABOMETYX-treated patients.

Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose [see Dosage and Administration (2.5)]. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis [see Dosage and Administration (2.5)].

CABOMETYX can cause diarrhea. Diarrhea occurred in 62% of patients treated with CABOMETYX. Grade 3 diarrhea occurred in 10% of patients treated with CABOMETYX [see Adverse Reactions (6.1)].

Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤Grade 1, resume CABOMETYX at a reduced dose [see Dosage and Administration (2.5)].

CABOMETYX can cause palmar-plantar erythrodysesthesia (PPE). PPE occurred in 45% of patients treated with CABOMETYX [see Adverse Reactions (6.1)]. Grade 3 PPE occurred in 13% of patients treated with CABOMETYX.

Withhold CABOMETYX until improvement to Grade 1 and resume CABOMETYX at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE [see Dosage and Administration (2.5)].

CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone.

Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids [see Dosage and Administration (2.5)].

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients [see Adverse Reactions (6.1)]. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab.

Withhold and then resume CABOMETYX at a reduced dose based on severity [see Dosage and Administration (2.5)].

CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency.

Adrenal insufficiency occurred in 4.7% (15/320) of patients treated with the combination of CABOMETYX and nivolumab including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions [see Adverse Reactions (6.1)]. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity [see Dosage and Administration (2.5)].

CABOMETYX can cause proteinuria.

Proteinuria was observed in 8% of patients receiving CABOMETYX [see Adverse Reactions (6.1)].

Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤Grade 1 proteinuria, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome [see Dosage and Administration (2.5)].

CABOMETYX can cause osteonecrosis of the jaw (ONJ).

ONJ occurred in <1% of patients treated with CABOMETYX [see Adverse Reactions (6.1)].

ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of CABOMETYX and periodically during CABOMETYX. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose [see Dosage and Administration (2.5)].

CABOMETYX can cause impaired wound healing [see Adverse Reactions (6.1)]. Withhold CABOMETYX for at least 3 weeks prior to elective surgery [see Dosage and Administration (2.1)]. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established [see Dosage and Administration (2.1, 2.5)].

CABOMETYX can cause reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue CABOMETYX in patients who develop RPLS [see Dosage and Administration (2.5)].

CABOMETYX can cause thyroid dysfunction, primarily hypothyroidism. Thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients [see Adverse Reactions (6.1)].

Assess patients for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitor for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated [see Dosage and Administration (2.5)].

CABOMETYX can cause hypocalcemia. Hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients [see Adverse Reactions (6.1)]. Laboratory abnormality data were not collected in CABOSUN and CABINET.

In COSMIC-311 (n=125) [see Clinical Studies (14.3)], hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients.

Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity [see Dosage and Administration (2.5)].

Based on data from animal studies and its mechanism of action, CABOMETYX can cause fetal harm when administered to a pregnant woman. Cabozantinib administration to pregnant animals during organogenesis resulted in embryolethality at exposures below those occurring clinically at the recommended dose, and in increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the WARNINGS AND PRECAUTIONS section and below reflect exposure to CABOMETYX as a single agent at 60 mg orally once daily until disease progression or unacceptable toxicity in 409 patients with RCC enrolled in a randomized, active-controlled trial (CABOSUN, METEOR), 467 patients with HCC enrolled in a randomized, placebo- controlled trial (CELESTIAL), 125 patients with DTC enrolled in a randomized, placebo- controlled trial (COSMIC-311), 195 patients with pNET or epNET enrolled in a randomized, placebo-controlled trial (CABINET), and at 40 mg CABOMETYX in combination with nivolumab 240 mg/m2 every 2 weeks, in 320 patients with RCC enrolled in a randomized, active- controlled trial (CHECKMATE-9ER).

Renal Cell Carcinoma

METEOR

The safety of CABOMETYX was evaluated in METEOR, a randomized, open-label trial in which 331 patients with advanced renal cell carcinoma received CABOMETYX 60 mg once daily and 322 patients received everolimus 10 mg once daily until disease progression or unacceptable toxicity. Patients on both arms who had disease progression could continue treatment at the discretion of the investigator [see Clinical Studies (14)]. The median duration of treatment was 7.6 months (range 0.3 – 20.5) for patients receiving CABOMETYX and 4.4 months (range 0.21 – 18.9) for patients receiving everolimus.

Adverse reactions which occurred in ≥ 25% of CABOMETYX-treated patients, in order of decreasing frequency, were: diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia (PPE), hypertension, vomiting, weight decreased, and constipation. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥ 5% of patients were hypertension, diarrhea, fatigue, PPE, hyponatremia, hypophosphatemia, hypomagnesemia, lymphopenia, anemia, hypokalemia, and increased GGT.

The dose was reduced in 60% of patients receiving CABOMETYX and in 24% of patients receiving everolimus. Twenty percent (20%) of patients received CABOMETYX 20 mg once daily as their lowest dose. The most frequent adverse reactions leading to dose reduction in patients treated with CABOMETYX were: diarrhea, PPE, fatigue, and hypertension. Adverse reactions leading to dose interruption occurred in 70% patients receiving CABOMETYX and in 59% patients receiving everolimus. Adverse reactions led to study treatment discontinuation in 10% of patients receiving CABOMETYX and in 10% of patients receiving everolimus. The most frequent adverse reactions leading to permanent discontinuation in patients treated with CABOMETYX were decreased appetite (2%) and fatigue (1%).

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 6. Adverse Reactions Occurring in ≥ 10% Patients Who Received CABOMETYX in METEOR</span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule" rowspan="2">   Adverse Reaction</th><th align="center" class="Botrule Lrule Rrule" colspan="2">CABOMETYX<br/> (n=331)<a class="Sup" href="#footnote-5" name="footnote-reference-5">*</a></th><th align="center" class="Botrule Lrule Rrule" colspan="2">Everolimus<br/> (n=322)</th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule">All<br/> Grades<a class="Sup" href="#footnote-6" name="footnote-reference-6">†</a></th><th align="center" class="Botrule Lrule Rrule">Grades<br/> 3-4</th><th align="center" class="Botrule Lrule Rrule">All<br/> Grades<a class="Sup" href="#footnote-6">†</a></th><th align="center" class="Botrule Lrule Rrule">Grades<br/> 3-4</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" colspan="1"></th><th align="center" class="Botrule Lrule Rrule" colspan="4">Percentage (%) of Patients</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-5" name="footnote-5">*</a> </dt> <dd>One subject randomized to everolimus received cabozantinib.</dd> <dt> <a href="#footnote-reference-6" name="footnote-6">†</a> </dt> <dd>National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">‡</a> </dt> <dd>Includes the following terms: abdominal pain, abdominal pain upper, and abdominal pain lower</dd> <dt> <a href="#footnote-reference-8" name="footnote-8">§</a> </dt> <dd>Includes the following terms: rash, rash erythematous, rash follicular, rash macular, rash papular, rash pustular, rash vesicular, genital rash, intermittent leg rash, rash on scrotum and penis, rash maculo- papular, rash pruritic, contact dermatitis, dermatitis acneiform</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">¶</a> </dt> <dd>Includes the following terms hypertension, blood pressure increased, hypertensive crisis, blood pressure fluctuation</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Gastrointestinal</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Diarrhea</td><td align="center" class="Botrule Rrule">74</td><td align="center" class="Botrule Rrule">11</td><td align="center" class="Botrule Rrule">28</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Nausea</td><td align="center" class="Botrule Rrule">50</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">28</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Vomiting</td><td align="center" class="Botrule Rrule">32</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">14</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Stomatitis</td><td align="center" class="Botrule Rrule">22</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">24</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Constipation</td><td align="center" class="Botrule Rrule">25</td><td align="center" class="Botrule Rrule">&lt;1</td><td align="center" class="Botrule Rrule">19</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Abdominal pain<a class="Sup" href="#footnote-7" name="footnote-reference-7">‡</a></td><td align="center" class="Botrule Rrule">23</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">13</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dyspepsia</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">&lt;1</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   General</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Fatigue</td><td align="center" class="Botrule Rrule">56</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">47</td><td align="center" class="Botrule Rrule">7</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Mucosal inflammation</td><td align="center" class="Botrule Rrule">19</td><td align="center" class="Botrule Rrule">&lt;1</td><td align="center" class="Botrule Rrule">23</td><td align="center" class="Botrule Rrule">3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Asthenia</td><td align="center" class="Botrule Rrule">19</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Metabolism and Nutrition</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Decreased appetite</td><td align="center" class="Botrule Rrule">46</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">34</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Skin and Subcutaneous Tissue</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Palmar-plantar erythrodysesthesia</td><td align="center" class="Botrule Rrule">42</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Rash<a class="Sup" href="#footnote-8" name="footnote-reference-8">§</a></td><td align="center" class="Botrule Rrule">23</td><td align="center" class="Botrule Rrule">&lt;1</td><td align="center" class="Botrule Rrule">43</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dry skin</td><td align="center" class="Botrule Rrule">11</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Vascular</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypertension<a class="Sup" href="#footnote-9" name="footnote-reference-9">¶</a></td><td align="center" class="Botrule Rrule">39</td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">3</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Investigations</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Weight decreased</td><td align="center" class="Botrule Rrule">31</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Nervous System</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dysgeusia</td><td align="center" class="Botrule Rrule">24</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Headache</td><td align="center" class="Botrule Rrule">11</td><td align="center" class="Botrule Rrule">&lt;1</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dizziness</td><td align="center" class="Botrule Rrule">11</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Endocrine</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypothyroidism</td><td align="center" class="Botrule Rrule">21</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">&lt;1</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Respiratory, Thoracic, and Mediastinal</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dysphonia</td><td align="center" class="Botrule Rrule">20</td><td align="center" class="Botrule Rrule">&lt;1</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dyspnea</td><td align="center" class="Botrule Rrule">19</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">29</td><td align="center" class="Botrule Rrule">4</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Cough</td><td align="center" class="Botrule Rrule">18</td><td align="center" class="Botrule Rrule">&lt;1</td><td align="center" class="Botrule Rrule">33</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Blood and Lymphatic</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Anemia</td><td align="center" class="Botrule Rrule">17</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">38</td><td align="center" class="Botrule Rrule">16</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Musculoskeletal and Connective Tissue</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Pain in extremity</td><td align="center" class="Botrule Rrule">14</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Muscle spasms</td><td align="center" class="Botrule Rrule">13</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Arthralgia</td><td align="center" class="Botrule Rrule">11</td><td align="center" class="Botrule Rrule">&lt;1</td><td align="center" class="Botrule Rrule">14</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Renal and Urinary</th> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">        Proteinuria</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> </tbody> </table></div>

Other clinically important adverse reactions (all grades) that were reported in <10% of patients treated with CABOMETYX included: wound complications (2%), convulsion (<1%), pancreatitis (<1%), osteonecrosis of the jaw (<1%), and hepatitis cholestatic (<1%).

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 7. Laboratory Abnormalities Occurring in ≥ 25% Patients Who Received CABOMETYX in METEOR</span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule" rowspan="2">   Laboratory Abnormality</th><th align="center" class="Botrule Lrule Rrule" colspan="2">CABOMETYX<br/> (n=331)</th><th align="center" class="Botrule Lrule Rrule" colspan="2">Everolimus<br/> (n=322)</th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule">All<br/> Grades</th><th align="center" class="Botrule Lrule Rrule">Grade 3-4</th><th align="center" class="Botrule Lrule Rrule">All<br/> Grades</th><th align="center" class="Botrule Lrule Rrule">Grade 3-4</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" colspan="1"></th><th align="center" class="Botrule Lrule Rrule" colspan="4">Percentage (%) of Patients</th> </tr> </thead> <tfoot> <tr class="First"> <td align="left" colspan="5" valign="top"><span class="Sub">ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyl transferase.</span></td> </tr> <tr class="Last"> <td align="left" colspan="5" valign="top"><span class="Sub">NCI CTCAE, Version 4.0</span></td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-10" name="footnote-10">*</a> </dt> <dd>Based on laboratory abnormalities</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Chemistry</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased AST</td><td align="center" class="Botrule Rrule">74</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">40</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased ALT</td><td align="center" class="Botrule Rrule">68</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">32</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased creatinine</td><td align="center" class="Botrule Rrule">58</td><td align="center" class="Botrule Rrule">&lt;1</td><td align="center" class="Botrule Rrule">71</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased triglycerides</td><td align="center" class="Botrule Rrule">53</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">73</td><td align="center" class="Botrule Rrule">13</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypophosphatemia</td><td align="center" class="Botrule Rrule">48</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">36</td><td align="center" class="Botrule Rrule">5</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hyperglycemia</td><td align="center" class="Botrule Rrule">37</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">59</td><td align="center" class="Botrule Rrule">8</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypoalbuminemia</td><td align="center" class="Botrule Rrule">36</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">28</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased ALP</td><td align="center" class="Botrule Rrule">35</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">29</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypomagnesemia</td><td align="center" class="Botrule Rrule">31</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hyponatremia</td><td align="center" class="Botrule Rrule">30</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">26</td><td align="center" class="Botrule Rrule">6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased GGT</td><td align="center" class="Botrule Rrule">27</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">43</td><td align="center" class="Botrule Rrule">9</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Hematology</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Leukopenia</td><td align="center" class="Botrule Rrule">35</td><td align="center" class="Botrule Rrule">&lt;1</td><td align="center" class="Botrule Rrule">31</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Neutropenia</td><td align="center" class="Botrule Rrule">31</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">17</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Anemia<a class="Sup" href="#footnote-10" name="footnote-reference-10">*</a></td><td align="center" class="Botrule Rrule">31</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">71</td><td align="center" class="Botrule Rrule">17</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Lymphopenia</td><td align="center" class="Botrule Rrule">25</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule Rrule">39</td><td align="center" class="Botrule Rrule">12</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">        Thrombocytopenia</td><td align="center" class="Botrule Rrule">25</td><td align="center" class="Botrule Rrule">&lt;1</td><td align="center" class="Botrule Rrule">27</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> </tbody> </table></div>

CABOSUN

The safety of CABOMETYX was evaluated in CABOSUN, a randomized, open-label trial in patients with advanced renal cell carcinoma, in which 78 patients received CABOMETYX 60 mg once daily and 72 patients received sunitinib 50 mg once daily (4 weeks on treatment followed by 2 weeks off), until disease progression or unacceptable toxicity [see Clinical Studies (14.1)]. The median duration of treatment was 6.5 months (range 0.2 – 28.7) for patients receiving CABOMETYX and 3.1 months (range 0.2 – 25.5) for patients receiving sunitinib.

Within 30 days of treatment, there were 4 deaths in patients treated with CABOMETYX and 6 deaths in patients treated with sunitinib. Of the 4 patients treated with CABOMETYX, 2 patients died due to gastrointestinal perforation, 1 patient had acute renal failure, and 1 patient died due to clinical deterioration. All Grade 3-4 adverse reactions were collected in the entire safety population. The most frequent Grade 3-4 adverse reactions (≥5%) in patients treated with CABOMETYX were hypertension, diarrhea, hyponatremia, hypophosphatemia, PPE, fatigue, increased ALT, decreased appetite, stomatitis, pain, hypotension, and syncope.

The median average daily dose was 50.3 mg for CABOMETYX and 44.7 mg for sunitinib (excluding scheduled sunitinib non-dosing days). The dose was reduced in 46% of patients receiving CABOMETYX and in 35% of patients receiving sunitinib. The dose was held in 73% of patients receiving CABOMETYX and in 71% of patients receiving sunitinib. Based on patient disposition, 21% of patients receiving CABOMETYX and 22% of patients receiving sunitinib discontinued due to an adverse reaction.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 8. Grade 3-4 Adverse Reactions Occurring in ≥ 1% Patients Who Received CABOMETYX in CABOSUN</span> </caption> <col align="left" valign="middle" width="60%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule" rowspan="3" valign="middle">   Adverse Reaction</th><th align="center" class="Botrule Lrule Rrule">CABOMETYX<br/>(n = 78)</th><th align="center" class="Botrule Lrule Rrule">Sunitinib<br/>(n = 72)</th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule">Grade 3-4<a class="Sup" href="#footnote-11" name="footnote-reference-11">*</a></th><th align="center" class="Botrule Lrule Rrule">Grade 3-4<a class="Sup" href="#footnote-11">*</a></th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule" colspan="2">Percentage (%) of Patients</th> </tr> <tr> <th align="left" class="Botrule Lrule Rrule">   Patients with any Grade 3-4 Adverse Reaction</th><th align="center" class="Botrule Lrule Rrule">68</th><th align="center" class="Botrule Lrule Rrule">65</th> </tr> <tr class="Last"> <th align="center" class="Botrule Lrule Rrule" colspan="3"></th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="3" valign="top"><span class="Sub">ALT, alanine aminotransferase; AST, aspartate aminotransferase</span></td> </tr> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-11" name="footnote-11">*</a> </dt> <dd>NCI CTCAE Version 4.0</dd> <dt> <a href="#footnote-reference-12" name="footnote-12">†</a> </dt> <dd>Laboratory abnormalities are reported as adverse reactions and not based on shifts in laboratory values</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">‡</a> </dt> <dd>Includes the following term: hypertension</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <th align="left" class="Botrule Lrule Rrule" colspan="3">   Gastrointestinal</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Diarrhea</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">11</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Stomatitis</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Nausea</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">4</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Vomiting</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Constipation</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">   General</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Fatigue</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">17</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Pain</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">   Metabolism and Nutrition</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hyponatremia<a class="Sup" href="#footnote-12" name="footnote-reference-12">†</a></td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">8</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypophosphatemia<a class="Sup" href="#footnote-12">†</a></td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">7</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Decreased appetite</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dehydration</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypocalcemia<a class="Sup" href="#footnote-12">†</a></td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypomagnesemia<a class="Sup" href="#footnote-12">†</a></td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypokalemia<a class="Sup" href="#footnote-12">†</a></td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">3</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">   Skin and Subcutaneous Tissue</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Palmar-plantar erythrodysesthesia</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">4</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Skin Ulcer</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">   Vascular</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypertension<a class="Sup" href="#footnote-13" name="footnote-reference-13">‡</a></td><td align="center" class="Botrule Rrule">28</td><td align="center" class="Botrule Rrule">21</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypotension</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Angiopathy</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">   Investigations</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased ALT<a class="Sup" href="#footnote-12">†</a></td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Weight decreased</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased AST<a class="Sup" href="#footnote-12">†</a></td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased blood creatinine<a class="Sup" href="#footnote-12">†</a></td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Lymphopenia<a class="Sup" href="#footnote-12">†</a></td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Thrombocytopenia<a class="Sup" href="#footnote-12">†</a></td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">11</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">   Nervous System</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Syncope</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">   Respiratory, Thoracic, and Mediastinal</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dyspnea</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dysphonia</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">   Blood and Lymphatic</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Anemia</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">3</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">   Psychiatric</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Depression</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Confusional state</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">   Infections</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Lung Infection</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">   Musculoskelatal and Connective Tissue</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Back pain</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Bone pain</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Pain in extremity</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Arthralgia</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="3">   Renal and Urinary</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Renal failure acute</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">        Proteinuria</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">1</td> </tr> </tbody> </table></div>

CHECKMATE-9ER

The safety of CABOMETYX with nivolumab was evaluated in CHECKMATE-9ER, a randomized, open-label study in patients with previously untreated advanced RCC [see Clinical Studies (14.1)]. Patients received CABOMETYX 40 mg orally once daily with nivolumab 240 mg over 30 minutes every 2 weeks (n=320) or sunitinib 50 mg daily, administered orally for 4 weeks on treatment followed by 2 weeks off (n=320) [see Clinical Studies (14.1)]. CABOMETYX could be interrupted or reduced to 20 mg daily or 20 mg every other day. The median duration of treatment was 14 months (range: 0.2 to 27 months) in CABOMETYX and nivolumab-treated patients. In this trial, 82% of patients in the CABOMETYX and nivolumab arm were exposed to treatment for >6 months and 60% of patients were exposed to treatment for >1 year.

Serious adverse reactions occurred in 48% of patients receiving CABOMETYX and nivolumab. The most frequent (≥2%) serious adverse reactions were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients.

Adverse reactions leading to discontinuation of either CABOMETYX or nivolumab occurred in 20% of patients: 8% CABOMETYX only, 7% nivolumab only, and 6% both drugs due to the same adverse reaction at the same time. Adverse reactions leading to dose interruption or reduction of either CABOMETYX or nivolumab occurred in 83% of patients: 46% CABOMETYX only, 3% nivolumab only, and 21% both drugs due to the same adverse reaction at the same time, and 6% both drugs sequentially.

The most common adverse reactions reported in ≥20% of patients treated with CABOMETYX and nivolumab were diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 9. Adverse Reactions in &gt;15% of Patients Receiving CABOMETYX and Nivolumab - CHECKMATE-9ER</span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule" rowspan="2">   Adverse Reaction</th><th align="center" class="Botrule Lrule Rrule" colspan="2">CABOMETYX and Nivolumab<br/>(n=320)</th><th align="center" class="Botrule Lrule Rrule" colspan="2">Sunitinib<br/>(n=320)</th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule">Grades 1-4</th><th align="center" class="Botrule Lrule Rrule">Grades 3-4</th><th align="center" class="Botrule Lrule Rrule">Grades 1-4</th><th align="center" class="Botrule Lrule Rrule">Grades 3-4</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" colspan="1"></th><th align="center" class="Botrule Lrule Rrule" colspan="4">Percentage (%) of Patients</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5" valign="top"><span class="Sub">Toxicity was graded per NCI CTCAE v4.</span></td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-14" name="footnote-14">*</a> </dt> <dd>Includes abdominal discomfort, abdominal pain lower, abdominal pain upper.</dd> <dt> <a href="#footnote-reference-15" name="footnote-15">†</a> </dt> <dd>Includes gastroesophageal reflux disease.</dd> <dt> <a href="#footnote-reference-16" name="footnote-16">‡</a> </dt> <dd>Includes asthenia.</dd> <dt> <a href="#footnote-reference-17" name="footnote-17">§</a> </dt> <dd>Includes hepatotoxicity, ALT increased, AST increased, blood alkaline phosphatase increased, gamma-glutamyl transferase increased, autoimmune hepatitis, blood bilirubin increased, drug induced liver injury, hepatic enzyme increased, hepatitis, hyperbilirubinemia, liver function test increased, liver function test abnormal, transaminases increased, hepatic failure.</dd> <dt> <a href="#footnote-reference-18" name="footnote-18">¶</a> </dt> <dd>Includes mucosal inflammation, aphthous ulcer, mouth ulceration.</dd> <dt> <a href="#footnote-reference-19" name="footnote-19">#</a> </dt> <dd>Includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic.</dd> <dt> <a href="#footnote-reference-20" name="footnote-20">Þ</a> </dt> <dd>Includes blood pressure increased, blood pressure systolic increased.</dd> <dt> <a href="#footnote-reference-21" name="footnote-21">ß</a> </dt> <dd>Includes primary hypothyroidism.</dd> <dt> <a href="#footnote-reference-22" name="footnote-22">à</a> </dt> <dd>Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain.</dd> <dt> <a href="#footnote-reference-23" name="footnote-23">è</a> </dt> <dd>Includes productive cough.</dd> <dt> <a href="#footnote-reference-24" name="footnote-24">ð</a> </dt> <dd>Includes nasopharyngitis, pharyngitis, rhinitis.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Gastrointestinal</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Diarrhea</td><td align="center" class="Botrule Rrule">64</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule Rrule">47</td><td align="center" class="Botrule Rrule">4.4</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Nausea</td><td align="center" class="Botrule Rrule">27</td><td align="center" class="Botrule Rrule">0.6</td><td align="center" class="Botrule Rrule">31</td><td align="center" class="Botrule Rrule">0.3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Abdominal pain<a class="Sup" href="#footnote-14" name="footnote-reference-14">*</a></td><td align="center" class="Botrule Rrule">22</td><td align="center" class="Botrule Rrule">1.9</td><td align="center" class="Botrule Rrule">15</td><td align="center" class="Botrule Rrule">0.3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Vomiting</td><td align="center" class="Botrule Rrule">17</td><td align="center" class="Botrule Rrule">1.9</td><td align="center" class="Botrule Rrule">21</td><td align="center" class="Botrule Rrule">0.3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dyspepsia<a class="Sup" href="#footnote-15" name="footnote-reference-15">†</a></td><td align="center" class="Botrule Rrule">15</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">22</td><td align="center" class="Botrule Rrule">0.3</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   General</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Fatigue<a class="Sup" href="#footnote-16" name="footnote-reference-16">‡</a></td><td align="center" class="Botrule Rrule">51</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">50</td><td align="center" class="Botrule Rrule">8</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Hepatobiliary</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hepatotoxicity<a class="Sup" href="#footnote-17" name="footnote-reference-17">§</a></td><td align="center" class="Botrule Rrule">44</td><td align="center" class="Botrule Rrule">11</td><td align="center" class="Botrule Rrule">26</td><td align="center" class="Botrule Rrule">5</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Skin and Subcutaneous Tissue</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Palmar-plantar erythrodysesthesia</td><td align="center" class="Botrule Rrule">40</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">41</td><td align="center" class="Botrule Rrule">8</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Stomatitis<a class="Sup" href="#footnote-18" name="footnote-reference-18">¶</a></td><td align="center" class="Botrule Rrule">37</td><td align="center" class="Botrule Rrule">3.4</td><td align="center" class="Botrule Rrule">46</td><td align="center" class="Botrule Rrule">4.4</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Rash<a class="Sup" href="#footnote-19" name="footnote-reference-19">#</a></td><td align="center" class="Botrule Rrule">36</td><td align="center" class="Botrule Rrule">3.1</td><td align="center" class="Botrule Rrule">14</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Pruritus</td><td align="center" class="Botrule Rrule">19</td><td align="center" class="Botrule Rrule">0.3</td><td align="center" class="Botrule Rrule">4.4</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Vascular</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypertension<a class="Sup" href="#footnote-20" name="footnote-reference-20">Þ</a></td><td align="center" class="Botrule Rrule">36</td><td align="center" class="Botrule Rrule">13</td><td align="center" class="Botrule Rrule">39</td><td align="center" class="Botrule Rrule">14</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Endocrine</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypothyroidism<a class="Sup" href="#footnote-21" name="footnote-reference-21">ß</a></td><td align="center" class="Botrule Rrule">34</td><td align="center" class="Botrule Rrule">0.3</td><td align="center" class="Botrule Rrule">30</td><td align="center" class="Botrule Rrule">0.3</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Musculoskeletal and Connective Tissue</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Musculoskeletal pain<a class="Sup" href="#footnote-22" name="footnote-reference-22">à</a></td><td align="center" class="Botrule Rrule">33</td><td align="center" class="Botrule Rrule">3.8</td><td align="center" class="Botrule Rrule">29</td><td align="center" class="Botrule Rrule">3.1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Arthralgia</td><td align="center" class="Botrule Rrule">18</td><td align="center" class="Botrule Rrule">0.3</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">0.3</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Metabolism and Nutrition</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Decreased appetite</td><td align="center" class="Botrule Rrule">28</td><td align="center" class="Botrule Rrule">1.9</td><td align="center" class="Botrule Rrule">20</td><td align="center" class="Botrule Rrule">1.3</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Nervous System Disorders</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dysgeusia</td><td align="center" class="Botrule Rrule">24</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">22</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Headache</td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">0.6</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Respiratory, Thoracic and Mediastinal</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Cough<a class="Sup" href="#footnote-23" name="footnote-reference-23">è</a></td><td align="center" class="Botrule Rrule">20</td><td align="center" class="Botrule Rrule">0.3</td><td align="center" class="Botrule Rrule">17</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dysphonia</td><td align="center" class="Botrule Rrule">17</td><td align="center" class="Botrule Rrule">0.3</td><td align="center" class="Botrule Rrule">3.4</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Infections and Infestations</th> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">        Upper respiratory tract infection<a class="Sup" href="#footnote-24" name="footnote-reference-24">ð</a></td><td align="center" class="Botrule Rrule">20</td><td align="center" class="Botrule Rrule">0.3</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">0.3</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 10. Laboratory Values Worsening from Baseline<a class="Sup" href="#footnote-25" name="footnote-reference-25">*</a> Occurring in &gt;20% of Patients Receiving CABOMETYX and Nivolumab - CHECKMATE-9ER</span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule" rowspan="2">   Laboratory Abnormality</th><th align="center" class="Botrule Lrule Rrule" colspan="2">CABOMETYX and<br/>Nivolumab</th><th align="center" class="Botrule Lrule Rrule" colspan="2">Sunitinib</th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule">Grades 1-4</th><th align="center" class="Botrule Lrule Rrule">Grades 3-4</th><th align="center" class="Botrule Lrule Rrule">Grades 1-4</th><th align="center" class="Botrule Lrule Rrule">Grades 3-4</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" colspan="1"></th><th align="center" class="Botrule Lrule Rrule" colspan="4">Percentage (%) of Patients</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-25" name="footnote-25">*</a> </dt> <dd>Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: CABOMETYX and nivolumab group (range: 170 to 317 patients) and sunitinib group (range: 173 to 311 patients).</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Chemistry</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased ALT</td><td align="center" class="Botrule Rrule">79</td><td align="center" class="Botrule Rrule">9.8</td><td align="center" class="Botrule Rrule">39</td><td align="center" class="Botrule Rrule">3.5</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased AST</td><td align="center" class="Botrule Rrule">77</td><td align="center" class="Botrule Rrule">7.9</td><td align="center" class="Botrule Rrule">57</td><td align="center" class="Botrule Rrule">2.6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypophosphatemia</td><td align="center" class="Botrule Rrule">69</td><td align="center" class="Botrule Rrule">28</td><td align="center" class="Botrule Rrule">48</td><td align="center" class="Botrule Rrule">10</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypocalcemia</td><td align="center" class="Botrule Rrule">54</td><td align="center" class="Botrule Rrule">1.9</td><td align="center" class="Botrule Rrule">24</td><td align="center" class="Botrule Rrule">0.6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypomagnesemia</td><td align="center" class="Botrule Rrule">47</td><td align="center" class="Botrule Rrule">1.3</td><td align="center" class="Botrule Rrule">25</td><td align="center" class="Botrule Rrule">0.3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hyperglycemia</td><td align="center" class="Botrule Rrule">44</td><td align="center" class="Botrule Rrule">3.5</td><td align="center" class="Botrule Rrule">44</td><td align="center" class="Botrule Rrule">1.7</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hyponatremia</td><td align="center" class="Botrule Rrule">43</td><td align="center" class="Botrule Rrule">11</td><td align="center" class="Botrule Rrule">36</td><td align="center" class="Botrule Rrule">12</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased lipase</td><td align="center" class="Botrule Rrule">41</td><td align="center" class="Botrule Rrule">14</td><td align="center" class="Botrule Rrule">38</td><td align="center" class="Botrule Rrule">13</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased amylase</td><td align="center" class="Botrule Rrule">41</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">28</td><td align="center" class="Botrule Rrule">6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased alkaline phosphatase</td><td align="center" class="Botrule Rrule">41</td><td align="center" class="Botrule Rrule">2.8</td><td align="center" class="Botrule Rrule">37</td><td align="center" class="Botrule Rrule">1.6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased creatinine</td><td align="center" class="Botrule Rrule">39</td><td align="center" class="Botrule Rrule">1.3</td><td align="center" class="Botrule Rrule">42</td><td align="center" class="Botrule Rrule">0.6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hyperkalemia</td><td align="center" class="Botrule Rrule">35</td><td align="center" class="Botrule Rrule">4.7</td><td align="center" class="Botrule Rrule">27</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypoglycemia</td><td align="center" class="Botrule Rrule">26</td><td align="center" class="Botrule Rrule">0.8</td><td align="center" class="Botrule Rrule">14</td><td align="center" class="Botrule Rrule">0.4</td> </tr> <tr> <th align="left" class="Botrule Lrule Rrule" colspan="5">   Hematology</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Lymphopenia</td><td align="center" class="Botrule Rrule">42</td><td align="center" class="Botrule Rrule">6.6</td><td align="center" class="Botrule Rrule">45</td><td align="center" class="Botrule Rrule">10</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Thrombocytopenia</td><td align="center" class="Botrule Rrule">41</td><td align="center" class="Botrule Rrule">0.3</td><td align="center" class="Botrule Rrule">70</td><td align="center" class="Botrule Rrule">9.7</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">       Anemia</td><td align="center" class="Botrule Rrule">37</td><td align="center" class="Botrule Rrule">2.5</td><td align="center" class="Botrule Rrule">61</td><td align="center" class="Botrule Rrule">4.8</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Leukopenia</td><td align="center" class="Botrule Rrule">37</td><td align="center" class="Botrule Rrule">0.3</td><td align="center" class="Botrule Rrule">66</td><td align="center" class="Botrule Rrule">5.1</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">        Neutropenia</td><td align="center" class="Botrule Rrule">35</td><td align="center" class="Botrule Rrule">3.2</td><td align="center" class="Botrule Rrule">67</td><td align="center" class="Botrule Rrule">12</td> </tr> </tbody> </table></div>

Hepatocellular Carcinoma

The safety of CABOMETYX was evaluated in CELESTIAL, a randomized, double-blind, placebo-controlled trial in which 704 patients with advanced hepatocellular carcinoma were randomized to receive CABOMETYX 60 mg orally once daily (n=467) or placebo (n=237) until disease progression or unacceptable toxicity [see Clinical Studies (14.2)]. The median duration of treatment was 3.8 months (range 0.1 – 37.3) for patients receiving CABOMETYX and 2.0 months (range 0.0 – 27.2) for patients receiving placebo. The population exposed to CABOMETYX was 81% male, 56% White, and had a median age of 64 years.

Adverse reactions occurring in ≥25% of CABOMETYX-treated patients, in order of decreasing frequency were: diarrhea, decreased appetite, PPE, fatigue, nausea, hypertension, and vomiting. Grade 3-4 adverse reactions which occurred in ≥5% of patients were PPE, hypertension, fatigue, diarrhea, asthenia, and decreased appetite. There were 6 adverse reactions leading to death in patients receiving CABOMETYX (hepatic failure, hepatorenal syndrome, esophagobronchial fistula, portal vein thrombosis, pulmonary embolism, upper gastrointestinal hemorrhage).

The median average daily dose was 35.8 mg for CABOMETYX. The dose was reduced in 62% of patients receiving CABOMETYX; 33% of patients required a reduction to 20 mg daily. The most frequent adverse reactions or laboratory abnormalities leading to dose reduction of CABOMETYX were: PPE, diarrhea, fatigue, hypertension, and increased AST. Adverse reactions leading to dose interruption occurred in 84% patients receiving CABOMETYX. Adverse reactions leading to permanent discontinuation of CABOMETYX occurred in 16% of patients. The most frequent adverse reactions leading to permanent discontinuation of CABOMETYX were PPE (2%), fatigue (2%), decreased appetite (1%), diarrhea (1%), and nausea (1%).

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 11. Adverse Reactions Occurring in ≥ 5% of CABOMETYX-Treated Patients in CELESTIAL<a class="Sup" href="#footnote-26" name="footnote-reference-26">*</a></span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule" rowspan="2" valign="bottom">   Adverse Reaction</th><th align="center" class="Botrule Lrule Rrule" colspan="2">CABOMETYX<br/> (n=467)</th><th align="center" class="Botrule Lrule Rrule" colspan="2">Placebo<br/> (n=237)</th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule">All Grades<a class="Sup" href="#footnote-27" name="footnote-reference-27">†</a></th><th align="center" class="Botrule Lrule Rrule">Grade 3-4</th><th align="center" class="Botrule Lrule Rrule">All Grades<a class="Sup" href="#footnote-27">†</a></th><th align="center" class="Botrule Lrule Rrule">Grade 3-4</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" colspan="1"></th><th align="center" class="Botrule Lrule Rrule" colspan="4">Percentage (%) of Patients</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-26" name="footnote-26">*</a> </dt> <dd>Includes terms with a between-arm difference of ≥ 5% (all grades) or ≥ 2% (Grade 3-4)</dd> <dt> <a href="#footnote-reference-27" name="footnote-27">†</a> </dt> <dd>NCI CTCAE Version 4.0</dd> <dt> <a href="#footnote-reference-28" name="footnote-28">‡</a> </dt> <dd>Includes the following terms: rash, rash erythematous, rash generalized, rash macular, rash maculo- papular, rash papular, rash pruritic, rash pustular, rash vesicular, dermatitis, dermatitis acneiform, dermatitis contact, dermatitis diaper, dermatitis exfoliative, dermatitis infected</dd> <dt> <a href="#footnote-reference-29" name="footnote-29">§</a> </dt> <dd>Includes the following terms: hypertension, blood pressure diastolic increased, blood pressure increased</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Gastrointestinal</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Diarrhea</td><td align="center" class="Botrule Rrule">54</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">19</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Nausea</td><td align="center" class="Botrule Rrule">31</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">18</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Vomiting</td><td align="center" class="Botrule Rrule">26</td><td align="center" class="Botrule Rrule">&lt;1</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Stomatitis</td><td align="center" class="Botrule Rrule">13</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dyspepsia</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">General</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Fatigue</td><td align="center" class="Botrule Rrule">45</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">30</td><td align="center" class="Botrule Rrule">4</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Asthenia</td><td align="center" class="Botrule Rrule">22</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Mucosal inflammation</td><td align="center" class="Botrule Rrule">14</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Metabolism and Nutrition</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Decreased appetite</td><td align="center" class="Botrule Rrule">48</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">18</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Skin and Subcutaneous Tissue</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Palmar-plantar erythrodysesthesia</td><td align="center" class="Botrule Rrule">46</td><td align="center" class="Botrule Rrule">17</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Rash<a class="Sup" href="#footnote-28" name="footnote-reference-28">‡</a></td><td align="center" class="Botrule Rrule">21</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Vascular</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypertension<a class="Sup" href="#footnote-29" name="footnote-reference-29">§</a></td><td align="center" class="Botrule Rrule">30</td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Investigations</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">       Weight decreased</td><td align="center" class="Botrule Rrule">17</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Nervous System</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dysgeusia</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Endocrine</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypothyroidism</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">&lt;1</td><td align="center" class="Botrule Rrule">&lt;1</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Respiratory, Thoracic, and Mediastinal</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dysphonia</td><td align="center" class="Botrule Rrule">19</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Dyspnea</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">&lt;1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Musculoskeletal and Connective Tissue</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Pain in extremity</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">&lt;1</td><td align="center" class="Botrule Rrule">4</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">        Muscle spasms</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">&lt;1</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">0</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 12. Laboratory Abnormalities Occurring in ≥5% of CABOMETYX-Treated Patients in CELESTIAL<a class="Sup" href="#footnote-30" name="footnote-reference-30">*</a></span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule" rowspan="2">   Laboratory Abnormality</th><th align="center" class="Botrule Lrule Rrule" colspan="2">CABOMETYX<br/> (n=467)</th><th align="center" class="Botrule Lrule Rrule" colspan="2">Placebo<br/> (n=237)</th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule">All Grades</th><th align="center" class="Botrule Lrule Rrule">Grade 3-4</th><th align="center" class="Botrule Lrule Rrule">All Grades</th><th align="center" class="Botrule Lrule Rrule">Grade 3-4</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" colspan="1"></th><th align="center" class="Botrule Lrule Rrule" colspan="4">Percentage (%) of Patients</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5" valign="top"><span class="Sub">ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDH, blood lactate dehydrogenase</span></td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-30" name="footnote-30">*</a> </dt> <dd>Includes laboratory abnormalities with a between-arm difference of ≥5% (all grades) or ≥2% (Grade 3-4)</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Chemistry</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased LDH</td><td align="center" class="Botrule Rrule">84</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">29</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased ALT</td><td align="center" class="Botrule Rrule">73</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">37</td><td align="center" class="Botrule Rrule">6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased AST</td><td align="center" class="Botrule Rrule">73</td><td align="center" class="Botrule Rrule">24</td><td align="center" class="Botrule Rrule">46</td><td align="center" class="Botrule Rrule">19</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypoalbuminemia</td><td align="center" class="Botrule Rrule">51</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">32</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased ALP</td><td align="center" class="Botrule Rrule">43</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">38</td><td align="center" class="Botrule Rrule">6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypophosphatemia</td><td align="center" class="Botrule Rrule">25</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">4</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypokalemia</td><td align="center" class="Botrule Rrule">23</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypomagnesemia</td><td align="center" class="Botrule Rrule">22</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Increased amylase</td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Hypocalcemia</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Hematology</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Decreased platelets</td><td align="center" class="Botrule Rrule">54</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">        Neutropenia</td><td align="center" class="Botrule Rrule">43</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">1</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">        Increased hemoglobin</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">0</td> </tr> </tbody> </table></div>

Differentiated Thyroid Cancer

The safety of CABOMETYX was evaluated in COSMIC-311, a randomized, double-blind, placebo-controlled trial in which 187 patients with advanced differentiated thyroid cancer were randomized to receive CABOMETYX 60 mg orally once daily (n=125) or placebo (n=62) with supportive care until disease progression or unacceptable toxicity [see Clinical Studies (14.3)]. At the time of the primary efficacy analysis, the median duration of treatment was 4.4 months (range 0.0 – 15.7) for patients receiving CABOMETYX and 2.3 months (range 0.3 – 11.6) for patients receiving placebo. The median age was 66 years (range 32 to 85 years), 55% were female, 70% were White, 18% were Asian, 2% were Black, 2% were American Indian or Alaska Native, and 63% received prior lenvatinib.

Adverse reactions occurring in ≥25% of CABOMETYX-treated patients, in order of decreasing frequency were: diarrhea, PPE, fatigue, hypertension, and stomatitis. Grade 3-4 adverse reactions which occurred in ≥5% of patients were PPE, hypertension, fatigue, diarrhea, and stomatitis. Serious adverse reactions occurred in 34% of patients who received CABOMETYX. Serious adverse reactions in ≥2% included diarrhea, pleural effusion, pulmonary embolism and dyspnea. Fatal adverse reactions occurred in 1.6% of patients in the CABOMETYX arm, including arterial hemorrhage (0.8%) and pulmonary embolism (0.8%).

The median average daily dose was 42.0 mg for CABOMETYX. The dose was reduced in 56% of patients receiving CABOMETYX; 22% of patients required a second dose reduction. The most frequent adverse reactions (≥5%) leading to dose reduction of CABOMETYX were PPE, diarrhea, fatigue, proteinuria, and decreased appetite. Dose interruptions occurred in 72% patients receiving CABOMETYX. Adverse reactions requiring dosage interruption in ≥5% of patients were PPE, diarrhea, dyspnea, hypertension, decreased appetite and proteinuria. Adverse reactions leading to permanent discontinuation of CABOMETYX occurred in 5% of patients.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 13. Adverse Reactions Occurring in ≥5% of CABOMETYX-Treated Patients in COSMIC-311<a class="Sup" href="#footnote-31" name="footnote-reference-31">*</a></span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule" rowspan="2">Adverse Reaction</th><th align="center" class="Botrule Lrule Rrule" colspan="2">CABOMETYX<br/> (N=125)</th><th align="center" class="Botrule Lrule Rrule" colspan="2">Placebo<br/> (N=62)</th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule">All Grades<a class="Sup" href="#footnote-32" name="footnote-reference-32">†</a></th><th align="center" class="Botrule Lrule Rrule">Grade 3-4</th><th align="center" class="Botrule Lrule Rrule">All Grades<a class="Sup" href="#footnote-32">†</a></th><th align="center" class="Botrule Lrule Rrule">Grade 3-4</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" colspan="1"></th><th align="center" class="Botrule Lrule Rrule" colspan="4">Percentage of Patients</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-31" name="footnote-31">*</a> </dt> <dd>Includes terms that are more frequent in the CABOMETYX arm and have a between-arm difference of 2 ≥5% (all grades) or ≥2% (Grade 3-4)</dd> <dt> <a href="#footnote-reference-32" name="footnote-32">†</a> </dt> <dd>NCI CTCAE Version 5.0</dd> <dt> <a href="#footnote-reference-33" name="footnote-33">‡</a> </dt> <dd>Includes the following terms: mucosal inflammation, stomatitis</dd> <dt> <a href="#footnote-reference-34" name="footnote-34">§</a> </dt> <dd>Includes the following terms: fatigue, asthenia</dd> <dt> <a href="#footnote-reference-35" name="footnote-35">¶</a> </dt> <dd>Includes the following terms: hypertension, blood pressure increased, hypertensive crisis</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Gastrointestinal</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Diarrhea</td><td align="center" class="Botrule Rrule">51</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Nausea</td><td align="center" class="Botrule Rrule">24</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Vomiting</td><td align="center" class="Botrule Rrule">14</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Stomatitis<a class="Sup" href="#footnote-33" name="footnote-reference-33">‡</a></td><td align="center" class="Botrule Rrule">26</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Dry mouth</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">General</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Fatigue<a class="Sup" href="#footnote-34" name="footnote-reference-34">§</a></td><td align="center" class="Botrule Rrule">42</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">23</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Metabolism and Nutrition</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Decreased appetite</td><td align="center" class="Botrule Rrule">23</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Skin and Subcutaneous Tissue</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Palmar-plantar erythrodysesthesia</td><td align="center" class="Botrule Rrule">46</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Vascular</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hypertension<a class="Sup" href="#footnote-35" name="footnote-reference-35">¶</a></td><td align="center" class="Botrule Rrule">30</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Investigations</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Weight decreased</td><td align="center" class="Botrule Rrule">18</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Nervous System</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Dysgeusia</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Headache</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Respiratory, Thoracic, and Mediastinal</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Dysphonia</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Pulmonary embolism</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Renal and Urinary</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">   Proteinuria</td><td align="center" class="Botrule Rrule">15</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">0</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 14. Laboratory Abnormalities Occurring in ≥10% of CABOMETYX-Treated Patients in COSMIC-311<a class="Sup" href="#footnote-36" name="footnote-reference-36">*</a></span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule" rowspan="2">Laboratory Abnormality</th><th align="center" class="Botrule Lrule Rrule" colspan="2">CABOMETYX<br/> (N=125)</th><th align="center" class="Botrule Lrule Rrule" colspan="2">Placebo<br/> (N=62)</th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule">All Grades</th><th align="center" class="Botrule Lrule Rrule">Grade 3 or 4</th><th align="center" class="Botrule Lrule Rrule">All Grades</th><th align="center" class="Botrule Lrule Rrule">Grade 3 or 4</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" colspan="1"></th><th align="center" class="Botrule Lrule Rrule" colspan="4">Percentage of Patients</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5" valign="top"><span class="Sub">ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyl transferase; LDH, blood lactate dehydrogenase</span></td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-36" name="footnote-36">*</a> </dt> <dd>Includes laboratory abnormalities that are more frequent in the CABOMETYX arm and have a between-arm difference of ≥5% (all grades) or ≥2% (Grade 3-4)</dd> <dt> <a href="#footnote-reference-37" name="footnote-37">†</a> </dt> <dd>Sponsor-defined grades for LDH were as follows: Grade 1 (&gt; ULN to ≤2 × ULN), Grade 2 (&gt;2 × ULN to ≤3 × ULN), Grade 3 (&gt;3 × ULN).</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Chemistry</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   LDH increased<a class="Sup" href="#footnote-37" name="footnote-reference-37">†</a></td><td align="center" class="Botrule Rrule">90</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">32</td><td align="center" class="Botrule Rrule">3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   AST increased</td><td align="center" class="Botrule Rrule">77</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">18</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   ALT increased</td><td align="center" class="Botrule Rrule">66</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">11</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hypocalcemia</td><td align="center" class="Botrule Rrule">36</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   ALP increased</td><td align="center" class="Botrule Rrule">34</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">15</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   GGT increased</td><td align="center" class="Botrule Rrule">26</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">21</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hypomagnesemia</td><td align="center" class="Botrule Rrule">25</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hypoalbuminemia</td><td align="center" class="Botrule Rrule">19</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hypokalemia</td><td align="center" class="Botrule Rrule">18</td><td align="center" class="Botrule Rrule">1</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hyponatremia</td><td align="center" class="Botrule Rrule">15</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hyperbilirubinemia</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Hematology</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Leukocytes decreased</td><td align="center" class="Botrule Rrule">38</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Neutrophils decreased</td><td align="center" class="Botrule Rrule">31</td><td align="center" class="Botrule Rrule">2</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">   Platelets decreased</td><td align="center" class="Botrule Rrule">26</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">5</td><td align="center" class="Botrule Rrule">0</td> </tr> </tbody> </table></div>

Neuroendocrine Tumors

Pancreatic Neuroendocrine Tumors (pNET)

The safety of CABOMETYX was evaluated in adult patients with unresectable, locally advanced or metastatic, well-differentiated neuroendocrine tumors in the CABINET trial [see Clinical Studies (14.4)]. Patients received CABOMETYX 60 mg (n=63) or placebo orally (n=31) once daily until disease progression or unacceptable toxicity. Patients with pNET were required to have disease progression after prior treatment with at least one FDA approved therapy (everolimus, sunitinib or lutetium Lu 177 dotatate), other than somatostatin analogs. The median duration of treatment was 8.3 months (range: 0.1 to 37.8) for patients receiving CABOMETYX and 2.9 months (range: 0.1 to 11.2) for patients receiving placebo.

The median age of patients who received CABOMETYX was 60 years (range: 29 to 79), 57% were male, 86% were White, 6% were Asian, 3.2% were Black, 1.6% were American Indian or Alaska Native, 1.6% were Native Hawaiian or Other Pacific Islanders, and 3.2% were Hispanic or Latino.

Serious adverse reactions occurred in 46% of patients who received CABOMETYX. Serious adverse reactions in ≥2% of patients included thromboembolic events (10%), vomiting (6%), sepsis (4.8%), nausea (4.8%), hypoxia (4.8%), hemorrhage (3.2%), abdominal pain (3.2%), musculoskeletal pain (3.2%), blood bilirubin increased (3.2%), fatigue (3.2%), hyperkalemia (3.2%), and hypertension (3.2%).

Permanent discontinuation of CABOMETYX due to an adverse reaction occurred in 19% of patients. Adverse reactions which resulted in permanent discontinuation of CABOMETYX included thromboembolic events, acute kidney injury, rash, dyspnea, fistulas, hemorrhage, cardiac arrest, musculoskeletal pain, COVID-19 infection, Cushing’s syndrome, pneumonia, proteinuria, and myocardial infarction.

The median average daily dose was 41.4 mg for CABOMETYX. Dosage interruptions of CABOMETYX due to an adverse reaction occurred in 83% of patients. Adverse reactions which required dosage interruption in ≥5% of patients included rash, diarrhea, fatigue, thromboembolic events, nausea, hypertension, increased ALT, blood bilirubin increased, musculoskeletal pain, stomatitis, vomiting, and increased AST.

Dose reductions of CABOMETYX due to an adverse reaction occurred in 49% of patients. Adverse reactions which required dose reductions in ≥5% of patients included rash, fatigue, hypertension, and stomatitis.

The most common adverse reactions occurring in ≥20% of CABOMETYX-treated patients were fatigue, increased AST, increased ALT, hypertension, diarrhea, rash, stomatitis, musculoskeletal pain, hyperglycemia, nausea, platelet count decreased, dysgeusia, neutrophil count decreased, abdominal pain, decreased appetite, hemoglobin decreased, dizziness, hypophosphatemia, hypothyroidism, vomiting, increased ALP, and lymphocyte count decreased.

Table 15 summarizes the adverse reactions in patients with pNET in CABINET.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 15. Adverse Reactions (≥15%) in Patients with pNET Who Received CABOMETYX in CABINET</span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule" rowspan="2">Adverse Reaction</th><th align="center" class="Botrule Lrule Rrule" colspan="2">CABOMETYX<br/> (N=63)</th><th align="center" class="Botrule Lrule Rrule" colspan="2">Placebo<br/> (N=31)</th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule">All Grades<a class="Sup" href="#footnote-38" name="footnote-reference-38">*</a></th><th align="center" class="Botrule Lrule Rrule">Grade 3 or 4</th><th align="center" class="Botrule Lrule Rrule">All Grades<a class="Sup" href="#footnote-38">*</a></th><th align="center" class="Botrule Lrule Rrule">Grade 3 or 4</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" colspan="1"></th><th align="center" class="Botrule Lrule Rrule" colspan="4">Percentage (%) of Patients</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-38" name="footnote-38">*</a> </dt> <dd>NCI CTCAE Version 5.0</dd> <dt> <a href="#footnote-reference-39" name="footnote-39">†</a> </dt> <dd>Includes fatigue, asthenia</dd> <dt> <a href="#footnote-reference-40" name="footnote-40">‡</a> </dt> <dd>Includes hypertension, blood pressure increased, blood pressure systolic increased, systolic hypertension</dd> <dt> <a href="#footnote-reference-41" name="footnote-41">§</a> </dt> <dd>Includes thromboembolic event, pulmonary embolism, embolism, deep vein thrombosis, vena cava thrombosis, embolism venous, embolism arterial</dd> <dt> <a href="#footnote-reference-42" name="footnote-42">¶</a> </dt> <dd>Includes diarrhea, colitis</dd> <dt> <a href="#footnote-reference-43" name="footnote-43">#</a> </dt> <dd>Includes stomatitis, aphthous ulcer, mucosal inflammation, cheilitis, glossitis</dd> <dt> <a href="#footnote-reference-44" name="footnote-44">Þ</a> </dt> <dd>Includes abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain, abdominal discomfort, hepatic pain</dd> <dt> <a href="#footnote-reference-45" name="footnote-45">ß</a> </dt> <dd>Includes dyspepsia, gastroesophageal reflux disease</dd> <dt> <a href="#footnote-reference-46" name="footnote-46">à</a> </dt> <dd>Includes rash, palmar-plantar erythrodysesthesia syndrome, dermatitis acneiform, skin exfoliation, erythema multiforme, rash macular, rash maculo-papular, rash pustular, dermatitis, dermatitis bullous, dermatitis contact, erythema, dermatitis psoriasiform</dd> <dt> <a href="#footnote-reference-47" name="footnote-47">è</a> </dt> <dd>Includes musculoskeletal pain, non-cardiac chest pain, back pain, arthralgia, pain in extremity, myalgia, bone pain, arthritis, neck pain, musculoskeletal chest pain, musculoskeletal stiffness, chest discomfort</dd> <dt> <a href="#footnote-reference-48" name="footnote-48">ð</a> </dt> <dd>Includes dysgeusia, taste disorder, ageusia, anosmia</dd> <dt> <a href="#footnote-reference-49" name="footnote-49">ø</a> </dt> <dd>Includes dizziness, vertigo</dd> <dt> <a href="#footnote-reference-50" name="footnote-50">ý</a> </dt> <dd> Includes hypothyroidism, blood thyroid stimulating hormone increased</dd> <dt> <a href="#footnote-reference-51" name="footnote-51">£</a> </dt> <dd>Includes dyspnea, dyspnea exertional</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">General</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Fatigue<a class="Sup" href="#footnote-39" name="footnote-reference-39">†</a></td><td align="center" class="Botrule Rrule">79</td><td align="center" class="Botrule Rrule">14</td><td align="center" class="Botrule Rrule">61</td><td align="center" class="Botrule Rrule">6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Vascular</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hypertension<a class="Sup" href="#footnote-40" name="footnote-reference-40">‡</a></td><td align="center" class="Botrule Rrule">67</td><td align="center" class="Botrule Rrule">25</td><td align="center" class="Botrule Rrule">55</td><td align="center" class="Botrule Rrule">16</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Thromboembolic events<a class="Sup" href="#footnote-41" name="footnote-reference-41">§</a></td><td align="center" class="Botrule Rrule">19</td><td align="center" class="Botrule Rrule">11</td><td align="center" class="Botrule Rrule">3.2</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Gastrointestinal</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Diarrhea<a class="Sup" href="#footnote-42" name="footnote-reference-42">¶</a></td><td align="center" class="Botrule Rrule">63</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">23</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Stomatitis<a class="Sup" href="#footnote-43" name="footnote-reference-43">#</a></td><td align="center" class="Botrule Rrule">49</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Nausea</td><td align="center" class="Botrule Rrule">37</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">32</td><td align="center" class="Botrule Rrule">3.2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Abdominal pain<a class="Sup" href="#footnote-44" name="footnote-reference-44">Þ</a></td><td align="center" class="Botrule Rrule">25</td><td align="center" class="Botrule Rrule">3.2</td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Vomiting</td><td align="center" class="Botrule Rrule">25</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Dyspepsia<a class="Sup" href="#footnote-45" name="footnote-reference-45">ß</a></td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Skin and Subcutaneous Tissue</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Rash<a class="Sup" href="#footnote-46" name="footnote-reference-46">à</a></td><td align="center" class="Botrule Rrule">57</td><td align="center" class="Botrule Rrule">11</td><td align="center" class="Botrule Rrule">23</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Musculoskeletal and Connective Tissue Disorders</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Musculoskeletal pain<a class="Sup" href="#footnote-47" name="footnote-reference-47">è</a></td><td align="center" class="Botrule Rrule">41</td><td align="center" class="Botrule Rrule">1.6</td><td align="center" class="Botrule Rrule">19</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Nervous System</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Dysgeusia<a class="Sup" href="#footnote-48" name="footnote-reference-48">ð</a></td><td align="center" class="Botrule Rrule">30</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Dizziness<a class="Sup" href="#footnote-49" name="footnote-reference-49">ø</a></td><td align="center" class="Botrule Rrule">25</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">3.2</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Endocrine disorders</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hypothyroidism<a class="Sup" href="#footnote-50" name="footnote-reference-50">ý</a></td><td align="center" class="Botrule Rrule">25</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">3.2</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Metabolism and Nutrition</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Decreased appetite</td><td align="center" class="Botrule Rrule">25</td><td align="center" class="Botrule Rrule">3.2</td><td align="center" class="Botrule Rrule">19</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Investigations</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Weight decreased</td><td align="center" class="Botrule Rrule">19</td><td align="center" class="Botrule Rrule">3.2</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Respiratory, Thoracic, and Mediastinal</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">   Dyspnea<a class="Sup" href="#footnote-51" name="footnote-reference-51">£</a></td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">3.2</td><td align="center" class="Botrule Rrule">0</td> </tr> </tbody> </table></div>

Clinically relevant adverse reactions in <15% of patients who received CABOMETYX included peripheral neuropathy, hemorrhage, cardiac arrhythmia, hypotension, alopecia, and hair color changes.

Table 16 summarizes the laboratory abnormalities in patients with pNET in CABINET.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 16: Select Laboratory Abnormalities (≥10%) Reported as Adverse Reactions in Patients with pNET Who Received CABOMETYX in CABINET</span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule" rowspan="2">Laboratory Abnormality</th><th align="center" class="Botrule Lrule Rrule" colspan="2">CABOMETYX<br/> (N=63)</th><th align="center" class="Botrule Lrule Rrule" colspan="2">Placebo<br/> (N=31)</th> </tr> <tr class="Last"> <th align="center" class="Botrule Lrule Rrule">All Grades<a class="Sup" href="#footnote-52" name="footnote-reference-52">*</a> <br/>(%)</th><th align="center" class="Botrule Lrule Rrule">Grade 3 or 4<br/>(%)</th><th align="center" class="Botrule Lrule Rrule">All Grades<a class="Sup" href="#footnote-52">*</a> <br/>(%)</th><th align="center" class="Botrule Lrule Rrule">Grade 3 or 4<br/>(%)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-52" name="footnote-52">*</a> </dt> <dd>NCI CTCAE Version 5.0</dd> <dt> <a href="#footnote-reference-53" name="footnote-53">†</a> </dt> <dd>Includes hyperglycemia, blood glucose increased</dd> <dt> <a href="#footnote-reference-54" name="footnote-54">‡</a> </dt> <dd>Includes hypophosphatemia, blood phosphorus decreased</dd> <dt> <a href="#footnote-reference-55" name="footnote-55">§</a> </dt> <dd>Includes blood alkaline phosphatase, blood alkaline phosphatase increased</dd> <dt> <a href="#footnote-reference-56" name="footnote-56">¶</a> </dt> <dd>Includes hypocalcemia, blood calcium decreased, adjusted calcium decreased</dd> <dt> <a href="#footnote-reference-57" name="footnote-57">#</a> </dt> <dd>Includes hyponatremia, blood sodium decreased</dd> <dt> <a href="#footnote-reference-58" name="footnote-58">Þ</a> </dt> <dd>Includes blood bilirubin increased, hyperbilirubinemia</dd> <dt> <a href="#footnote-reference-59" name="footnote-59">ß</a> </dt> <dd>Includes hyperkalemia, blood potassium increased</dd> <dt> <a href="#footnote-reference-60" name="footnote-60">à</a> </dt> <dd>Includes hypoalbuminemia, blood albumin decreased</dd> <dt> <a href="#footnote-reference-61" name="footnote-61">è</a> </dt> <dd>Includes hypoglycemia, blood glucose decreased</dd> <dt> <a href="#footnote-reference-62" name="footnote-62">ð</a> </dt> <dd>Includes hypomagnesemia, blood magnesium decreased</dd> <dt> <a href="#footnote-reference-63" name="footnote-63">ø</a> </dt> <dd>Includes hypokalemia, blood potassium decreased</dd> <dt> <a href="#footnote-reference-64" name="footnote-64">ý</a> </dt> <dd>Includes platelet count decreased, thrombocytopenia</dd> <dt> <a href="#footnote-reference-65" name="footnote-65">£</a> </dt> <dd>Includes neutrophil count decreased, neutropenia</dd> <dt> <a href="#footnote-reference-66" name="footnote-66">¥</a> </dt> <dd>Includes hemoglobin decreased, anemia</dd> <dt> <a href="#footnote-reference-67" name="footnote-67">Œ</a> </dt> <dd>Includes lymphocyte count decreased, lymphopenia</dd> <dt> <a href="#footnote-reference-68" name="footnote-68">œ</a> </dt> <dd>Includes white blood cell count decreased, leukopenia</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Chemistry</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Increased AST </td><td align="center" class="Botrule Rrule">76</td><td align="center" class="Botrule Rrule">1.6</td><td align="center" class="Botrule Rrule">48</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Increased ALT</td><td align="center" class="Botrule Rrule">75</td><td align="center" class="Botrule Rrule">1.6</td><td align="center" class="Botrule Rrule">39</td><td align="center" class="Botrule Rrule">3.2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hyperglycemia<a class="Sup" href="#footnote-53" name="footnote-reference-53">†</a></td><td align="center" class="Botrule Rrule">37</td><td align="center" class="Botrule Rrule">3.2</td><td align="center" class="Botrule Rrule">48</td><td align="center" class="Botrule Rrule">3.2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hypophosphatemia<a class="Sup" href="#footnote-54" name="footnote-reference-54">‡</a></td><td align="center" class="Botrule Rrule">25</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Increased ALP<a class="Sup" href="#footnote-55" name="footnote-reference-55">§</a></td><td align="center" class="Botrule Rrule">22</td><td align="center" class="Botrule Rrule">3.2</td><td align="center" class="Botrule Rrule">23</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hypocalcemia<a class="Sup" href="#footnote-56" name="footnote-reference-56">¶</a></td><td align="center" class="Botrule Rrule">17</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">3.2</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hyponatremia<a class="Sup" href="#footnote-57" name="footnote-reference-57">#</a></td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">1.6</td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Blood bilirubin increased<a class="Sup" href="#footnote-58" name="footnote-reference-58">Þ</a></td><td align="center" class="Botrule Rrule">14</td><td align="center" class="Botrule Rrule">4.8</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">3.2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hyperkalemia<a class="Sup" href="#footnote-59" name="footnote-reference-59">ß</a></td><td align="center" class="Botrule Rrule">14</td><td align="center" class="Botrule Rrule">1.6</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hypoalbuminemia<a class="Sup" href="#footnote-60" name="footnote-reference-60">à</a></td><td align="center" class="Botrule Rrule">14</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hypoglycemia<a class="Sup" href="#footnote-61" name="footnote-reference-61">è</a></td><td align="center" class="Botrule Rrule">11</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hypomagnesemia<a class="Sup" href="#footnote-62" name="footnote-reference-62">ð</a></td><td align="center" class="Botrule Rrule">11</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hypokalemia<a class="Sup" href="#footnote-63" name="footnote-reference-63">ø</a></td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">1.6</td><td align="center" class="Botrule Rrule">3.2</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Hematology</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Platelet count decreased<a class="Sup" href="#footnote-64" name="footnote-reference-64">ý</a></td><td align="center" class="Botrule Rrule">37</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">19</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Neutrophil count decreased<a class="Sup" href="#footnote-65" name="footnote-reference-65">£</a></td><td align="center" class="Botrule Rrule">27</td><td align="center" class="Botrule Rrule">1.6</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hemoglobin decreased<a class="Sup" href="#footnote-66" name="footnote-reference-66">¥</a></td><td align="center" class="Botrule Rrule">25</td><td align="center" class="Botrule Rrule">1.6</td><td align="center" class="Botrule Rrule">32</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Lymphocyte count decreased<a class="Sup" href="#footnote-67" name="footnote-reference-67">Œ</a></td><td align="center" class="Botrule Rrule">22</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">   White blood cell count decreased<a class="Sup" href="#footnote-68" name="footnote-reference-68">œ</a></td><td align="center" class="Botrule Rrule">19</td><td align="center" class="Botrule Rrule">1.6</td><td align="center" class="Botrule Rrule">3.2</td><td align="center" class="Botrule Rrule">0</td> </tr> </tbody> </table></div>

Extra-Pancreatic Neuroendocrine Tumors (epNET)

The safety of CABOMETYX was evaluated in adult patients with unresectable, locally advanced or metastatic, well-differentiated neuroendocrine tumors in the CABINET trial [see Clinical Studies (14.4)]. Patients received CABOMETYX 60 mg (n=132) or placebo (n=67) orally once daily until disease progression or unacceptable toxicity. Patients with epNET were required to have disease progression after prior treatment with at least one FDA approved therapy (everolimus or lutetium Lu 177 dotatate), other than somatostatin analogs. The median duration of treatment was 5.4 months (range 0.1 to 32.4) for patients receiving CABOMETYX and 2.8 months (range 0.5 to 22.8) for patients receiving placebo.

The median age was 66 years (range 28 to 86), 55% were female, 86% were White, 7% were Black, 2.3% were Asian, 5% had unknown race or race not reported, and 6% were Hispanic or Latino.

Serious adverse reactions occurred in 44% of patients who received CABOMETYX. Serious adverse reactions in ≥2% included hypertension (6%), abdominal pain (5%), musculoskeletal pain (5%), diarrhea (3.0%), vomiting (3.0%), blood bilirubin increased (3.0%), thromboembolic events (3.0%), nausea (2.3%), hemoglobin decreased (2.3%), muscular weakness (2.3%), fatigue (2.3%), sepsis (2.3%), and syncope (2.3%). Fatal adverse reactions occurred in 4.5% of patients who received CABOMETYX, including hepatic failure, multi-organ dysfunction, gastrointestinal hemorrhage, cardiac arrest, ruptured ascending aortic aneurysm, and sudden death not otherwise specified, occurring in one patient each.

Permanent discontinuation of CABOMETYX due to an adverse reaction occurred in 28% of patients receiving CABOMETYX. Adverse reactions which resulted in permanent discontinuation of CABOMETYX included diarrhea, fatigue, increased AST, increased ALT, blood bilirubin increased, rash, thromboembolic events, hypertension, increased ALP, nausea, and stomatitis.

The median average daily dose was 42.9 mg for CABOMETYX. Dosage interruptions of CABOMETYX due to an adverse reaction occurred in 81% of patients. Adverse reactions which required dosage interruption in ≥5% of patients included diarrhea, fatigue, rash, hypertension, nausea, stomatitis, abdominal pain, increased AST, vomiting, and musculoskeletal pain.

Dose reductions of CABOMETYX due to an adverse reaction occurred in 38% of patients. Adverse reactions which required dose reductions in ≥5% of patients included rash, fatigue, diarrhea, and hypertension.

The most common adverse reactions occurring in ≥20% of CABOMETYX-treated patients were fatigue, increased AST, diarrhea, hypertension, increased ALT, platelet count decreased, rash, stomatitis, nausea, white blood cell count decreased, neutrophil count decreased, musculoskeletal pain, dysgeusia, hypothyroidism, decreased appetite, hemoglobin decreased, hyperglycemia, abdominal pain, increased ALP, lymphocyte count decreased, weight decreased, blood creatinine increased, hypoalbuminemia, blood bilirubin increased, hypocalcemia, hypokalemia, and hypomagnesemia.

Table 17 summarizes the adverse reactions in patients with epNET in CABINET.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 17. Adverse Reactions (≥15%) in Patients with epNET Who Received CABOMETYX in CABINET</span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule" rowspan="2">Adverse Reaction</th><th align="center" class="Botrule Lrule Rrule" colspan="2">CABOMETYX<br/> (N=132)</th><th align="center" class="Botrule Lrule Rrule" colspan="2">Placebo<br/> (N=67)</th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule">All Grades<a class="Sup" href="#footnote-69" name="footnote-reference-69">*</a></th><th align="center" class="Botrule Lrule Rrule">Grade 3-4</th><th align="center" class="Botrule Lrule Rrule">All Grades<a class="Sup" href="#footnote-69">*</a></th><th align="center" class="Botrule Lrule Rrule">Grade 3-4</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" colspan="1"></th><th align="center" class="Botrule Lrule Rrule" colspan="4">Percentage (%) of Patients</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-69" name="footnote-69">*</a> </dt> <dd>NCI CTCAE Version 5.0</dd> <dt> <a href="#footnote-reference-70" name="footnote-70">†</a> </dt> <dd>Includes fatigue, asthenia</dd> <dt> <a href="#footnote-reference-71" name="footnote-71">‡</a> </dt> <dd>Includes edema, edema peripheral, generalized edema, localized edema, periorbital edema, face edema, eye edema</dd> <dt> <a href="#footnote-reference-72" name="footnote-72">§</a> </dt> <dd>Includes diarrhea, colitis</dd> <dt> <a href="#footnote-reference-73" name="footnote-73">¶</a> </dt> <dd>Includes stomatitis, aphthous ulcer, mucosal inflammation, cheilitis, glossitis</dd> <dt> <a href="#footnote-reference-74" name="footnote-74">#</a> </dt> <dd>Includes abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain, abdominal discomfort, hepatic pain</dd> <dt> <a href="#footnote-reference-75" name="footnote-75">Þ</a> </dt> <dd>Includes hypertension, blood pressure increased, blood pressure systolic increased, systolic hypertension</dd> <dt> <a href="#footnote-reference-76" name="footnote-76">ß</a> </dt> <dd>Includes rash, palmar-plantar erythrodysesthesia syndrome, dermatitis acneiform, skin exfoliation, rash macular, rash pustular, dermatitis bullous, dermatitis, erythema multiforme, rash maculo-papular, dermatitis contact, erythema, dermatitis psoriasiform</dd> <dt> <a href="#footnote-reference-77" name="footnote-77">à</a> </dt> <dd>Includes musculoskeletal pain, non-cardiac chest pain, back pain, arthralgia, pain in extremity, myalgia, bone pain, arthritis, neck pain, musculoskeletal chest pain, musculoskeletal stiffness, chest discomfort</dd> <dt> <a href="#footnote-reference-78" name="footnote-78">è</a> </dt> <dd>Includes hypothyroidism, blood thyroid stimulating hormone increased</dd> <dt> <a href="#footnote-reference-79" name="footnote-79">ð</a> </dt> <dd>Includes dysgeusia, taste disorder, ageusia, anosmia</dd> <dt> <a href="#footnote-reference-80" name="footnote-80">ø</a> </dt> <dd>Includes dizziness, vertigo</dd> <dt> <a href="#footnote-reference-81" name="footnote-81">ý</a> </dt> <dd>Includes cough, upper-airway cough syndrome, productive cough</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">General</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Fatigue<a class="Sup" href="#footnote-70" name="footnote-reference-70">†</a></td><td align="center" class="Botrule Rrule">73</td><td align="center" class="Botrule Rrule">14</td><td align="center" class="Botrule Rrule">58</td><td align="center" class="Botrule Rrule">9</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Edema<a class="Sup" href="#footnote-71" name="footnote-reference-71">‡</a></td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">1.5</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Gastrointestinal</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Diarrhea<a class="Sup" href="#footnote-72" name="footnote-reference-72">§</a></td><td align="center" class="Botrule Rrule">65</td><td align="center" class="Botrule Rrule">11</td><td align="center" class="Botrule Rrule">42</td><td align="center" class="Botrule Rrule">4.5</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Stomatitis<a class="Sup" href="#footnote-73" name="footnote-reference-73">¶</a></td><td align="center" class="Botrule Rrule">40</td><td align="center" class="Botrule Rrule">3.8</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Nausea</td><td align="center" class="Botrule Rrule">39</td><td align="center" class="Botrule Rrule">2.3</td><td align="center" class="Botrule Rrule">21</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Abdominal pain<a class="Sup" href="#footnote-74" name="footnote-reference-74">#</a></td><td align="center" class="Botrule Rrule">29</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">43</td><td align="center" class="Botrule Rrule">8</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Vomiting</td><td align="center" class="Botrule Rrule">17</td><td align="center" class="Botrule Rrule">2.3</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">1.5</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Vascular</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hypertension<a class="Sup" href="#footnote-75" name="footnote-reference-75">Þ</a></td><td align="center" class="Botrule Rrule">64</td><td align="center" class="Botrule Rrule">27</td><td align="center" class="Botrule Rrule">37</td><td align="center" class="Botrule Rrule">6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Skin and Subcutaneous Tissue</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Rash<a class="Sup" href="#footnote-76" name="footnote-reference-76">ß</a></td><td align="center" class="Botrule Rrule">50</td><td align="center" class="Botrule Rrule">3.0</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Musculoskeletal and Connective Tissue Disorders</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Musculoskeletal pain<a class="Sup" href="#footnote-77" name="footnote-reference-77">à</a></td><td align="center" class="Botrule Rrule">36</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">33</td><td align="center" class="Botrule Rrule">1.5</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Endocrine System</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hypothyroidism<a class="Sup" href="#footnote-78" name="footnote-reference-78">è</a></td><td align="center" class="Botrule Rrule">34</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">4.5</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Metabolism and Nutrition</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Decreased appetite</td><td align="center" class="Botrule Rrule">33</td><td align="center" class="Botrule Rrule">1.5</td><td align="center" class="Botrule Rrule">15</td><td align="center" class="Botrule Rrule">1.5</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Nervous System</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Dysgeusia<a class="Sup" href="#footnote-79" name="footnote-reference-79">ð</a></td><td align="center" class="Botrule Rrule">35</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">1.5</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Dizziness<a class="Sup" href="#footnote-80" name="footnote-reference-80">ø</a></td><td align="center" class="Botrule Rrule">17</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Investigations</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Weight decreased</td><td align="center" class="Botrule Rrule">27</td><td align="center" class="Botrule Rrule">4.5</td><td align="center" class="Botrule Rrule">8</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Respiratory, Thoracic, and Mediastinal</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">   Cough<a class="Sup" href="#footnote-81" name="footnote-reference-81">ý</a></td><td align="center" class="Botrule Rrule">17</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">0</td> </tr> </tbody> </table></div>

Clinically relevant adverse reactions in <15% of patients who received CABOMETYX included cardiac arrhythmia, hemorrhage, thromboembolic events, kidney injury, proteinuria, hypotension, peripheral neuropathy, reversible posterior leukoencephalopathy syndrome, alopecia, and hair color changes.

Table 18 summarizes the laboratory abnormalities in patients with epNET in CABINET.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 18: Select Laboratory Abnormalities (≥10%) Reported as Adverse Reactions in Patients with epNET Who Received CABOMETYX in CABINET</span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <col align="center" valign="middle" width="12.5%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule" rowspan="2">Laboratory Abnormality</th><th align="center" class="Botrule Lrule Rrule" colspan="2">CABOMETYX<br/> (N=132)</th><th align="center" class="Botrule Lrule Rrule" colspan="2">Placebo<br/> (N=67)</th> </tr> <tr class="Last"> <th align="center" class="Botrule Lrule Rrule">All Grades<a class="Sup" href="#footnote-82" name="footnote-reference-82">*</a> <br/>(%)</th><th align="center" class="Botrule Lrule Rrule">Grade 3 or 4<br/>(%)</th><th align="center" class="Botrule Lrule Rrule">All Grades<a class="Sup" href="#footnote-82">*</a> <br/>(%)</th><th align="center" class="Botrule Lrule Rrule">Grade 3 or 4<br/>(%)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-82" name="footnote-82">*</a> </dt> <dd>NCI CTCAE Version 5.0</dd> <dt> <a href="#footnote-reference-83" name="footnote-83">†</a> </dt> <dd>Includes hyperglycemia, blood glucose increased</dd> <dt> <a href="#footnote-reference-84" name="footnote-84">‡</a> </dt> <dd>Includes blood alkaline phosphatase, blood alkaline phosphatase increased</dd> <dt> <a href="#footnote-reference-85" name="footnote-85">§</a> </dt> <dd>Includes blood bilirubin increased, hyperbilirubinemia</dd> <dt> <a href="#footnote-reference-86" name="footnote-86">¶</a> </dt> <dd>Includes hypoalbuminemia, blood albumin decreased</dd> <dt> <a href="#footnote-reference-87" name="footnote-87">#</a> </dt> <dd>Includes hypocalcemia, blood calcium decreased, adjusted calcium decreased</dd> <dt> <a href="#footnote-reference-88" name="footnote-88">Þ</a> </dt> <dd>Includes hypokalemia, blood potassium decreased</dd> <dt> <a href="#footnote-reference-89" name="footnote-89">ß</a> </dt> <dd>Includes hypomagnesemia, blood magnesium decreased</dd> <dt> <a href="#footnote-reference-90" name="footnote-90">à</a> </dt> <dd>Includes hypophosphatemia, blood phosphorus decreased</dd> <dt> <a href="#footnote-reference-91" name="footnote-91">è</a> </dt> <dd>Includes hyponatremia, blood sodium decreased</dd> <dt> <a href="#footnote-reference-92" name="footnote-92">ð</a> </dt> <dd>Includes platelet count decreased, thrombocytopenia</dd> <dt> <a href="#footnote-reference-93" name="footnote-93">ø</a> </dt> <dd>Includes white blood cell count decreased, leukopenia</dd> <dt> <a href="#footnote-reference-94" name="footnote-94">ý</a> </dt> <dd>Includes neutrophil count decreased, neutropenia</dd> <dt> <a href="#footnote-reference-95" name="footnote-95">£</a> </dt> <dd>Includes hemoglobin decreased, anemia</dd> <dt> <a href="#footnote-reference-96" name="footnote-96">¥</a> </dt> <dd>Includes lymphocyte count decreased, lymphopenia</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Chemistry</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Increased AST </td><td align="center" class="Botrule Rrule">70</td><td align="center" class="Botrule Rrule">3.8</td><td align="center" class="Botrule Rrule">21</td><td align="center" class="Botrule Rrule">1.5</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Increased ALT</td><td align="center" class="Botrule Rrule">63</td><td align="center" class="Botrule Rrule">0.8</td><td align="center" class="Botrule Rrule">18</td><td align="center" class="Botrule Rrule">1.5</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hyperglycemia<a class="Sup" href="#footnote-83" name="footnote-reference-83">†</a></td><td align="center" class="Botrule Rrule">30</td><td align="center" class="Botrule Rrule">0.8</td><td align="center" class="Botrule Rrule">39</td><td align="center" class="Botrule Rrule">1.5</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Increased ALP<a class="Sup" href="#footnote-84" name="footnote-reference-84">‡</a></td><td align="center" class="Botrule Rrule">29</td><td align="center" class="Botrule Rrule">4.5</td><td align="center" class="Botrule Rrule">30</td><td align="center" class="Botrule Rrule">6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Blood creatinine increased</td><td align="center" class="Botrule Rrule">23</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">1.5</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Blood bilirubin increased<a class="Sup" href="#footnote-85" name="footnote-reference-85">§</a></td><td align="center" class="Botrule Rrule">20</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hypoalbuminemia<a class="Sup" href="#footnote-86" name="footnote-reference-86">¶</a></td><td align="center" class="Botrule Rrule">20</td><td align="center" class="Botrule Rrule">0.8</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hypocalcemia<a class="Sup" href="#footnote-87" name="footnote-reference-87">#</a></td><td align="center" class="Botrule Rrule">20</td><td align="center" class="Botrule Rrule">0</td><td align="center" class="Botrule Rrule">4.5</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hypokalemia<a class="Sup" href="#footnote-88" name="footnote-reference-88">Þ</a></td><td align="center" class="Botrule Rrule">20</td><td align="center" class="Botrule Rrule">2.3</td><td align="center" class="Botrule Rrule">10</td><td align="center" class="Botrule Rrule">1.5</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hypomagnesemia<a class="Sup" href="#footnote-89" name="footnote-reference-89">ß</a></td><td align="center" class="Botrule Rrule">20</td><td align="center" class="Botrule Rrule">0.8</td><td align="center" class="Botrule Rrule">4.5</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hypophosphatemia<a class="Sup" href="#footnote-90" name="footnote-reference-90">à</a></td><td align="center" class="Botrule Rrule">19</td><td align="center" class="Botrule Rrule">0.8</td><td align="center" class="Botrule Rrule">4.5</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hyponatremia<a class="Sup" href="#footnote-91" name="footnote-reference-91">è</a></td><td align="center" class="Botrule Rrule">16</td><td align="center" class="Botrule Rrule">2.3</td><td align="center" class="Botrule Rrule">7</td><td align="center" class="Botrule Rrule">1.5</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Hematology</span></td><td align="center" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Platelet count decreased<a class="Sup" href="#footnote-92" name="footnote-reference-92">ð</a></td><td align="center" class="Botrule Rrule">55</td><td align="center" class="Botrule Rrule">1.5</td><td align="center" class="Botrule Rrule">13</td><td align="center" class="Botrule Rrule">1.5</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   White blood cell count deceased<a class="Sup" href="#footnote-93" name="footnote-reference-93">ø</a></td><td align="center" class="Botrule Rrule">37</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">4.5</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Neutrophil count decreased<a class="Sup" href="#footnote-94" name="footnote-reference-94">ý</a></td><td align="center" class="Botrule Rrule">36</td><td align="center" class="Botrule Rrule">3</td><td align="center" class="Botrule Rrule">6</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hemoglobin decreased<a class="Sup" href="#footnote-95" name="footnote-reference-95">£</a></td><td align="center" class="Botrule Rrule">30</td><td align="center" class="Botrule Rrule">2.3</td><td align="center" class="Botrule Rrule">19</td><td align="center" class="Botrule Rrule">0</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">   Lymphocyte count decreased<a class="Sup" href="#footnote-96" name="footnote-reference-96">¥</a></td><td align="center" class="Botrule Rrule">28</td><td align="center" class="Botrule Rrule">9</td><td align="center" class="Botrule Rrule">18</td><td align="center" class="Botrule Rrule">1.5</td> </tr> </tbody> </table></div>

The following adverse reactions have been identified during post-approval use of CABOMETYX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Vascular Disorders: Arterial (including aortic) aneurysms, dissections, and rupture

Strong CYP3A4 Inhibitors

Coadministration of a cabozantinib capsule formulation with a strong CYP3A4 inhibitor increased the exposure of cabozantinib, which may increase the risk of exposure-related adverse reactions [see Clinical Pharmacology (12.3)]. Avoid coadministration of CABOMETYX with strong CYP3A4 inhibitors. Reduce the dosage of CABOMETYX if coadministration with strong CYP3A4 inhibitors cannot be avoided [see Dosage and Administration (2.6)]. Avoid grapefruit or grapefruit juice which may also increase exposure of cabozantinib.

Strong or Moderate CYP3A Inducers

Coadministration of a cabozantinib capsule formulation with a strong CYP3A4 inducer decreased the exposure of cabozantinib, which may reduce efficacy [see Clinical Pharmacology (12.3)]. Avoid coadministration of CABOMETYX with strong or moderate CYP3A4 inducers. Increase the dosage of CABOMETYX if coadministration with strong or moderate CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.7)]. Avoid St. John’s wort which may also decrease exposure of cabozantinib.

Risk Summary

Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], CABOMETYX can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal developmental and reproductive toxicology studies administration of cabozantinib to pregnant rats and rabbits during organogenesis resulted in embryofetal lethality and structural anomalies at exposures that were below those occurring clinically at the recommended dose (see Data). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

In an embryo-fetal development study in pregnant rats, daily oral administration of cabozantinib throughout organogenesis caused increased embryo-fetal lethality compared to controls at a dose of 0.03 mg/kg (approximately 0.12-fold of human area under the curve [AUC] at the recommended dose). Findings included delayed ossification and skeletal variations at a dose of 0.01 mg/kg/day (approximately 0.04-fold of human AUC at the recommended dose).

In pregnant rabbits, daily oral administration of cabozantinib throughout organogenesis resulted in findings of visceral malformations and variations including reduced spleen size and missing lung lobe at 3 mg/kg (approximately 1.1-fold of the human AUC at the recommended dose).

In a pre- and postnatal study in rats, cabozantinib was administered orally from gestation day 10 through postnatal day 20. Cabozantinib did not produce adverse maternal toxicity or affect pregnancy, parturition or lactation of female rats, and did not affect the survival, growth or postnatal development of the offspring at doses up to 0.3 mg/kg/day (0.05-fold of the maximum recommended clinical dose).

Risk Summary

There is no information regarding the presence of cabozantinib or its metabolites in human milk, or their effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with CABOMETYX and for 4 months after the final dose.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX [see Use in Specific Populations (8.1)].

Contraception

CABOMETYX can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the final dose.

Infertility

Females and Males

Based on findings in animals, CABOMETYX may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of CABOMETYX for the treatment of differentiated thyroid cancer (DTC) and neuroendocrine tumors (NETs) have been established in pediatric patients aged 12 years and older.

Use of CABOMETYX in pediatric patients aged 12 years and older with DTC and NETs is supported by evidence from adequate and well-controlled studies of CABOMETYX in adults with additional population pharmacokinetic data demonstrating that cabozantinib exposure is within the same range between adults and pediatric patients aged 12 years and older at the recommended dosages [see Dosage and Administration (2.4, 2.5), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.3, 14.4)].

Physeal widening has been observed in children with open growth plates when treated with CABOMETYX. Based on the limited available data of the effects of CABOMETYX on longitudinal growth, physeal and longitudinal growth monitoring is recommended in children with open growth plates.

The safety and effectiveness of CABOMETYX in pediatric patients less than 12 years of age have not been established.

Juvenile Animal Toxicity Data

Juvenile rats were administered cabozantinib at doses of 1 or 2 mg/kg/day from Postnatal Day 12 (comparable to less than 2 years in humans) through Postnatal Day 35 or 70. Mortalities occurred at doses ≥1 mg/kg/day (approximately 0.16 times the clinical dose of 60 mg/day based on body surface area). Hypoactivity was observed at both doses tested on Postnatal Day 22. Targets were generally similar to those seen in adult animals, occurred at both doses, and included the kidney (nephropathy, glomerulonephritis), reproductive organs, gastrointestinal tract (cystic dilatation and hyperplasia in Brunner’s gland and inflammation of duodenum; and epithelial hyperplasia of colon and cecum), bone marrow (hypocellularity and lymphoid depletion), and liver. Tooth abnormalities and whitening as well as effects on bones including reduced bone mineral content and density, physeal hypertrophy, and decreased cortical bone also occurred at all dose levels. Recovery was not assessed at a dose of 2 mg/kg (approximately 0.32 times the clinical dose of 60 mg based on body surface area) due to high levels of mortality. At the low dose level, effects on bone parameters were partially resolved but effects on the kidney and epididymis/testis persisted after treatment ceased.

In CABOSUN and METEOR, 41% of 409 patients treated with CABOMETYX were age 65 years and older, and 8% were 75 years and older. In CELESTIAL, 49% of 467 patients treated with CABOMETYX were age 65 years and older, and 15% were 75 years and older. In COSMIC-311, 50% of 125 patients treated with CABOMETYX were age 65 years and older, and 12% were 75 years and older. In CABINET, 38% of 63 patients treated with CABOMETYX were age 65 years and older, and 5% were 75 years and older in the pNET cohort, and 55% of 132 patients treated with CABOMETYX were age 65 years and older, and 13% were 75 years and older in the epNET cohort [see Clinical Studies (14)].

No overall differences in safety or effectiveness were observed between these patients and younger patients.

Of the 320 patients with RCC treated with CABOMETYX in combination with nivolumab in CHECKMATE-9ER, 41% were 65 years or older and 9% were 75 years or older [see Clinical Studies (14.1)].

No overall difference in safety was reported between older and younger patients receiving both CABOMETYX and nivolumab.

Increased exposure to cabozantinib has been observed in patients with moderate (Child-Pugh B) hepatic impairment. Reduce the CABOMETYX dose in patients with moderate hepatic impairment. Avoid CABOMETYX in patients with severe hepatic impairment (Child-Pugh C), since it has not been studied in this population [see Dosage and Administration (2.8, 2.9), Clinical Pharmacology (12.3)].

No dosage adjustment is recommended in patients with mild or moderate renal impairment. There is no experience with CABOMETYX in patients with severe renal impairment [see Clinical Pharmacology (12.3)].

One case of overdosage was reported following administration of another formulation of cabozantinib; a patient inadvertently took twice the intended dose for 9 days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented.

{ "type": "p", "children": [], "text": "One case of overdosage was reported following administration of another formulation of cabozantinib; a patient inadvertently took twice the intended dose for 9 days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented." }

CABOMETYX is the (S)-malate salt of cabozantinib, a kinase inhibitor. Cabozantinib (S)-malate is described chemically as N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate. The molecular formula is C28H24FN3O5•C4H6O5 and the molecular weight is 635.6 Daltons as malate salt. The chemical structure of cabozantinib (S)-malate salt is:

{ "type": "p", "children": [], "text": "CABOMETYX is the (S)-malate salt of cabozantinib, a kinase inhibitor. Cabozantinib (S)-malate is described chemically as N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate. The molecular formula is C28H24FN3O5•C4H6O5 and the molecular weight is 635.6 Daltons as malate salt. The chemical structure of cabozantinib (S)-malate salt is:" }

Cabozantinib (S)-malate salt is a white to off-white solid that is practically insoluble in aqueous media.

{ "type": "p", "children": [], "text": "Cabozantinib (S)-malate salt is a white to off-white solid that is practically insoluble in aqueous\nmedia." }

CABOMETYX (cabozantinib) tablets for oral use are supplied as film-coated tablets containing 20 mg, 40 mg, or 60 mg of cabozantinib, which is equivalent to 25 mg, 51 mg, or 76 mg of cabozantinib (S)-malate, respectively. CABOMETYX also contains the following inactive ingredients: microcrystalline cellulose, lactose anhydrous, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

{ "type": "p", "children": [], "text": "CABOMETYX (cabozantinib) tablets for oral use are supplied as film-coated tablets containing 20 mg, 40 mg, or 60 mg of cabozantinib, which is equivalent to 25 mg, 51 mg, or 76 mg of cabozantinib (S)-malate, respectively. CABOMETYX also contains the following inactive ingredients: microcrystalline cellulose, lactose anhydrous, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate." }

The film coating contains hypromellose, titanium dioxide, triacetin, and iron oxide yellow.

{ "type": "p", "children": [], "text": "The film coating contains hypromellose, titanium dioxide, triacetin, and iron oxide yellow." }

In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the tyrosine kinase activity of MET, VEGFR-1, -2 and -3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.

The exposure-response or safety relationship for cabozantinib is not fully characterized.

Cardiac Electrophysiology

The effect of cabozantinib on QTc interval was evaluated in a randomized, double-blinded, placebo-controlled trial in patients with medullary thyroid cancer administered a cabozantinib capsule formulation. A mean increase in QTcF of 10 - 15 ms was observed at 4 weeks after initiation. A concentration-QTc relationship could not be definitively established. Changes in cardiac wave form morphology or new rhythms were not observed. No patients in this study had a confirmed QTcF > 500 ms nor did any patients in METEOR, CABOSUN, CELESTIAL, CHECKMATE-9ER, COSMIC-311, or CABINET.

Repeat daily dosing of a cabozantinib capsule formulation for 19 days resulted in 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady state was achieved by Day 15.

Absorption

Median time to peak cabozantinib concentrations (Tmax) ranged from 3 to 4 hours post-dose. A 19% increase in the Cmax of CABOMETYX compared to a cabozantinib capsule formulation was observed following a single 140 mg dose. A less than 10% difference in the AUC was observed between CABOMETYX and a cabozantinib capsule formulation [see Dosage and Administration (2.1)].

Food Effect

Cabozantinib Cmax and AUC increased by 41% and 57%, respectively, following a high-fat meal relative to fasted conditions in healthy subjects administered a single oral dose of a cabozantinib capsule formulation.

Distribution

The oral volume of distribution (Vz/F) of cabozantinib is approximately 319 L. Cabozantinib is highly protein bound in human plasma (≥99.7%).

Elimination

The predicted terminal half-life is approximately 99 hours and the clearance (CL/F) at steady-state is estimated to be 2.2 L/hr.

Metabolism

Cabozantinib is a substrate of CYP3A4 in vitro.

Excretion

Approximately 81% of the total administered radioactivity was recovered within a 48-day collection period following a single dose of radiolabeled 14C-cabozantinib in healthy subjects. Approximately 54% was recovered in feces and 27% in urine. Unchanged cabozantinib accounted for 43% of the total radioactivity in feces and was not detectable in urine following a 72-hour collection.

Specific Populations

The following patient characteristics did not result in a clinically relevant difference in the pharmacokinetics of cabozantinib: age (32-86 years), sex, race (Whites and non-Whites), or mild to moderate renal impairment (eGFR ≥30 mL/min/1.73 m2 as estimated by MDRD (modification of diet in renal disease equation)). The pharmacokinetics of cabozantinib is unknown in patients with eGFR <29 mL/min/1.73m2 as estimated by MDRD equation or requiring dialysis.

Pediatric Patients

The systemic exposures to cabozantinib in pediatric patients 12 years and older at the recommended dosages are expected to be comparable to the exposure in adults at the dose of CABOMETYX 60 mg once daily.

Patients with Hepatic Impairment

Based on a population pharmacokinetic analysis of cabozantinib in healthy subjects and patients with cancer, no clinically significant differences in the mean cabozantinib exposure were observed between subjects with normal liver function (total bilirubin and AST ≤ULN) and those with mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin >1 to 1.5x ULN and any AST value). In a dedicated pharmacokinetic study, cabozantinib exposure (AUC0-INF) increased by 63% in patients with moderate hepatic impairment (Child-Pugh B). Patients with severe hepatic impairment have not been studied [see Dosage and Administration (2.8), Use in Specific Populations (8.6)].

Drug Interaction Studies

Clinical Studies

CYP3A4 Inhibitors:

Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), with a cabozantinib capsule formulation to healthy subjects increased single-dose cabozantinib exposure (AUC0-INF) by 38%.

CYP3A4 Inducers:

Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), with a cabozantinib capsule formulation to healthy subjects decreased single-dose cabozantinib exposure (AUC0-INF) by 77%.

CYP2C8 Substrates:

No clinically-significant effect on single-dose rosiglitazone (a CYP2C8 substrate) exposure (Cmax and AUC) was observed when co-administered with a cabozantinib capsule formulation at steady-state concentrations.

Gastric Acid Reducing Agents:

No clinically-significant effect on cabozantinib exposure (AUC) was observed following co- administration of the proton pump inhibitor (PPI) esomeprazole (40 mg daily for 6 days) with a single 100 mg dose of a cabozantinib capsule formulation to healthy subjects.

In vitro Studies

CYP Enzymes:

Inhibition of CYP3A4 reduced the formation of the oxidative metabolite by >80%. Inhibition of CYP2C9 had a minimal effect on cabozantinib metabolite formation (i.e., a <20% reduction). Inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation.

Although cabozantinib is an inhibitor of CYP2C8 in vitro, a clinical study of this potential interaction concluded that concurrent use did not result in a clinically relevant effect on CYP2C8 substrate exposure. Given this finding, other less sensitive substrates of pathways affected by cabozantinib in vitro (i.e., CYP2C9, CYP2C19, and CYP3A4) were not evaluated in a clinical study, because, although a clinically relevant exposure effect cannot be ruled out, it is unlikely. Cabozantinib does not inhibit CYP1A2 and CYP2D6 isozymes in vitro.

Cabozantinib is an inducer of CYP1A1 mRNA; however, the clinical relevance of this finding is unknown. Cabozantinib does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4.

Transporters:

Cabozantinib is an inhibitor, but not a substrate, of P-gp transport activities and has the potential to increase concentrations of co-administered substrates of P-gp. The clinical relevance of this finding is unknown.

Cabozantinib is a substrate of MRP2 in vitro and MRP2 inhibitors have the potential to increase concentrations of cabozantinib. The clinical relevance of this finding is unknown.

The carcinogenic potential of cabozantinib has been evaluated in two species: rasH2 transgenic mice and Sprague-Dawley rats. In the 2-year rat carcinogenicity study, once daily oral administration of cabozantinib resulted in a statistically significant increase in the incidence of malignant/complex malignant pheochromocytoma in combination with benign pheochromocytoma or in benign pheochromocytoma alone in male rats at a dose of 1 mg/kg (approximately 5 times the human exposure by AUC at the recommended 60 mg dose). Cabozantinib was not carcinogenic in a 26-week carcinogenicity study in rasH2 transgenic mice at a slightly higher exposure than the intended human therapeutic exposure.

Cabozantinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Based on nonclinical findings, male and female fertility may be impaired by treatment with CABOMETYX. In a fertility study in which cabozantinib was administered to male and female rats at doses of 1, 2.5, and 5 mg/kg/day, male fertility was significantly compromised at doses equal to or greater than 2.5 mg/kg/day (approximately 13-fold of human AUC at the recommended dose), with a decrease in sperm counts and reproductive organ weights. In females, fertility was significantly reduced at doses equal to or greater than 1 mg/kg/day (5-fold of human AUC at the recommended dose) with a significant decrease in the number of live embryos and a significant increase in pre- and post-implantation losses.

Observations of effects on reproductive tract tissues in general toxicology studies were supportive of effects noted in the dedicated fertility study and included hypospermia and absence of corpora lutea in male and female dogs in a 6-month repeat dose study at plasma exposures (AUC) approximately 0.5-fold (males) and <0.1-fold (females) of those expected in humans at the recommended dose. In addition, female rats administered 5 mg/kg/day for 14 days (approximately 9-fold of human AUC at the recommended dose) exhibited ovarian necrosis.

Previously Treated with Anti-angiogenic Therapy

The efficacy of CABOMETYX was evaluated in METEOR (NCT01865747), a randomized (1:1), open-label, multicenter trial of CABOMETYX versus everolimus conducted in patients with advanced RCC who had received at least 1 prior anti-angiogenic therapy. Patients had to have a Karnofsky Performance Score (KPS) ≥70%. Patients were stratified by the number of prior VEGFR tyrosine kinase inhibitors (TKIs) and Memorial Sloan Kettering Cancer Center (MSKCC) Risk Group.

Patients were randomized to receive CABOMETYX (N=330) 60 mg orally once daily or everolimus (N=328) 10 mg orally once daily. The majority of the patients were male (75%), with a median age of 62 years. Sixty-nine percent (69%) received only one prior anti-angiogenic therapy. Patient distribution by MSKCC risk groups was 46% favorable (0 risk factors), 42% intermediate (1 risk factor), and 13% poor (2 or 3 risk factors). Fifty-four percent (54%) of patients had 3 or more organs with metastatic disease, including lung (63%), lymph nodes (62%), liver (29%), and bone (22%).

The main efficacy outcome measure was progression-free survival (PFS) assessed by a blinded independent radiology review committee among the first 375 subjects randomized. Other efficacy endpoints were objective response rate (ORR) and overall survival (OS) in the Intent-to- Treat (ITT) population. Tumor assessments were conducted every 8 weeks for the first 12 months, then every 12 weeks thereafter. Patients received treatment until disease progression or experiencing unacceptable toxicity. Patients on both arms who had disease progression could continue treatment at the discretion of the investigator.

Statistically significant improvements in PFS, OS, and ORR were demonstrated for CABOMETYX compared to everolimus. Efficacy results are presented in Tables 19 and 20 and Figures 1 and 2.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 19: Efficacy Results in METEOR (First 375 Randomized)</span> </caption> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="30%"/> <col align="center" valign="middle" width="30%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule">   Endpoint</th><th align="center" class="Botrule Lrule Rrule">CABOMETYX</th><th align="center" class="Botrule Lrule Rrule">Everolimus</th> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Lrule Rrule">N = 187</td><td align="center" class="Botrule Lrule Rrule">N = 188</td> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-97" name="footnote-97">*</a> </dt> <dd>stratified log-rank test with prior VEGFR-targeting TKI therapy (1 vs 2 or more) and MSKCC prognostic criteria for previously treated patients with RCC (0 vs 1 vs 2 or 3) as stratification factors (per IVRS data)</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule">   Median PFS (95% CI), months</td><td align="center" class="Botrule Rrule">7.4 (5.6, 9.1)</td><td align="center" class="Botrule Rrule">3.8 (3.7, 5.4)</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">   HR (95% CI), p-value<a class="Sup" href="#footnote-97" name="footnote-reference-97">*</a></td><td align="center" class="Botrule Rrule" colspan="2">0.58 (0.45, 0.74), p&lt;0.0001</td> </tr> </tbody> </table></div>

Figure 1: Kaplan-Meier Curves of Progression-Free Survival in METEOR (First 375 Randomized)

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 20: Efficacy Results in METEOR (ITT)</span> </caption> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="30%"/> <col align="center" valign="middle" width="30%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule">   Endpoint</th><th align="center" class="Botrule Lrule Rrule">CABOMETYX</th><th align="center" class="Botrule Lrule Rrule">Everolimus</th> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Lrule Rrule">N = 330</td><td align="center" class="Botrule Lrule Rrule">N = 328</td> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-98" name="footnote-98">*</a> </dt> <dd>stratified log-rank test with prior VEGFR-targeting TKI therapy (1 vs 2 or more) and MSKCC prognostic criteria for previously treated patients with RCC (0 vs 1 vs 2 or 3) as stratification factors (per IVRS data)</dd> <dt> <a href="#footnote-reference-99" name="footnote-99">†</a> </dt> <dd>chi-squared test</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule">   Median OS (95% CI), months</td><td align="center" class="Botrule Rrule">21.4 (18.7, NE)</td><td align="center" class="Botrule Rrule">16.5 (14.7, 18.8)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   HR (95% CI), p-value<a class="Sup" href="#footnote-98" name="footnote-reference-98">*</a></td><td align="center" class="Botrule Rrule" colspan="2">0.66 (0.53, 0.83), p=0.0003</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Confirmed ORR (partial responses only) (95% CI)</td><td align="center" class="Botrule Rrule">17% (13%, 22%)</td><td align="center" class="Botrule Rrule">3% (2%, 6%)</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">   p-value<a class="Sup" href="#footnote-99" name="footnote-reference-99">†</a></td><td align="center" class="Botrule Rrule" colspan="2">p&lt;0.0001</td> </tr> </tbody> </table></div>

Figure 2: Kaplan-Meier Curve of Overall Survival in METEOR (ITT)

First-line Treatment

CABOSUN

The efficacy of CABOMETYX was evaluated in CABOSUN (NCT01835158), a randomized (1:1), open-label, multicenter trial of CABOMETYX versus sunitinib conducted in patients with advanced RCC who had not received prior therapy. Patients were randomized to receive CABOMETYX (N=79) 60 mg orally once daily or sunitinib (N=78) 50 mg orally once daily (4 weeks on treatment followed by 2 weeks off) until disease progression or unacceptable toxicity. All patients were required to have intermediate or poor risk disease as defined by the International Metastatic RCC Database Consortium (IMDC) risk group categories. Patients were stratified by IMDC risk group and presence of bone metastases (yes/no).

The majority of patients were male (78%), with a median age of 63 years. Patient distribution by IMDC risk groups was 81% intermediate (1-2 risk factors) and 19% poor (≥3 risk factors). Thirty-six percent (36%) patients had bone metastases. Forty-six percent (46%) of patients were ECOG 0, 41% ECOG 1, and 13% ECOG 2.

The major efficacy outcome measure was progression-free survival (PFS) by a retrospective blinded independent radiology review committee (BIRC).

A statistically significant improvement in PFS, as assessed by a blinded independent radiology review committee, was demonstrated for CABOMETYX compared to sunitinib. Efficacy results are presented in Table 21, Figure 3, and Figure 4.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 21: Efficacy Results in CABOSUN</span> </caption> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="30%"/> <col align="center" valign="middle" width="30%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule">   Endpoint</th><th align="center" class="Botrule Lrule Rrule">CABOMETYX</th><th align="center" class="Botrule Lrule Rrule">Sunitinib</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Lrule Rrule">N = 79</td><td align="center" class="Botrule Lrule Rrule">N = 78</td> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" colspan="3">   Progression-Free Survival<a class="Sup" href="#footnote-100" name="footnote-reference-100">*</a></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-100" name="footnote-100">*</a> </dt> <dd>as assessed by a retrospective blinded independent radiology review committee (BIRC)</dd> <dt> <a href="#footnote-reference-101" name="footnote-101">†</a> </dt> <dd>estimated from stratified Cox proportional hazards model with stratification factors IMDC risk group and presence of bone metastases and treatment as covariate</dd> <dt> <a href="#footnote-reference-102" name="footnote-102">‡</a> </dt> <dd>two-sided stratified log-rank test with stratification factors IMDC risk group and presence of bone metastases</dd> <dt> <a href="#footnote-reference-103" name="footnote-103">§</a> </dt> <dd>no multiplicity adjustments were made for overall survival or ORR</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule">   Events, n(%)</td><td align="center" class="Botrule Rrule">43 (54)</td><td align="center" class="Botrule Rrule">49 (63)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Median PFS (95% CI), months<a class="Sup" href="#footnote-100">*</a></td><td align="center" class="Botrule Rrule">8.6 (6.8, 14.0)</td><td align="center" class="Botrule Rrule">5.3 (3.0, 8.2)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hazard Ratio<a class="Sup" href="#footnote-101" name="footnote-reference-101">†</a> (95% CI), p-value<a class="Sup" href="#footnote-102" name="footnote-reference-102">‡</a></td><td align="center" class="Botrule Rrule" colspan="2">0.48 (0.31, 0.74), p=0.0008</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3"><span class="Bold">Overall Survival</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Events, n(%)</td><td align="center" class="Botrule Rrule">43 (54)</td><td align="center" class="Botrule Rrule">47 (60)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hazard Ratio<a class="Sup" href="#footnote-101">†</a><span class="Sup">, </span><a class="Sup" href="#footnote-103" name="footnote-reference-103">§</a> (95% CI)</td><td align="center" class="Botrule Rrule" colspan="2">0.80 (0.53, 1.21)</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Confirmed ORR, partial responses only (95% CI)</span><a class="Sup" href="#footnote-100">*</a><span class="Sup">, </span><a class="Sup" href="#footnote-103">§</a></td><td align="center" class="Botrule Rrule">20% (12.0, 30.8)</td><td align="center" class="Botrule Rrule">9% (3.7, 17.6)</td> </tr> </tbody> </table></div>

Figure 3: Kaplan-Meier Curve of Progression-Free Survival in CABOSUN

Figure 4: Kaplan-Meier Curve of Overall Survival in CABOSUN

CHECKMATE-9ER

CHECKMATE-9ER (NCT03141177) was a randomized, open-label study of CABOMETYX combined with nivolumab versus sunitinib in patients with previously untreated advanced RCC. CHECKMATE-9ER excluded patients with autoimmune disease or other medical conditions requiring systemic immunosuppression. Patients were stratified by IMDC prognostic score (favorable vs. intermediate vs. poor), PD-L1 tumor expression (≥1% vs. <1% or indeterminate), and region (US/Canada/Western Europe/Northern Europe vs. Rest of World).

Patients were randomized to CABOMETYX 40mg orally daily and nivolumab 240mg intravenously every 2 weeks (n=323), or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (4 weeks on treatment followed by 2 weeks off) (n=328). Treatment continued until disease progression per RECIST v1.1 or unacceptable toxicity. Treatment beyond RECIST- defined disease progression was permitted if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Tumor assessments were performed at baseline, after randomization at Week 12, then every 6 weeks until Week 60, and then every 12 weeks thereafter.

The trial population characteristics were: median age 61 years (range: 28 to 90) with 38% ≥65 years of age and 10% ≥75 years of age. The majority of patients were male (74%) and White (82%) and 23% and 77% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively. Patient distribution by IMDC risk categories was 22% favorable, 58% intermediate, and 20% poor.

The major efficacy outcome measure was PFS (BICR assessed). Additional efficacy outcome measures were OS and ORR (BICR assessed). The trial demonstrated a statistically significant improvement in PFS, OS, and ORR for patients randomized to CABOMETYX and nivolumab compared with sunitinib. Consistent results for PFS were observed across pre-specified subgroups of IMDC risk categories and PD-L1 tumor expression status. An updated efficacy analysis was conducted when 271 deaths were observed based on the pre-specified number of deaths for the pre-planned final analysis of OS. Efficacy results are shown in Table 22 and Figures 5 and 6.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 22: Efficacy Results in CHECKMATE-9ER</span> </caption> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="30%"/> <col align="center" valign="middle" width="30%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule"></th><th align="center" class="Botrule Lrule Rrule">CABOMETYX and<br/>Nivolumab<br/>(n=323)</th><th align="center" class="Botrule Lrule Rrule">Sunitinib<br/>(n=328)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-104" name="footnote-104">*</a> </dt> <dd>Based on Kaplan-Meier estimates.</dd> <dt> <a href="#footnote-reference-105" name="footnote-105">†</a> </dt> <dd>Stratified Cox proportional hazards model.</dd> <dt> <a href="#footnote-reference-106" name="footnote-106">‡</a> </dt> <dd>Based on stratified log-rank test</dd> <dt> <a href="#footnote-reference-107" name="footnote-107">§</a> </dt> <dd>2-sided p-values from stratified log-rank test.</dd> <dt> <a href="#footnote-reference-108" name="footnote-108">¶</a> </dt> <dd>Not Reached</dd> <dt> <a href="#footnote-reference-109" name="footnote-109">#</a> </dt> <dd>p-value is compared with the allocated alpha of 0.0111 for this interim analysis.</dd> <dt> <a href="#footnote-reference-110" name="footnote-110">Þ</a> </dt> <dd>CI based on the Clopper and Pearson method.</dd> <dt> <a href="#footnote-reference-111" name="footnote-111">ß</a> </dt> <dd>2-sided p-value from Cochran-Mantel-Haenszel test.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule" colspan="3"><span class="Bold">Progression-free Survival</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Disease progression or deaths (%)</td><td align="center" class="Botrule Rrule">144 (45)</td><td align="center" class="Botrule Rrule">191 (58)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Median PFS (months)<a class="Sup" href="#footnote-104" name="footnote-reference-104">*</a> (95% CI)</td><td align="center" class="Botrule Rrule">16.6 (12.5, 24.9)</td><td align="center" class="Botrule Rrule">8.3 (7.0, 9.7)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hazard ratio (95% CI)<a class="Sup" href="#footnote-105" name="footnote-reference-105">†</a></td><td align="center" class="Botrule Rrule" colspan="2">0.51 (0.41, 0.64)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   p-value<a class="Sup" href="#footnote-106" name="footnote-reference-106">‡</a><span class="Sup">, </span><a class="Sup" href="#footnote-107" name="footnote-reference-107">§</a></td><td align="center" class="Botrule Rrule" colspan="2">&lt;0.0001</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3"><span class="Bold">Overall Survival</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Deaths (%)</td><td align="center" class="Botrule Rrule">67 (21)</td><td align="center" class="Botrule Rrule">99 (30)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Median OS (months)<a class="Sup" href="#footnote-104">*</a> (95% CI)</td><td align="center" class="Botrule Rrule">NR<a class="Sup" href="#footnote-108" name="footnote-reference-108">¶</a></td><td align="center" class="Botrule Rrule">NR (22.6, NR<a class="Sup" href="#footnote-108">¶</a>)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hazard ratio (95% CI)<a class="Sup" href="#footnote-105">†</a></td><td align="center" class="Botrule Rrule" colspan="2">0.60 (0.40, 0.89)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   p-value<a class="Sup" href="#footnote-106">‡</a><span class="Sup">, </span><a class="Sup" href="#footnote-107">§</a><span class="Sup">, </span><a class="Sup" href="#footnote-109" name="footnote-reference-109">#</a></td><td align="center" class="Botrule Rrule" colspan="2">0.0010</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3"><span class="Bold">Updated Overall Survival</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Deaths (%)</td><td align="center" class="Botrule Rrule">121 (37)</td><td align="center" class="Botrule Rrule">150 (46)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Median OS (months)<a class="Sup" href="#footnote-104">*</a> (95% CI)</td><td align="center" class="Botrule Rrule">37.7 (35.5, NR<a class="Sup" href="#footnote-108">¶</a>) </td><td align="center" class="Botrule Rrule">34.3 (29.0, NR<a class="Sup" href="#footnote-108">¶</a>)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hazard ratio (95% CI)<a class="Sup" href="#footnote-105">†</a></td><td align="center" class="Botrule Rrule" colspan="2">0.70 (0.55, 0.90)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Confirmed Objective Response Rate (95% CI)</span><a class="Sup" href="#footnote-110" name="footnote-reference-110">Þ</a></td><td align="center" class="Botrule Rrule">55.7% (50.1, 61.2)</td><td align="center" class="Botrule Rrule">27.1% (22.4, 32.3)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   p-value<a class="Sup" href="#footnote-111" name="footnote-reference-111">ß</a></td><td align="center" class="Botrule Rrule" colspan="2">&lt;0.0001</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Complete Response (CR)</td><td align="center" class="Botrule Rrule">26 (8%)</td><td align="center" class="Botrule Rrule">15 (4.6%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Partial Response (PR)</td><td align="center" class="Botrule Rrule">154 (48%)</td><td align="center" class="Botrule Rrule">74 (23%)</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">   Median duration of response in months (95% CI)<a class="Sup" href="#footnote-104">*</a></td><td align="center" class="Botrule Rrule">20.2 (17.3, NR<a class="Sup" href="#footnote-108">¶</a>)</td><td align="center" class="Botrule Rrule">11.5 (8.3, 18.4)</td> </tr> </tbody> </table></div>

Figure 5: Kaplan-Meier Curve of Progression-Free Survival in CHECKMATE-9ER

Figure 6: Kaplan-Meier Curve of Updated Overall Survival in CHECKMATE-9ER

In an exploratory analysis, the updated analysis of OS in patients with IMDC favorable, intermediate, intermediate/poor, and poor risk demonstrated a HR (95% CI) of 1.03 (0.55, 1.92), 0.74 (0.54, 1.01), 0.65 (0.50, 0.85), and 0.49 (0.31, 0.79), respectively.

The efficacy of CABOMETYX was evaluated in CELESTIAL (NCT01908426), a randomized (2:1), double-blind, placebo-controlled, multicenter trial in patients with hepatocellular carcinoma (HCC) who had previously received sorafenib and had Child Pugh Class A liver impairment. Patients were randomized to receive CABOMETYX 60 mg orally once daily or placebo until disease progression or unacceptable toxicity. Randomization was stratified by etiology of disease (hepatitis B virus [HBV] with or without hepatitis C virus [HCV] vs. HCV [without HBV] vs. other [without HBV and HCV]), geographic region (Asia vs. other regions), and presence of extrahepatic spread of disease and/or macrovascular invasion (yes vs. no). The primary efficacy outcome measure was overall survival (OS). Additional outcome measures were progression-free survival (PFS) and objective response rate (ORR), as assessed by investigators per RECIST 1.1. Tumor assessments were conducted every 8 weeks.

In CELESTIAL, a total of 707 patients were randomized, 470 to CABOMETYX and 237 to placebo. The median age was 64 years (range 22 to 86 years), 82% were male, 56% were White and 34% were Asian. Baseline ECOG performance status was 0 (53%) or 1 (47%). The etiology of HCC was attributed to HBV in 38% of patients and HCV in 21%; etiology was attributed to causes other than HBV or HCV in 40%. Macroscopic vascular invasion or extra-hepatic tumor spread was present in 78% of patients and 41% had alpha-fetoprotein (AFP) levels ≥400 mcg/L. All patients received prior sorafenib and 27% received two prior systemic therapy regimens.

Efficacy results are summarized in Table 23, Figure 7, and Figure 8.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 23: Efficacy Results from CELESTIAL</span> </caption> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="30%"/> <col align="center" valign="middle" width="30%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule">   Endpoint</th><th align="center" class="Botrule Lrule Rrule">CABOMETYX</th><th align="center" class="Botrule Lrule Rrule">Placebo</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"></td><td align="center" class="Botrule Lrule Rrule">N = 470</td><td align="center" class="Botrule Lrule Rrule">N = 237</td> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" colspan="3">   Overall Survival</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5" valign="top"><span class="Sub">CI, confidence interval</span></td> </tr> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-112" name="footnote-112">*</a> </dt> <dd>estimated using the Cox proportional-hazard model</dd> <dt> <a href="#footnote-reference-113" name="footnote-113">†</a> </dt> <dd>log-rank test stratified by etiology of disease (HBV [with or without HCV], HCV [without HBV], or Other), geographic region (Asia, Other Regions), and presence of extrahepatic spread of disease and/or macrovascular invasion (Yes, No) as stratification factors (per IVRS data)</dd> <dt> <a href="#footnote-reference-114" name="footnote-114">‡</a> </dt> <dd>significance level = 0.021 for 78% information (484 deaths) based on O’Brien-Fleming method</dd> <dt> <a href="#footnote-reference-115" name="footnote-115">§</a> </dt> <dd>Fisher’s exact test</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule">   Number of Deaths, (%)</td><td align="center" class="Botrule Rrule">317 (67)</td><td align="center" class="Botrule Rrule">167 (70)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Median OS in Months (95% CI)</td><td align="center" class="Botrule Rrule">10.2 (9.1, 12.0)</td><td align="center" class="Botrule Rrule">8.0 (6.8, 9.4)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hazard Ratio (95% CI)<a class="Sup" href="#footnote-112" name="footnote-reference-112">*</a></td><td align="center" class="Botrule Rrule" colspan="2">0.76 (0.63, 0.92)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   p-value<a class="Sup" href="#footnote-113" name="footnote-reference-113">†</a></td><td align="center" class="Botrule Rrule" colspan="2">p=0.0049<a class="Sup" href="#footnote-114" name="footnote-reference-114">‡</a></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3"><span class="Bold">Progression-Free Survival</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Number of Events, (%)</td><td align="center" class="Botrule Rrule">349 (74)</td><td align="center" class="Botrule Rrule">205 (86)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Progressive Disease</td><td align="center" class="Botrule Rrule">284 (60)</td><td align="center" class="Botrule Rrule">186 (78)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Death</td><td align="center" class="Botrule Rrule">65 (14)</td><td align="center" class="Botrule Rrule">19 (8)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Median PFS in Months (95% CI)</td><td align="center" class="Botrule Rrule">5.2 (4.0, 5.5)</td><td align="center" class="Botrule Rrule">1.9 (1.9, 1.9)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hazard Ratio (95% CI)<a class="Sup" href="#footnote-112">*</a></td><td align="center" class="Botrule Rrule" colspan="2">0.44 (0.36, 0.52)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   p-value<a class="Sup" href="#footnote-113">†</a></td><td align="center" class="Botrule Rrule" colspan="2">p&lt;0.0001</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3"><span class="Bold">Overall Response Rate (ORR)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Confirmed ORR (partial responses only) (95% CI)<a class="Sup" href="#footnote-114">‡</a></td><td align="center" class="Botrule Rrule">4% (2.3, 6.0)</td><td align="center" class="Botrule Rrule">0.4% (0.0, 2.3)</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">   p-value<a class="Sup" href="#footnote-115" name="footnote-reference-115">§</a></td><td align="center" class="Botrule Rrule" colspan="2">p=0.0086</td> </tr> </tbody> </table></div>

Figure 7: Kaplan-Meier Curve of Overall Survival in CELESTIAL

Figure 8: Kaplan-Meier Curve of Progression-Free Survival in CELESTIAL

The efficacy of CABOMETYX was evaluated in COSMIC-311 (NCT03690388), a randomized (2:1), double-blind, placebo-controlled, multicenter trial in patients with locally advanced or metastatic differentiated thyroid cancer (DTC) that had progressed following prior VEGFR-targeted therapy and were radioactive iodine-refractory or ineligible. Patients were randomized to receive CABOMETYX 60 mg orally once daily or placebo with supportive care until disease progression or unacceptable toxicity. Randomization was stratified by prior receipt of lenvatinib (yes vs. no) and age (≤65 years vs >65 years). Eligible patients randomized to placebo were allowed to cross-over to CABOMETYX upon confirmation of progressive disease by blinded independent radiology review committee (BIRC). The multiple primary efficacy outcome measures were progression-free survival (PFS) in the ITT population, and overall response rate (ORR) in the first 100 randomized patients, as assessed by BIRC per RECIST 1.1. Tumor assessments were conducted every 8 weeks. Overall survival (OS) was a descriptive outcome measure.

The primary analysis of PFS included 187 randomized patients. An updated analysis of PFS was performed and included 258 randomized patients. The median age was 65 years (range 31 to 85 years), 53% were female, 70% were White, 19% were Asian, 2% were Black, 2% were American Indian or Alaska Native, and 63% received prior lenvatinib. Baseline ECOG performance status was 0 (46%) or 1 (54%) and 93% of patients had metastatic disease.

The trial demonstrated a statistically significant improvement in PFS, while it failed to demonstrate a statistically significant improvement in ORR, for patients randomized to CABOMETYX compared with placebo. Efficacy results are summarized in Table 24 and Figure 9.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 24: Efficacy Results from COSMIC-311</span> </caption> <col align="left" valign="middle" width="30%"/> <col align="center" valign="middle" width="15.5%"/> <col align="center" valign="middle" width="15.5%"/> <col align="center" valign="middle" width="15.5%"/> <col align="center" valign="middle" width="15.5%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule"></th><th align="center" class="Botrule Lrule Rrule" colspan="2">Primary Analysis</th><th align="center" class="Botrule Lrule Rrule" colspan="2">Updated Analysis<a class="Sup" href="#footnote-116" name="footnote-reference-116">*</a></th> </tr> <tr> <th align="left" class="Botrule Lrule Rrule"></th><th align="center" class="Botrule Lrule Rrule">CABOMETYX<br/>(n=125)</th><th align="center" class="Botrule Lrule Rrule">Placebo<br/>(n=62)</th><th align="center" class="Botrule Lrule Rrule">CABOMETYX<br/>(n=170)</th><th align="center" class="Botrule Lrule Rrule">Placebo<br/>(n=88)</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" colspan="1">Progression-Free Survival</th><th align="center" class="Botrule Lrule Rrule"></th><th align="center" class="Botrule Rrule"></th><th align="center" class="Botrule Rrule"></th><th align="center" class="Botrule Rrule"></th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5" valign="top"><span class="Sub">CI, confidence interval; NR, not reached; NE, not evaluable</span></td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-116" name="footnote-116">*</a> </dt> <dd>No formal statistical testing was conducted at the time of the updated analysis</dd> <dt> <a href="#footnote-reference-117" name="footnote-117">†</a> </dt> <dd>Estimated using the Cox proportional-hazard model</dd> <dt> <a href="#footnote-reference-118" name="footnote-118">‡</a> </dt> <dd>Log-rank test stratified by receipt of prior lenvatinib (yes vs no) and age (≤65 years vs &gt;65 years)</dd> <dt> <a href="#footnote-reference-119" name="footnote-119">§</a> </dt> <dd>All responses were partial responses</dd> <dt> <a href="#footnote-reference-120" name="footnote-120">¶</a> </dt> <dd>The analysis population overall response rate was the first 100 randomized patients (67 in the CABOMETYX arm, and 33 in the placebo arm)</dd> <dt> <a href="#footnote-reference-121" name="footnote-121">#</a> </dt> <dd>Fisher’s exact test compared to an alpha boundary of 0.01</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule">Number of Events, (%)</td><td align="center" class="Botrule Rrule">31 (25)</td><td align="center" class="Botrule Rrule">43 (69)</td><td align="center" class="Botrule Rrule">62 (36)</td><td align="center" class="Botrule Rrule">69 (78)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Median PFS in Months (95% CI)</td><td align="center" class="Botrule Rrule">NR (5.7, NE)</td><td align="center" class="Botrule Rrule">1.9 (1.8, 3.6)</td><td align="center" class="Botrule Rrule">11.0 (7.4, 13.8)</td><td align="center" class="Botrule Rrule">1.9 (1.9, 3.7)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">Hazard Ratio (95% CI)<a class="Sup" href="#footnote-117" name="footnote-reference-117">†</a></td><td align="center" class="Botrule Rrule" colspan="2">0.22 (0.14, 0.35)</td><td align="center" class="Botrule Rrule" colspan="2">0.22 (0.15, 0.31)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">p-value<a class="Sup" href="#footnote-118" name="footnote-reference-118">‡</a></td><td align="center" class="Botrule Rrule" colspan="2">&lt; 0.0001</td><td align="center" class="Botrule Rrule" colspan="2"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold">Overall Response Rate (95% CI)</span></td><td align="center" class="Botrule Rrule" colspan="2"></td><td align="center" class="Botrule Rrule" colspan="2"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Overall Response, % (95% CI)<a class="Sup" href="#footnote-119" name="footnote-reference-119">§</a><span class="Sup">,</span><a class="Sup" href="#footnote-120" name="footnote-reference-120">¶</a></td><td align="center" class="Botrule Rrule">15% (7%, 26%)</td><td align="center" class="Botrule Rrule">0% (0.0%, 11%)</td><td align="center" class="Botrule Rrule">18% (10%, 29%)</td><td align="center" class="Botrule Rrule">0% (0.0%, 11%)</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">    p-value<a class="Sup" href="#footnote-121" name="footnote-reference-121">#</a></td><td align="center" class="Botrule Rrule" colspan="2">0.0281</td><td align="center" class="Botrule Rrule" colspan="2"></td> </tr> </tbody> </table></div>

Figure 9: Kaplan-Meier Curve of Progression-Free Survival in COSMIC-311 (Updated Analysis, N=258)

Pancreatic Neuroendocrine Tumors

The efficacy of CABOMETYX for the treatment of pancreatic neuroendocrine tumors (pNET) was evaluated in CABINET (NCT03375320), a randomized, double-blind, placebo-controlled, multicenter study in patients with unresectable, locally advanced or metastatic pNET that had progressed on prior therapy. Eligible patients were required to have been previously treated with at least one FDA approved therapy (everolimus, sunitinib, or lutetium Lu 177 dotatate), other than somatostatin analogs. Patients with active brain metastases or cranial epidural disease, and those who had prior treatment with cabozantinib were excluded. The study also excluded patients with clinically significant gastrointestinal (GI) bleeding, GI abnormalities, and tumor with invasion into the GI tract that may increase the risk for GI bleeding or perforation, and patients with tumor invading or encasing major blood vessels. Patients were randomized (2:1) to receive treatment with CABOMETYX 60 mg orally once daily or placebo until disease progression or unacceptable toxicity. Randomization was stratified by concurrent somatostatin analog (SSA) use (yes/no) and prior sunitinib therapy (yes/no). Tumor assessments were performed every 12 weeks. The study included patients with functional and non-functional tumors, and use of somatostatin analogs at a stable dose was permitted for symptom control. Eligible patients randomized to the placebo arm were allowed to crossover to CABOMETYX upon confirmation of progressive disease by blinded real time central review.

The major efficacy outcome measure was progression-free survival (PFS) assessed by blinded independent radiology review committee (BIRC) per RECIST 1.1. Additional efficacy outcome measures included overall response rate (ORR), duration of response (DOR) and overall survival (OS).

A total of 99 pNET patients were randomized (2:1) to receive CABOMETYX 60 mg orally once daily (n=66) or placebo (n=33). The median age was 60 years (range: 29 to 79); 57% were male; 83% were White, 6% Black or African American, 4.0% Asian, 1.0% American Indian or Alaska Native, 1.0% Native Hawaiian or other Pacific Islander, 1.0% multiple races, 4.0% not reported or unknown; and 5% were Hispanic or Latino. In the 99 patients with pNET, 27% had received one prior systemic therapy, 26% had received two prior systemic therapies and 46% had received three or more prior systemic therapies.

As recommended by the Data and Safety Monitoring Board, the CABINET study was unblinded prior to the final prespecified efficacy analysis and all patients remaining on the placebo arm were permitted to crossover to treatment with cabozantinib. At the time of unblinding, the trial demonstrated a statistically significant improvement in PFS assessed by BIRC for CABOMETYX compared to placebo. An updated OS analysis was conducted when 49 deaths were observed. OS data were not mature with 32 (48%) deaths in CABOMETYX arm and 17 (52%) deaths in placebo arm (OS HR=1.01 [95% CI: 0.55, 1.83]). Fifty-two percent of placebo arm patients crossed over to open label CABOMETYX, which may impact the OS endpoint.

Efficacy results are summarized in Table 25 and Figure 10.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 25: Efficacy Results in Patients with pNET in CABINET</span> </caption> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="30%"/> <col align="center" valign="middle" width="30%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule"></th><th align="center" class="Botrule Lrule Rrule">CABOMETYX<br/>(N=66)</th><th align="center" class="Botrule Lrule Rrule">Placebo<br/>(N=33)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5" valign="top"><span class="Sub">CI, confidence interval; NE, not evaluable</span></td> </tr> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-122" name="footnote-122">*</a> </dt> <dd>Kaplan-Meier method</dd> <dt> <a href="#footnote-reference-123" name="footnote-123">†</a> </dt> <dd>Stratified Cox proportional hazards model stratified by concurrent somatostatin analog (SSA) use (yes/no) and prior sunitinib therapy (yes/no)</dd> <dt> <a href="#footnote-reference-124" name="footnote-124">‡</a> </dt> <dd>Stratified log-rank test stratified by concurrent somatostatin analog (SSA) use (yes/no) and prior sunitinib therapy (yes/no) (compared to one-sided alpha=0.001)</dd> <dt> <a href="#footnote-reference-125" name="footnote-125">§</a> </dt> <dd>Clopper-Pearson method</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule" colspan="3"><span class="Bold">Progression-Free Survival (PFS)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Number of events (%)</td><td align="center" class="Botrule Rrule">33 (50)</td><td align="center" class="Botrule Rrule">26 (79)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Median (95% CI)<a class="Sup" href="#footnote-122" name="footnote-reference-122">*</a> , in months</td><td align="center" class="Botrule Rrule">13.8 (8.9, 17.0)</td><td align="center" class="Botrule Rrule">3.3 (2.8, 5.7)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hazard Ratio (95% CI)<a class="Sup" href="#footnote-123" name="footnote-reference-123">†</a></td><td align="center" class="Botrule Rrule" colspan="2">0.22 (0.12, 0.41)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   p-value<a class="Sup" href="#footnote-124" name="footnote-reference-124">‡</a></td><td align="center" class="Botrule Rrule" colspan="2">&lt;0.0001</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3"><span class="Bold">Overall Response Rate (ORR)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   ORR (95% CI)<a class="Sup" href="#footnote-125" name="footnote-reference-125">§</a>, %</td><td align="center" class="Botrule Rrule">18 (10, 30)</td><td align="center" class="Botrule Rrule">0 (0, 11)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3"><span class="Bold">Duration of Response (DOR)</span></td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">   Median (95% CI)<a class="Sup" href="#footnote-122">*</a>, in months</td><td align="center" class="Botrule Rrule">11.4 (6.1, NE)</td><td align="center" class="Botrule Rrule">NE</td> </tr> </tbody> </table></div>

Figure 10: Kaplan-Meier Curve of Progression-Free Survival in Patients with pNET in CABINET

Extra-Pancreatic Neuroendocrine Tumors

The efficacy of CABOMETYX for the treatment of extra-pancreatic neuroendocrine tumors (epNET) was evaluated in CABINET (NCT03375320), a randomized, double-blind, placebo- controlled, multicenter study in patients with unresectable, locally advanced or metastatic epNET that had progressed on prior therapy. Eligible patients were required to have been previously treated with at least one FDA approved therapy (everolimus or lutetium Lu 177 dotatate), other than somatostatin analogs. Patients with active brain metastases or cranial epidural disease, and those who had prior treatment with cabozantinib were excluded. The study also excluded patients with clinically significant gastrointestinal (GI) bleeding, GI abnormalities, and tumor with invasion into the GI tract that may increase the risk for GI bleeding or perforation, and patients with tumor invading or encasing major blood vessels. Patients were randomized (2:1) to receive treatment with CABOMETYX 60 mg orally once daily or placebo until disease progression or unacceptable toxicity. Randomization was stratified by concurrent somatostatin analog (SSA) use (yes/no) and primary site (midgut GI/unknown vs non-midgut GI/lung/other). Tumor assessments were performed every 12 weeks. The study included patients with functional and non-functional tumors, and use of somatostatin analogs at a stable dose was permitted for symptom control. Eligible patients randomized to the placebo arm were allowed to crossover to CABOMETYX upon confirmation of progressive disease by blinded real time central review.

The major efficacy outcome measure was progression-free survival (PFS) assessed by blinded independent radiology review committee (BIRC) per RECIST 1.1. Additional efficacy outcome measures included overall response rate (ORR), duration of response (DOR) and overall survival (OS).

A total of 199 epNET patients were randomized (2:1) to receive CABOMETYX 60 mg orally once daily (n=132) or placebo (n=67). The median age was 66 years (range: 28 to 86), 51% were female; 84% were White; 8% were Black or African American; 2.0% were Asian; 6% had race unknown or race not reported; and 8% were Hispanic or Latino. The primary sites of tumor were small bowel (34%) including duodenum, jejunum & ileum; lung (20%); thymus (5%); rectum (6%); cecum (2.0%); stomach (3.0%); non-cecum colon (1.0%); appendix (0.5%); others (18%); and unknown (12%). In the 199 patients with epNET, 46% had received one prior systemic therapy, 29% had received two prior systemic therapies and 25% had received three or more prior systemic therapies.

The trial demonstrated a statistically significant improvement in PFS as assessed by BIRC, for CABOMETYX compared to placebo. An updated OS analysis was conducted when 123 deaths were observed. OS data were not mature with 83 (63%) deaths in CABOMETYX arm and 40 (60%) deaths in placebo arm (OS HR=1.05 [95% CI: 0.71, 1.54]). Thirty-seven percent of placebo arm patients crossed over to open label CABOMETYX, which may impact the OS endpoint.

Efficacy results are summarized in Table 26 and Figure 11.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 26: Efficacy Results in Patients with epNET in CABINET</span> </caption> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="30%"/> <col align="center" valign="middle" width="30%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule"></th><th align="center" class="Botrule Lrule Rrule">CABOMETYX<br/>(N=132)</th><th align="center" class="Botrule Lrule Rrule">Placebo<br/>(N=67)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5" valign="top"><span class="Sub">CI, confidence interval; NE, not evaluable</span></td> </tr> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-126" name="footnote-126">*</a> </dt> <dd>Kaplan-Meier method</dd> <dt> <a href="#footnote-reference-127" name="footnote-127">†</a> </dt> <dd>Stratified Cox proportional hazards model stratified by concurrent somatostatin analog (SSA) use (yes/no) and primary site (midgut GI/unknown vs non-midgut GI/lung/other)</dd> <dt> <a href="#footnote-reference-128" name="footnote-128">‡</a> </dt> <dd>Stratified log-rank test stratified by concurrent somatostatin analog (SSA) use (yes/no) and primary site (midgut GI/unknown vs non-midgut GI/lung/other) (compared to one-sided alpha=0.001)</dd> <dt> <a href="#footnote-reference-129" name="footnote-129">§</a> </dt> <dd>Clopper-Pearson method</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule" colspan="3"><span class="Bold">Progression-Free Survival (PFS)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Number of events (%)</td><td align="center" class="Botrule Rrule">68 (52)</td><td align="center" class="Botrule Rrule">39 (58)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Median (95% CI)<a class="Sup" href="#footnote-126" name="footnote-reference-126">*</a>, in months</td><td align="center" class="Botrule Rrule">8.5 (6.8, 12.5)</td><td align="center" class="Botrule Rrule">4.2 (3.0, 5.7)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   Hazard Ratio (95% CI)<a class="Sup" href="#footnote-127" name="footnote-reference-127">†</a></td><td align="center" class="Botrule Rrule" colspan="2">0.40 (0.26, 0.61)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   p-value<a class="Sup" href="#footnote-128" name="footnote-reference-128">‡</a></td><td align="center" class="Botrule Rrule" colspan="2">&lt;0.0001</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3"><span class="Bold">Overall Response Rate (ORR)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">   ORR (95% CI)<a class="Sup" href="#footnote-129" name="footnote-reference-129">§</a>, %</td><td align="center" class="Botrule Rrule">5 (2.2, 11)</td><td align="center" class="Botrule Rrule">0 (0, 5)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3"><span class="Bold">Duration of Response (DOR)</span></td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule">   Median (95% CI)<a class="Sup" href="#footnote-126">*</a>, in months</td><td align="center" class="Botrule Rrule">8.3 (4.5, NE)</td><td align="center" class="Botrule Rrule">NE</td> </tr> </tbody> </table></div>

Figure 11: Kaplan-Meier Curve of Progression-Free Survival in Patients with epNET in CABINET

CABOMETYX tablets are supplied as follows:

{ "type": "p", "children": [], "text": "CABOMETYX tablets are supplied as follows:" }

60 mg tables are yellow film-coated, oval shaped with no score, debossed with "XL" on one side and "60" on the other side of the tablet; available in: bottle of 30 tablets: NDC 42388-023-26 bottle of 30 tablets packaged in a carton: NDC 42388-023-46

{ "type": "p", "children": [], "text": "60 mg tables are yellow film-coated, oval shaped with no score, debossed with \"XL\" on one side and \"60\" on the other side of the tablet; available in:\n bottle of 30 tablets: NDC 42388-023-26\n bottle of 30 tablets packaged in a carton: NDC 42388-023-46" }

40 mg tablets are yellow film-coated, triangle shaped with no score, debossed with "XL" on one side and "40" on the other side of the tablet; available in: bottle of 30 tablets: NDC 42388-025-26 bottle of 30 tablets packaged in a carton: NDC 42388-025-46

{ "type": "p", "children": [], "text": "40 mg tablets are yellow film-coated, triangle shaped with no score, debossed with \"XL\" on one side and \"40\" on the other side of the tablet; available in:\n bottle of 30 tablets: NDC 42388-025-26\n bottle of 30 tablets packaged in a carton: NDC 42388-025-46" }

20 mg tablets are yellow film-coated, round shaped with no score, debossed with "XL" on one side and "20" on the other side of the tablet; available in: bottle of 30 tablets: NDC 42388-024-26 bottle of 30 tablets packaged in a carton: NDC 42388-024-46

{ "type": "p", "children": [], "text": "20 mg tablets are yellow film-coated, round shaped with no score, debossed with \"XL\" on one side and \"20\" on the other side of the tablet; available in:\n bottle of 30 tablets: NDC 42388-024-26\n bottle of 30 tablets packaged in a carton: NDC 42388-024-46" }

Store CABOMETYX at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store CABOMETYX at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]." }

Advise the patient to read the FDA-approved patient labeling (Patient Information).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Patient Information)." }

{ "type": "ul", "children": [ "\nHemorrhage: Instruct patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual severe bleeding or hemorrhage [see Warnings and Precautions (5.1)].", "\nPerforations and fistulas: Advise patients that gastrointestinal disorders such as diarrhea, nausea, vomiting, and constipation may develop during CABOMETYX treatment and to seek immediate medical attention if they experience persistent or severe abdominal pain because cases of gastrointestinal perforation and fistula have been reported in patients taking CABOMETYX [see Warnings and Precautions (5.2)].", "\nThromboembolic Events: Venous and arterial thrombotic events have been reported. Advise patients to report signs or symptoms of an arterial thrombosis. Venous thromboembolic events including pulmonary embolus have been reported. Advise patients to contact their health care provider if new onset of dyspnea, chest pain, or localized limb edema occurs [see Warnings and Precautions (5.3)].", "\nHypertension and hypertensive crisis: Inform patients of the signs and symptoms of hypertension. Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if they experience signs or symptoms of hypertension [see Warnings and Precautions (5.4)].", "\nDiarrhea: Advise patients to notify their healthcare provider at the first signs of poorly formed or loose stool or an increased frequency of bowel movements [see Warnings and Precautions (5.5)].", "\nPalmar-plantar erythrodysesthesia: Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.6)].", "\nHepatotoxicity: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding [see Warnings and Precautions (5.7)].", "\nAdrenal insufficiency: Advise patients receiving with nivolumab to contact their healthcare provider immediately for signs or symptoms of adrenal insufficiency [see Warnings and Precautions (5.8)].", "\nProteinuria: Advise patients to contact their healthcare provider for signs or symptoms of proteinuria [see Warnings and Precautions (5.9)].", "\nOsteonecrosis of the jaw: Advise patients regarding good oral hygiene practices. Advise patients to immediately contact their healthcare provider for signs or symptoms associated with osteonecrosis of the jaw [see Warnings and Precautions (5.10)].", "\nImpaired wound healing: Advise patients that CABOMETYX may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Dosage and Administration (2.1), Warnings and Precautions (5.11)].", "\nReversible posterior leukoencephalopathy syndrome: Advise patients to immediately contact their health care provider for new onset or worsening neurological function [see Warnings and Precautions (5.12)].", "\nThyroid dysfunction: Advise patients that CABOMETYX can cause thyroid dysfunction and that their thyroid function should be monitored regularly during treatment. Advise patients to immediately contact their healthcare provider for signs or symptoms of thyroid dysfunction [see Warnings and Precautions (5.13)].", "\nHypocalcemia: Advise patients that CABOMETYX can cause low calcium levels and that their serum calcium levels should be monitored regularly during treatment. Advise patients to immediately contact their healthcare provider for signs or symptoms of hypocalcemia [see Warnings and Precautions (5.14)].", "\nEmbryo-fetal toxicity:\nAdvise females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.15), Use in Specific Populations (8.1)].\nAdvise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the final dose [Use in Specific Populations (8.3)].\n\n", "\nLactation: Advise women not to breastfeed during treatment with CABOMETYX and for 4 months following the last dose [Use in Specific Populations (8.2)].", "\nDrug interactions: Advise patients to inform their healthcare provider of all prescription or nonprescription medications, vitamins or herbal products. Inform patients to avoid grapefruit, grapefruit juice, and St. John’s wort [see Drug Interactions (7.1)]." ], "text": "" }

Important administration information

{ "type": "p", "children": [], "text": "\nImportant administration information\n" }

{ "type": "ul", "children": [ "Instruct patients to take CABOMETYX on an empty stomach, at least 1 hour before or at least 2 hours after eating." ], "text": "" }

Manufactured for Exelixis, Inc. Alameda, CA 94502

{ "type": "p", "children": [], "text": "Manufactured for Exelixis, Inc. Alameda, CA 94502" }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="60%"/> <col align="right" valign="bottom" width="40%"/> <tfoot> <tr class="First Last"> <td align="left" valign="top"><span class="Sub">This Patient Information has been approved by the U.S. Food and Drug Administration.</span></td><td align="right" valign="top"><span class="Sub">Revised: 03/2025</span></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule" colspan="2"><span class="Bold">PATIENT INFORMATION<br/>CABOMETYX<span class="Sup">®</span> (Ka-boe-met-iks)<br/>cabozantinib<br/> tablets</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2">If your healthcare provider prescribes CABOMETYX in combination with nivolumab, also read the Medication Guide that comes with nivolumab.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2"><span class="Bold">What is CABOMETYX?</span> <br/>CABOMETYX is a prescription medicine used to treat:<ul> <li>people with advanced kidney cancer (renal cell carcinoma). CABOMETYX may be used:<ul> <li>alone to treat people with renal cell carcinoma (RCC) that has spread (advanced RCC).</li> <li>in combination with nivolumab when your cancer has spread (advanced RCC), and you have not already had treatment for your advanced RCC.</li> </ul> </li> <li>people with liver cancer (hepatocellular carcinoma) who have been previously treated with the medicine sorafenib.</li> <li>adults and children 12 years of age and older who have a type of thyroid cancer called differentiated thyroid cancer (DTC), that has spread (locally advanced or metastatic), <span class="Bold">and</span>,<ul> <li>has progressed after treatment with a VEGFR-targeted treatment, <span class="Bold">and</span> </li> <li>your DTC can no longer be treated with radioactive iodine, or you are not able to receive radioactive iodine treatment</li> </ul> </li> <li>adults and children 12 years of age and older who have a type of cancer called pancreatic neuroendocrine tumors (pNET) or extra-pancreatic neuroendocrine tumors (epNET) that has been previously treated, cannot be treated by surgery, and has spread (locally advanced or metastatic).</li> </ul> It is not known if CABOMETYX is safe and effective in children younger than 12 years of age.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2"><span class="Bold">Before you take CABOMETYX,</span> tell your healthcare provider about all of your medical conditions, including if you:<ul> <li>have had a liver problem other than liver cancer</li> <li>have a recent history of bleeding, including coughing up or vomiting blood, or black tarry stools.</li> <li>have an open or healing wound</li> <li>have high blood pressure</li> <li>have a low calcium level in your blood (hypocalcemia)</li> <li>plan to have any surgery, dental procedure, or have had a recent surgery. You should stop taking CABOMETYX at least 3 weeks before planned surgery. See "<span class="Bold">What are the possible side effects of CABOMETYX?</span>"</li> <li>are pregnant, or plan to become pregnant. CABOMETYX can harm your unborn baby.<ul> <li>If you are able to become pregnant, your healthcare provider will check your pregnancy status before you start treatment with CABOMETYX.</li> <li>Females who are able to become pregnant should use effective birth control (contraception) during treatment and for 4 months after your last dose of CABOMETYX.</li> <li>Talk to your healthcare provider about birth control methods that may be right for you.</li> <li>If you become pregnant or think you are pregnant, tell your healthcare provider right away.</li> </ul> </li> <li>are breastfeeding or plan to breastfeed. It is not known if CABOMETYX passes into your breast milk. Do not breastfeed during treatment and for 4 months after your last dose of CABOMETYX.</li> </ul> <span class="Bold">Tell your healthcare provider about all the medicines you take,</span> including prescription or over-the-counter medicines, vitamins, and herbal supplements. CABOMETYX and certain other medicines may affect each other causing side effects.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2"><span class="Bold">How should I take CABOMETYX?</span> <ul> <li>Take CABOMETYX exactly as your healthcare provider tells you to take it.</li> <li> <span class="Bold">Do not</span> take CABOMETYX with food. Take CABOMETYX at least 1 hour before or at least 2 hours after eating.</li> <li>Swallow CABOMETYX tablets whole.</li> <li> <span class="Bold">Do not</span> crush, chew or split CABOMETYX tablets.</li> <li>If you miss a dose and your next scheduled dose is in less than 12 hours, take your next dose at the normal time. Do not make up the missed dose. </li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2"><span class="Bold">What should I avoid while taking CABOMETYX?</span> <br/> Avoid drinking grapefruit juice, eating grapefruit or taking supplements that contain grapefruit or St. John’s wort during treatment with CABOMETYX.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2"><span class="Bold">What are the possible side effects of CABOMETYX?</span> <br/> <span class="Bold">CABOMETYX may cause serious side effects, including:</span> <ul> <li> <span class="Bold">bleeding (hemorrhage).</span> CABOMETYX can cause severe bleeding that may lead to death. Tell your healthcare provider right away if you get any signs of bleeding during treatment with CABOMETYX, including:<ul> <li>coughing up blood or blood clots</li> <li>vomiting blood or if your vomit looks like coffee-grounds</li> <li>red or black (looks like tar) stools</li> <li>menstrual bleeding that is heavier than normal</li> <li>any unusual or heavy bleeding</li> </ul> </li> <li> <span class="Bold">a tear in your stomach or intestinal wall (perforation) or an abnormal connection between 2 parts of your body (fistula).</span> Tell your healthcare provider right away if you get tenderness or pain in your stomach-area (abdomen) that is severe or that does not go away.</li> <li> <span class="Bold">blood clots, stroke, heart attack, and chest pain.</span> Get emergency help right away if you get:<ul> <li>swelling or pain in your arms or legs </li> <li>shortness of breath</li> <li>feel lightheaded or faint</li> <li>sweating more than usual</li> <li>numbness or weakness of your face, arm or leg, especially on one side of your body</li> <li>sudden confusion, trouble speaking or understanding</li> <li>sudden trouble seeing in one or both eyes</li> <li>sudden trouble walking</li> <li>dizziness, loss of balance or coordination</li> <li>a sudden severe headache</li> </ul> </li> <li> <span class="Bold">high blood pressure (hypertension).</span> Hypertension is common with CABOMETYX and sometimes can be severe. Your healthcare provider will check your blood pressure before starting CABOMETYX and regularly during treatment with CABOMETYX. If needed, your healthcare provider may prescribe medicine to treat your high blood pressure. Tell your healthcare provider if you develop severe headaches, nose bleeds, tiredness or confusion, vision changes, chest pain, trouble breathing, irregular heartbeat, or blood in your urine.</li> <li> <span class="Bold">diarrhea.</span> Diarrhea is common with CABOMETYX and can be severe. If needed, your healthcare provider may prescribe medicine to treat your diarrhea. Tell your healthcare provider right away if you have frequent loose, watery bowel movements.</li> <li> <span class="Bold">a skin problem called hand-foot skin reaction.</span> Hand-foot skin reactions are common with CABOMETYX and can be severe. Tell your healthcare provider right away if you have rashes, redness, pain, swelling, or blisters on the palms of your hands or soles of your feet.</li> <li> <span class="Bold">liver problems.</span> Liver problems may happen during treatment with CABOMETYX. When CABOMETYX is taken in combination with nivolumab, severe changes in liver function tests may happen more often than if you take CABOMETYX alone. Your healthcare provider will do blood tests to check your liver function before and during treatment with CABOMETYX. Tell your healthcare provider right away if you develop symptoms of liver problems including: yellowing of your skin or the whites of your eyes, severe nausea or vomiting, pain on the right side of your stomach-area (abdomen), dark urine, bleeding or bruising more easily than normal.</li> <li> <span class="Bold">adrenal gland problems.</span> Your healthcare provider will monitor you for this problem. Your healthcare provider may prescribe hormone replacement therapy or corticosteroid medicines if needed. Tell your healthcare provider right away if you develop any of the following signs or symptoms: extreme tiredness, dizziness or fainting, weakness, nausea, or vomiting.</li> <li> <span class="Bold">protein in your urine and possible kidney problems.</span> Symptoms may include swelling in your hands, arms, legs, or feet. Your healthcare provider will check you for this problem during treatment with CABOMETYX.</li> <li> <span class="Bold">severe jaw bone problems (osteonecrosis).</span> Your healthcare provider should examine your mouth before you start and during treatment with CABOMETYX. Tell your dentist that you are taking CABOMETYX. It is important for you to practice good mouth care during treatment with CABOMETYX. Tell your healthcare provider right away if you develop any symptoms of jaw problems, including: jaw pain, toothache, or sores on your gums.</li> <li> <span class="Bold">wound healing problems.</span> Wound healing problems have happened in some people who take CABOMETYX. Tell your healthcare provider if you plan to have any surgery before or during treatment with CABOMETYX.<ul> <li>You should stop taking CABOMETYX at least 3 weeks before planned surgery.</li> <li>Your healthcare provider should tell you when you may start taking CABOMETYX again after surgery.</li> </ul> </li> <li> <span class="Bold">Reversible Posterior Leukoencephalopathy Syndrome (RPLS).</span> A condition called reversible posterior leukoencephalopathy syndrome can happen during treatment with CABOMETYX. Tell your healthcare provider right away if you have headaches, seizures, confusion, changes in vision, or problems thinking.</li> <li> <span class="Bold">change in thyroid function.</span> CABOMETYX can cause changes in your thyroid function, including changes to thyroid hormone levels in your blood. Your healthcare provider will do blood tests to check your thyroid function before and during treatment with CABOMETYX.</li> <li> <span class="Bold">decreased calcium level in your blood (hypocalcemia)</span>. CABOMETYX can cause you to have a decreased amount of calcium in your blood. Your healthcare provider will do blood tests to check you for this problem and give you calcium if needed. <span class="Bold">Tell your healthcare provider right away if you get any of the following signs or symptoms:</span> <ul> <li>muscle stiffness or muscle spasms</li> <li>numbness or tingling in your fingers, toes, or around your mouth</li> <li>seizures</li> <li>sudden weight gain</li> <li>swelling of your arms, hands, legs, and ankles</li> </ul> </li> </ul>Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with CABOMETYX if you have certain side effects.<br/> <br/> <span class="Bold">The most common side effects of CABOMETYX include:</span> <ul> <li>tiredness</li> <li>nausea and vomiting</li> <li>constipation</li> <li>decreased appetite</li> <li>weight decreased</li> </ul> <span class="Bold">The most common side effects of CABOMETYX when used in combination with nivolumab include:</span> <ul> <li>tiredness</li> <li>mouth sores</li> <li>rash</li> <li>low thyroid hormone levels (hypothyroidism)</li> <li>pain in muscles, bones, and joints</li> <li>decreased appetite</li> <li>nausea</li> <li>changes in the way things taste</li> <li>stomach-area (abdominal) pain</li> <li>cough</li> <li>upper respiratory tract infection</li> </ul> CABOMETYX may cause fertility problems in females and males, which may affect your ability to have children. Talk to your healthcare provider if you have concerns about fertility.<br/>These are not all of the possible side effects of CABOMETYX. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2"><span class="Bold">How should I store CABOMETYX?</span> <ul> <li>Store CABOMETYX at room temperature between 68°F to 77°F (20°C to 25°C).</li> </ul> <span class="Bold">Keep CABOMETYX and all medicines out of the reach of children.</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2"><span class="Bold">General information about the safe and effective use of CABOMETYX.</span> <br/>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use CABOMETYX for a condition for which it was not prescribed. Do not give CABOMETYX to other people, even if they have the same symptoms you have. It may harm them.<br/>You can ask your pharmacist or healthcare provider for information about CABOMETYX that is written for health professionals.</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" colspan="2"><span class="Bold">What are the ingredients in CABOMETYX?</span> <br/> <span class="Bold">Active ingredient:</span> cabozantinib<br/> <span class="Bold">Inactive ingredients:</span> microcrystalline cellulose, lactose anhydrous, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. The film coating contains hypromellose, titanium dioxide, triacetin, and iron oxide yellow.<br/> <br/> <span class="Sup">Manufactured for Exelixis, Inc. Alameda, CA 94502</span> <br/> <span class="Sup">For more information, go to www.cabometyx.com or call 1-855-292-3935.</span></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"60%\"/>\n<col align=\"right\" valign=\"bottom\" width=\"40%\"/>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" valign=\"top\"><span class=\"Sub\">This Patient Information has been approved by the U.S. Food and Drug Administration.</span></td><td align=\"right\" valign=\"top\"><span class=\"Sub\">Revised: 03/2025</span></td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">PATIENT INFORMATION<br/>CABOMETYX<span class=\"Sup\">®</span> (Ka-boe-met-iks)<br/>cabozantinib<br/> tablets</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\">If your healthcare provider prescribes CABOMETYX in combination with nivolumab, also read the Medication Guide that comes with nivolumab.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">What is CABOMETYX?</span>\n<br/>CABOMETYX is a prescription medicine used to treat:<ul>\n<li>people with advanced kidney cancer (renal cell carcinoma). CABOMETYX may be used:<ul>\n<li>alone to treat people with renal cell carcinoma (RCC) that has spread (advanced RCC).</li>\n<li>in combination with nivolumab when your cancer has spread (advanced RCC), and you have not\nalready had treatment for your advanced RCC.</li>\n</ul>\n</li>\n<li>people with liver cancer (hepatocellular carcinoma) who have been previously treated with the\nmedicine sorafenib.</li>\n<li>adults and children 12 years of age and older who have a type of thyroid cancer called differentiated thyroid cancer (DTC), that has spread (locally advanced or metastatic), <span class=\"Bold\">and</span>,<ul>\n<li>has progressed after treatment with a VEGFR-targeted treatment, <span class=\"Bold\">and</span>\n</li>\n<li>your DTC can no longer be treated with radioactive iodine, or you are not able to receive\nradioactive iodine treatment</li>\n</ul>\n</li>\n<li>adults and children 12 years of age and older who have a type of cancer called pancreatic\nneuroendocrine tumors (pNET) or extra-pancreatic neuroendocrine tumors (epNET) that has been previously treated, cannot be treated by surgery, and has spread (locally advanced or metastatic).</li>\n</ul>\n It is not known if CABOMETYX is safe and effective in children younger than 12 years of age.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Before you take CABOMETYX,</span> tell your healthcare provider about all of your medical conditions, including if you:<ul>\n<li>have had a liver problem other than liver cancer</li>\n<li>have a recent history of bleeding, including coughing up or vomiting blood, or black tarry stools.</li>\n<li>have an open or healing wound</li>\n<li>have high blood pressure</li>\n<li>have a low calcium level in your blood (hypocalcemia)</li>\n<li>plan to have any surgery, dental procedure, or have had a recent surgery. You should stop taking CABOMETYX at least 3 weeks before planned surgery. See \"<span class=\"Bold\">What are the possible side effects of CABOMETYX?</span>\"</li>\n<li>are pregnant, or plan to become pregnant. CABOMETYX can harm your unborn baby.<ul>\n<li>If you are able to become pregnant, your healthcare provider will check your pregnancy status before you start treatment with CABOMETYX.</li>\n<li>Females who are able to become pregnant should use effective birth control (contraception) during treatment and for 4 months after your last dose of CABOMETYX.</li>\n<li>Talk to your healthcare provider about birth control methods that may be right for you.</li>\n<li>If you become pregnant or think you are pregnant, tell your healthcare provider right away.</li>\n</ul>\n</li>\n<li>are breastfeeding or plan to breastfeed. It is not known if CABOMETYX passes into your breast milk. Do not breastfeed during treatment and for 4 months after your last dose of CABOMETYX.</li>\n</ul>\n<span class=\"Bold\">Tell your healthcare provider about all the medicines you take,</span> including prescription or over-the-counter medicines, vitamins, and herbal supplements. CABOMETYX and certain other medicines may affect each other causing side effects.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">How should I take CABOMETYX?</span>\n<ul>\n<li>Take CABOMETYX exactly as your healthcare provider tells you to take it.</li>\n<li>\n<span class=\"Bold\">Do not</span> take CABOMETYX with food. Take CABOMETYX at least 1 hour before or at least 2 hours after eating.</li>\n<li>Swallow CABOMETYX tablets whole.</li>\n<li>\n<span class=\"Bold\">Do not</span> crush, chew or split CABOMETYX tablets.</li>\n<li>If you miss a dose and your next scheduled dose is in less than 12 hours, take your next dose at the normal time. Do not make up the missed dose.\n </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">What should I avoid while taking CABOMETYX?</span>\n<br/>\n Avoid drinking grapefruit juice, eating grapefruit or taking supplements that contain grapefruit or St. John’s wort during treatment with CABOMETYX.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">What are the possible side effects of CABOMETYX?</span>\n<br/>\n<span class=\"Bold\">CABOMETYX may cause serious side effects, including:</span>\n<ul>\n<li>\n<span class=\"Bold\">bleeding (hemorrhage).</span> CABOMETYX can cause severe bleeding that may lead to death. Tell your healthcare provider right away if you get any signs of bleeding during treatment with CABOMETYX, including:<ul>\n<li>coughing up blood or blood clots</li>\n<li>vomiting blood or if your vomit looks like coffee-grounds</li>\n<li>red or black (looks like tar) stools</li>\n<li>menstrual bleeding that is heavier than normal</li>\n<li>any unusual or heavy bleeding</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">a tear in your stomach or intestinal wall (perforation) or an abnormal connection between 2 parts of your body (fistula).</span> Tell your healthcare provider right away if you get tenderness or pain in your stomach-area (abdomen) that is severe or that does not go away.</li>\n<li>\n<span class=\"Bold\">blood clots, stroke, heart attack, and chest pain.</span> Get emergency help right away if you get:<ul>\n<li>swelling or pain in your arms or legs </li>\n<li>shortness of breath</li>\n<li>feel lightheaded or faint</li>\n<li>sweating more than usual</li>\n<li>numbness or weakness of your face, arm or leg, especially on one side of your body</li>\n<li>sudden confusion, trouble speaking or understanding</li>\n<li>sudden trouble seeing in one or both eyes</li>\n<li>sudden trouble walking</li>\n<li>dizziness, loss of balance or coordination</li>\n<li>a sudden severe headache</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">high blood pressure (hypertension).</span> Hypertension is common with CABOMETYX and sometimes can be severe. Your healthcare provider will check your blood pressure before starting CABOMETYX and regularly during treatment with CABOMETYX. If needed, your healthcare provider may prescribe medicine to treat your high blood pressure. Tell your healthcare provider if you develop severe headaches, nose bleeds, tiredness or confusion, vision changes, chest pain, trouble breathing, irregular heartbeat, or blood in your urine.</li>\n<li>\n<span class=\"Bold\">diarrhea.</span> Diarrhea is common with CABOMETYX and can be severe. If needed, your healthcare provider may prescribe medicine to treat your diarrhea. Tell your healthcare provider right away if you have frequent loose, watery bowel movements.</li>\n<li>\n<span class=\"Bold\">a skin problem called hand-foot skin reaction.</span> Hand-foot skin reactions are common with CABOMETYX and can be severe. Tell your healthcare provider right away if you have rashes, redness, pain, swelling, or blisters on the palms of your hands or soles of your feet.</li>\n<li>\n<span class=\"Bold\">liver problems.</span> Liver problems may happen during treatment with CABOMETYX. When CABOMETYX is taken in combination with nivolumab, severe changes in liver function tests may happen more often than if you take CABOMETYX alone. Your healthcare provider will do blood tests to check your liver function before and during treatment with CABOMETYX. Tell your healthcare provider right away if you develop symptoms of liver problems including: yellowing of your skin or the whites of your eyes, severe nausea or vomiting, pain on the right side of your stomach-area (abdomen), dark urine, bleeding or bruising more easily than normal.</li>\n<li>\n<span class=\"Bold\">adrenal gland problems.</span> Your healthcare provider will monitor you for this problem. Your healthcare provider may prescribe hormone replacement therapy or corticosteroid medicines if needed. Tell your healthcare provider right away if you develop any of the following signs or symptoms: extreme tiredness, dizziness or fainting, weakness, nausea, or vomiting.</li>\n<li>\n<span class=\"Bold\">protein in your urine and possible kidney problems.</span> Symptoms may include swelling in your hands, arms, legs, or feet. Your healthcare provider will check you for this problem during treatment with CABOMETYX.</li>\n<li>\n<span class=\"Bold\">severe jaw bone problems (osteonecrosis).</span> Your healthcare provider should examine your mouth before you start and during treatment with CABOMETYX. Tell your dentist that you are taking CABOMETYX. It is important for you to practice good mouth care during treatment with CABOMETYX. Tell your healthcare provider right away if you develop any symptoms of jaw problems, including: jaw pain, toothache, or sores on your gums.</li>\n<li>\n<span class=\"Bold\">wound healing problems.</span> Wound healing problems have happened in some people who take CABOMETYX. Tell your healthcare provider if you plan to have any surgery before or during treatment with CABOMETYX.<ul>\n<li>You should stop taking CABOMETYX at least 3 weeks before planned surgery.</li>\n<li>Your healthcare provider should tell you when you may start taking CABOMETYX again after surgery.</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">Reversible Posterior Leukoencephalopathy Syndrome (RPLS).</span> A condition called reversible posterior leukoencephalopathy syndrome can happen during treatment with CABOMETYX. Tell your healthcare provider right away if you have headaches, seizures, confusion, changes in vision, or problems thinking.</li>\n<li>\n<span class=\"Bold\">change in thyroid function.</span> CABOMETYX can cause changes in your thyroid function, including changes to thyroid hormone levels in your blood. Your healthcare provider will do blood tests to check your thyroid function before and during treatment with CABOMETYX.</li>\n<li>\n<span class=\"Bold\">decreased calcium level in your blood (hypocalcemia)</span>. CABOMETYX can cause you to have a decreased amount of calcium in your blood. Your healthcare provider will do blood tests to check you for this problem and give you calcium if needed. <span class=\"Bold\">Tell your healthcare provider right away if you get any of the following signs or symptoms:</span>\n<ul>\n<li>muscle stiffness or muscle spasms</li>\n<li>numbness or tingling in your fingers, toes, or around your mouth</li>\n<li>seizures</li>\n<li>sudden weight gain</li>\n<li>swelling of your arms, hands, legs, and ankles</li>\n</ul>\n</li>\n</ul>Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with CABOMETYX if you have certain side effects.<br/>\n<br/>\n<span class=\"Bold\">The most common side effects of CABOMETYX include:</span>\n<ul>\n<li>tiredness</li>\n<li>nausea and vomiting</li>\n<li>constipation</li>\n<li>decreased appetite</li>\n<li>weight decreased</li>\n</ul>\n<span class=\"Bold\">The most common side effects of CABOMETYX when used in combination with nivolumab include:</span>\n<ul>\n<li>tiredness</li>\n<li>mouth sores</li>\n<li>rash</li>\n<li>low thyroid hormone levels (hypothyroidism)</li>\n<li>pain in muscles, bones, and joints</li>\n<li>decreased appetite</li>\n<li>nausea</li>\n<li>changes in the way things taste</li>\n<li>stomach-area (abdominal) pain</li>\n<li>cough</li>\n<li>upper respiratory tract infection</li>\n</ul>\n CABOMETYX may cause fertility problems in females and males, which may affect your ability to have children. Talk to your healthcare provider if you have concerns about fertility.<br/>These are not all of the possible side effects of CABOMETYX. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">How should I store CABOMETYX?</span>\n<ul>\n<li>Store CABOMETYX at room temperature between 68°F to 77°F (20°C to 25°C).</li>\n</ul>\n<span class=\"Bold\">Keep CABOMETYX and all medicines out of the reach of children.</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">General information about the safe and effective use of CABOMETYX.</span>\n<br/>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use CABOMETYX for a condition for which it was not prescribed. Do not give CABOMETYX to other people, even if they have the same symptoms you have. It may harm them.<br/>You can ask your pharmacist or healthcare provider for information about CABOMETYX that is written for health professionals.</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">What are the ingredients in CABOMETYX?</span>\n<br/>\n<span class=\"Bold\">Active ingredient:</span> cabozantinib<br/>\n<span class=\"Bold\">Inactive ingredients:</span> microcrystalline cellulose, lactose anhydrous, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. The film coating contains hypromellose, titanium dioxide, triacetin, and iron oxide yellow.<br/>\n<br/>\n<span class=\"Sup\">Manufactured for Exelixis, Inc. Alameda, CA 94502</span>\n<br/>\n<span class=\"Sup\">For more information, go to www.cabometyx.com or call 1-855-292-3935.</span></td>\n</tr>\n</tbody>\n</table></div>" }

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Cabometyx® (cabozantinib) tablets 60 mg*

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Rx Only30 tabletsExelixis®

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Package Label - Bottle - 30 Tablets - 40mg CABOMETYX - Made in Canada

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NDC 42388-025-26

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Cabometyx® (cabozantinib) tablets 40 mg*

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Rx Only30 tabletsExelixis®

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Package Label - Bottle - 30 Tablets - 20mg CABOMETYX - Made in Canada

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NDC 42388-024-26

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Cabometyx® (cabozantinib) tablets 20 mg*

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Rx Only30 tabletsExelixis®

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Package Label - Professional Sample - Bottle - 15 Tablets - 60mg CABOMETYX

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PROFESSIONAL SAMPLE - NOT FOR SALE

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NDC 42388-023-37

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Cabometyx® (cabozantinib) tablets 60 mg*

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Rx Only15 tabletsExelixis®

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Package Label - Professional Sample - Bottle - 15 Tablets - 40mg CABOMETYX

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NDC 42388-025-37

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Cabometyx® (cabozantinib) tablets 40 mg*

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Rx Only15 tabletsExelixis®

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Package Label - Professional Sample - Bottle - 15 Tablets - 20mg CABOMETYX

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Cabometyx® (cabozantinib) tablets 20 mg*

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Rx Only15 tabletsExelixis®

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Package Label - Bottle - 30 Tablets - 60mg CABOMETYX - Made in Germany

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Cabometyx® (cabozantinib) tablets 60 mg*

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Rx Only30 tabletsExelixis®

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Package Label - Bottle - 30 Tablets - 40mg CABOMETYX - Made in Germany

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NDC 42388-025-26

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Cabometyx® (cabozantinib) tablets 40 mg*

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Rx Only30 tabletsExelixis®

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Package Label - Bottle - 30 Tablets - 20mg CABOMETYX - Made in Germany

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NDC 42388-024-26

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Cabometyx® (cabozantinib) tablets 20 mg*

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Rx Only30 tabletsExelixis®

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Package Carton - 30 Tablets - 60mg CABOMETYX - Made in Canada

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NDC 42388-023-46

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Cabometyx® (cabozantinib) tablets 60 mg*

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Rx Only30 tabletsExelixis®

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Package Carton - 30 Tablets - 40mg CABOMETYX - Made in Canada

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Cabometyx® (cabozantinib) tablets 20 mg*

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Rx Only30 tabletsExelixis®

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Package Carton - Professional Sample - 15 Tablets - 60mg CABOMETYX

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Rx Only15 tabletsExelixis®

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Rx Only15 tabletsExelixis®

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Package Carton - Professional Sample - 15 Tablets - 20mg CABOMETYX

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Cabometyx® (cabozantinib) tablets 20 mg*

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Rx Only15 tabletsExelixis®

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Package Carton - 30 Tablets - 60mg CABOMETYX - Made in Germany

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Cabometyx® (cabozantinib) tablets 60 mg*

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Rx Only30 tabletsExelixis®

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Package Carton - 30 Tablets - 40mg CABOMETYX - Made in Germany

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Rx Only30 tabletsExelixis®

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Package Carton - 30 Tablets - 20mg CABOMETYX - Made in Germany

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Rx Only30 tabletsExelixis®

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