CABOZANTINIB S-MALATE: 39,270 Adverse Event Reports & Safety Profile

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, (2 S )-hydroxybutanedioate. The molecular formula is C 28 H 24 FN 3 O 5

• C 4 H 6 O 5 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. 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.

AND USAGE CABOMETYX is a kinase inhibitor indicated for the treatment of patients with advanced renal cell carcinoma (RCC). ( 1.1 ) patients with advanced renal cell carcinoma, as a first-line treatment in combination with nivolumab ( 1.1 ) patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib ( 1.2 ) 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 ( 1.3 ) adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic neuroendocrine tumors (pNET). ( 1.4 ) 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). ( 1.4 )

1.1 Renal Cell Carcinoma 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.

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

1.3 Differentiated Thyroid Cancer 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.

1.4 Neuroendocrine Tumors 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).

AND ADMINISTRATION Do NOT substitute CABOMETYX tablets with cabozantinib capsules. ( 2.1 ) Administer on an empty stomach at least 1 hour before or at least 2 hours after eating. ( 2.2 ) Stop treatment with CABOMETYX at least 3 weeks prior to scheduled surgery, including dental surgery. ( 2.1 )

Recommended

Dose: RCC (Single Agent): 60 mg orally, once daily. ( 2.2 ) RCC (Combination Therapy): 40 mg orally, once daily with: 240 mg nivolumab every 2 weeks by intravenous infusion; -OR- 480 mg nivolumab every 4 weeks by intravenous infusion; -OR- 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks administered subcutaneously; -OR- 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks administered subcutaneously. ( 2.2 ) HCC: 60 mg orally, once daily. ( 2.2 ) DTC, pNET, epNET Adult patients and pediatric patients 12 years of age and older with bodyweight greater than or equal to 40 kg: 60 mg orally once daily. ( 2.2 ) Pediatric patients 12 years of age and older with bodyweight less than 40 kg: 40 mg orally once daily. (2.2)

2.1 Important Dosage Information and Recommended Evaluation and Testing Before Initiating CABOMETYX Do not substitute CABOMETYX tablets with cabozantinib capsules. Stop treatment with CABOMETYX 3 weeks prior to scheduled surgery, including dental surgery to reduce the risk of hemorrhage. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1 , 5.11 , 5.12) ]</span> .

2.2 Recommended Dosage Administer CABOMETYX on an empty stomach. Administer at least 1 hour before or at least 2 hours after eating <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Swallow CABOMETYX tablets whole. Do not crush, chew, or split CABOMETYX tablets. Do not take a missed dose within 12 hours of the next dose. Modify the CABOMETYX dose for patients taking drugs known to moderately or strongly induce CYP3A4 or strongly inhibit CYP3A4 and for patients with moderate hepatic impairment <span class="opacity-50 text-xs">[see Dosage and Administration (2.4 , 2.5 , 2.6) ]</span> . The recommended dosages of CABOMETYX are presented in Table 1.

Table

1.

Recommended

Dosage for CABOMETYX Indication Recommended Dosage Duration Renal Cell Carcinoma Single Agent 60 mg orally once daily Until disease progression or unacceptable toxicity Combination Therapy 40 mg orally once daily in combination with: 240 mg nivolumab every 2 weeks (30- minute intravenous infusion); -OR- 480 mg nivolumab every 4 weeks (30- minute intravenous infusion); -OR- 600 mg nivolumab and 10,000 units hyaluronidase administered subcutaneously over approximately 3-5 minutes every 2 weeks; -OR- 1,200 mg nivolumab and 20,000 units hyaluronidase administered subcutaneously over approximately 3-5 minutes every 4 weeks CABOMETYX Until disease progression or unacceptable toxicity Nivolumab -OR- nivolumab and hyaluronidase Until disease progression or unacceptable toxicity for up to 2 years Hepatocellular Carcinoma 60 mg orally once daily Until disease progression or unacceptable toxicity Differentiated Thyroid Cancer and Neuroendocrine Tumors Adult Patients and Pediatric Patients 12 years of age and older with bodyweight greater than or equal to 40 kg: 60 mg orally once daily Pediatric patients 12 years of age and older with bodyweight less than 40 kg: 40 mg orally once daily Until disease progression or unacceptable toxicity

2.3 Dosage Modifications for Adverse Reactions Withhold CABOMETYX for: Intolerable Grade 2 adverse reactions Grade 3 or 4 adverse reactions Osteonecrosis of the jaw Upon resolution/improvement (i.e., return to baseline or resolution to Grade 1) of an adverse reaction, reduce the dose as follows: Table 2.

Recommended Dosage

Reductions for CABOMETYX for Adverse Reactions Recommended Dosage First Dosage Reduction To Second Dosage Reduction To CABOMETYX 60 mg daily in adult and pediatric patients 12 years of age and older with bodyweight greater than or equal to 40 kg 40 mg daily 20 mg daily If previously receiving lowest dose, resume at same dose. If lowest dose not tolerated, discontinue CABOMETYX. CABOMETYX 40 mg daily in pediatric patients 12 years of age and older with bodyweight less than 40 kg 20 mg daily 20 mg every other day CABOMETYX 40 mg daily in combination with nivolumab 20 mg daily 20 mg every other day Table 3.

Recommended Dosage

Modifications for CABOMETYX Adverse Reactions Adverse Reaction Severity Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0)

Cabometyx

Dosage Modification Hemorrhage [see Warnings and Precautions (5.1) ]

Grade

3 or 4 Permanently discontinue CABOMETYX Perforations and Fistulas [see Warnings and Precautions (5.2) ] Any grade gastrointestinal perforation or Grade 4 fistula Permanently discontinue CABOMETYX Thromboembolic Events [see Warnings and Precautions (5.3) ] Any grade acute myocardial infarction or Grade 2 or higher cerebral infarction or Grade 3 or 4 arterial thromboembolic events or Grade 4 venous thromboembolic events Permanently discontinue CABOMETYX Hypertension and Hypertensive Crisis [see Warnings and Precautions (5.4) ]

Grade

3 Withhold CABOMETYX until hypertension is adequately controlled to ≤Grade 2 Resume at reduced dose Permanently discontinue CABOMETYX for hypertension that cannot be controlled Grade 4 Permanently discontinue CABOMETYX Diarrhea [see Warnings and Precautions (5.6) ]

Grade

2, Grade 3, or Grade 4 Withhold CABOMETYX until ≤Grade 1 Resume at reduced dose Palmar-Plantar Erythrodysesthesia [see Warnings and Precautions (5.7) ]

Intolerable Grade

2 or Grade 3 Withhold CABOMETYX until ≤Grade 1 Resume at reduced dose Proteinuria [see Warnings and Precautions (5.10) ]

Grade

2 or 3 Withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria Resume at a reduced dose Permanently discontinue CABOMETYX for nephrotic syndrome Osteonecrosis of the jaw (ONJ) [see Warnings and Precautions (5.11) ] Any grade Withhold CABOMETYX for development of ONJ until complete resolution Resume at reduced dose Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.13) ] Any grade Permanently discontinue CABOMETYX Other Adverse Reactions [see Adverse Reactions (6.1) ]

Intolerable Grade

2, or Grade 3, or Grade 4 Withhold CABOMETYX until improvement to baseline or ≤Grade 1 Resume at reduced dose or permanently discontinue depending on severity 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: Table 4.

Recommended Specific Dosage

Modifications for Hepatic Adverse Reactions for Combination CABOMETYX in combination with nivolumab ALT or AST >3 times ULN but ≤10 times ULN with concurrent total bilirubin <2 times ULN Withhold Consider corticosteroid therapy for hepatic adverse reactions if CABOMETYX is withheld or discontinued when administered in combination with nivolumab both CABOMETYX and nivolumab until adverse reactions recover 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. to Grades 0 or 1 ALT or AST >10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN Permanently discontinue both CABOMETYX and nivolumab When administering CABOMETYX in combination with nivolumab for the treatment of advanced RCC, refer to the nivolumab prescribing information.

2.4 Dosage Modifications for Coadministration with Strong CYP3A4 Inhibitors 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 <span class="opacity-50 text-xs">[see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ]</span> .

2.5 Dosage Modifications for Coadministration with Strong or Moderate CYP3A4 Inducers 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 <span class="opacity-50 text-xs">[see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ]</span> .

2.6 Dosage Modifications for Patients with Hepatic Impairment 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) <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ]</span> .

None. None ( 4 )

REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: Hemorrhage [see Warnings and Precautions (5.1) ] Perforations and Fistulas [see Warnings and Precautions (5.2) ]

Thromboembolic

Events [see Warnings and Precautions (5.3) ] Hypertension and Hypertensive Crisis [see Warnings and Precautions (5.4) ]

Cardiac

Failure [see Warnings and Precautions (5.5) ] Diarrhea [see Warnings and Precautions (5.6) ] Palmar-plantar Erythrodysesthesia [see Warnings and Precautions (5.7) ] Hepatotoxicity [see Warnings and Precautions (5.8) ]

Adrenal

Insufficiency [see Warnings and Precautions (5.9) ] Proteinuria [see Warnings and Precautions (5.10) ] Osteonecrosis of the Jaw [see Warnings and Precautions (5.11) ]

Impaired Wound

Healing [see Warnings and Precautions (5.12) ]

Reversible Posterior Leukoencephalopathy

Syndrome [see Warnings and Precautions (5.13) ]

Thyroid

Dysfunction [see Warnings and Precautions (5.14) ] Hypocalcemia [see Warnings and Precautions (5.15) ] The most common (≥ 20%) adverse reactions are: as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, constipation. ( 6.1 ) in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Exelixis, Inc. at 1-855-500-3935 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial Experience 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/m 2 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%).

Table

5.

Adverse Reactions

Occurring in ≥ 10% Patients Who Received CABOMETYX in METEOR Adverse Reaction CABOMETYX (n=331) One subject randomized to everolimus received cabozantinib. Everolimus (n=322)

All Grades National Cancer

Institute (NCI)

Common Terminology

Criteria for Adverse Events (CTCAE) Version

4.0 Grades 3-4 All Grades Grades 3-4 Percentage (%) of Patients Gastrointestinal Diarrhea 74 11 28 2 Nausea 50 4 28 &lt;1 Vomiting 32 2 14 &lt;1 Stomatitis 22 2 24 2 Constipation 25 &lt;1 19 &lt;1 Abdominal pain Includes the following terms: abdominal pain, abdominal pain upper, and abdominal pain lower 23 4 13 2 Dyspepsia 12 &lt;1 5 0 General Fatigue 56 9 47 7 Mucosal inflammation 19 &lt;1 23 3 Asthenia 19 4 16 2 Metabolism and Nutrition Decreased appetite 46 3 34 &lt;1 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia 42 8 6 &lt;1 Rash 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 23 &lt;1 43 &lt;1 Dry skin 11 0 10 0 Vascular Hypertension Includes the following terms hypertension, blood pressure increased, hypertensive crisis, blood pressure fluctuation 39 16 8 3 Investigations Weight decreased 31 2 12 0 Nervous System Dysgeusia 24 0 9 0 Headache 11 &lt;1 12 &lt;1 Dizziness 11 0 7 0 Endocrine Hypothyroidism 21 0 &lt;1 &lt;1 Respiratory, Thoracic, and Mediastinal Dysphonia 20 &lt;1 4 0 Dyspnea 19 3 29 4 Cough 18 &lt;1 33 &lt;1 Blood and Lymphatic Anemia 17 5 38 16 Musculoskeletal and Connective Tissue Pain in extremity 14 1 8 &lt;1 Muscle spasms 13 0 5 0 Arthralgia 11 &lt;1 14 1 Renal and Urinary Proteinuria 12 2 9 &lt;1 Other clinically relevant adverse reactions (all grades) that were reported in &lt;10% of patients treated with CABOMETYX included: wound complications (2%), cardiac failure (&lt;1%), convulsion (&lt;1%), pancreatitis (&lt;1%), osteonecrosis of the jaw (&lt;1%), and hepatitis cholestatic (&lt;1%).

Table

6.

Laboratory Abnormalities

Occurring in ≥ 25% Patients Who Received CABOMETYX in METEOR Laboratory Abnormality CABOMETYX (n=331) Everolimus (n=322)

All Grades Grade

3-4 All Grades Grade 3-4 Percentage (%) of Patients ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyl transferase. NCI CTCAE, Version

4.0 Chemistry Increased AST 74 3 40 &lt;1 Increased ALT 68 3 32 &lt;1 Increased creatinine 58 &lt;1 71 0 Increased triglycerides 53 4 73 13 Hypophosphatemia 48 8 36 5 Hyperglycemia 37 2 59 8 Hypoalbuminemia 36 2 28 &lt;1 Increased ALP 35 2 29 1 Hypomagnesemia 31 7 4 &lt;1 Hyponatremia 30 8 26 6 Increased GGT 27 5 43 9 Hematology Leukopenia 35 &lt;1 31 &lt;1 Neutropenia 31 2 17 &lt;1 Anemia Based on laboratory abnormalities 31 4 71 17 Lymphopenia 25 7 39 12 Thrombocytopenia 25 &lt;1 27 &lt;1 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 <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span> . 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.

Table

7.

Grade

3-4 Adverse Reactions Occurring in ≥ 1% Patients Who Received CABOMETYX in CABOSUN Adverse Reaction CABOMETYX (n = 78) Sunitinib (n = 72)

Grade

3-4 NCI CTCAE Version

4.0 Grade 3-4 Percentage (%) of Patients Patients with any Grade 3-4 Adverse Reaction 68 65 ALT, alanine aminotransferase; AST, aspartate aminotransferase Gastrointestinal Diarrhea 10 11 Stomatitis 5 6 Nausea 3 4 Vomiting 1 3 Constipation 1 0 General Fatigue 6 17 Pain 5 0 Metabolism and Nutrition Hyponatremia Laboratory abnormalities are reported as adverse reactions and not based on shifts in laboratory values 9 8 Hypophosphatemia 9 7 Decreased appetite 5 1 Dehydration 4 1 Hypocalcemia 3 0 Hypomagnesemia 3 0 Hypokalemia 1 3 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia 8 4 Skin Ulcer 3 0 Vascular Hypertension Includes the following term: hypertension 28 21 Hypotension 5 1 Angiopathy 1 1 Investigations Increased ALT 5 0 Weight decreased 4 0 Increased AST 3 3 Increased blood creatinine 3 3 Lymphopenia 1 6 Thrombocytopenia 1 11 Nervous System Syncope 5 0 Respiratory, Thoracic, and Mediastinal Dyspnea 1 6 Dysphonia 1 0 Blood and Lymphatic Anemia 1 3 Psychiatric Depression 4 0 Confusional state 1 1 Infections Lung Infection 4 0 Musculoskelatal and Connective Tissue Back pain 4 0 Bone pain 3 1 Pain in extremity 3 0 Arthralgia 1 0 Renal and Urinary Renal failure acute 4 1 Proteinuria 3 1 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 <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span> . 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) <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span> . 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 &gt;6 months and 60% of patients were exposed to treatment for &gt;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.

Table

8.

Adverse

Reactions in >15% of Patients Receiving CABOMETYX and Nivolumab - CHECKMATE-9ER Adverse Reaction CABOMETYX and Nivolumab (n=320) Sunitinib (n=320)

Grades

1-4 Grades 3-4 Grades 1-4 Grades 3-4 Percentage (%) of Patients Toxicity was graded per NCI CTCAE v4.

Gastrointestinal Diarrhea

64 7 47

4.4 Nausea 27 0.6 31

0.3 Abdominal pain Includes abdominal discomfort, abdominal pain lower, abdominal pain upper. 22 1.9 15

0.3 Vomiting 17 1.9 21

0.3 Dyspepsia Includes gastroesophageal reflux disease. 15 0 22

0.3 General Fatigue Includes asthenia. 51 8 50 8 Hepatobiliary Hepatotoxicity 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. 44 11 26 5 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia 40 8 41 8 Stomatitis Includes mucosal inflammation, aphthous ulcer, mouth ulceration. 37 3.4 46

4.4 Rash Includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic. 36 3.1 14 0 Pruritus 19 0.3 4.4 0 Vascular Hypertension Includes blood pressure increased, blood pressure systolic increased. 36 13 39 14 Endocrine Hypothyroidism Includes primary hypothyroidism. 34 0.3 30

0.3 Musculoskeletal and Connective Tissue Musculoskeletal pain Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain. 33 3.8 29

3.1 Arthralgia 18 0.3 9

0.3 Metabolism and Nutrition Decreased appetite 28 1.9 20

1.3 Nervous System Disorders Dysgeusia 24 0 22 0 Headache 16 0 12

0.6 Respiratory, Thoracic and Mediastinal Cough Includes productive cough. 20 0.3 17 0 Dysphonia 17 0.3 3.4 0 Infections and Infestations Upper respiratory tract infection Includes nasopharyngitis, pharyngitis, rhinitis. 20 0.3 8

0.3 Table 9.

Laboratory Values

Worsening from Baseline 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). Occurring in >20% of Patients Receiving CABOMETYX and Nivolumab - CHECKMATE-9ER Laboratory Abnormality CABOMETYX and Nivolumab Sunitinib Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 Percentage (%) of Patients Chemistry Increased ALT 79 9.8 39

3.5 Increased AST 77 7.9 57

2.6 Hypophosphatemia 69 28 48 10 Hypocalcemia 54 1.9 24

0.6 Hypomagnesemia 47 1.3 25

0.3 Hyperglycemia 44 3.5 44

1.7 Hyponatremia 43 11 36 12 Increased lipase 41 14 38 13 Increased amylase 41 10 28 6 Increased alkaline phosphatase 41 2.8 37

1.6 Increased creatinine 39 1.3 42

0.6 Hyperkalemia 35 4.7 27 1 Hypoglycemia 26 0.8 14

0.4 Hematology Lymphopenia 42 6.6 45 10 Thrombocytopenia 41 0.3 70

9.7 Anemia 37 2.5 61

4.8 Leukopenia 37 0.3 66

5.1 Neutropenia 35 3.2 67 12 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 <span class="opacity-50 text-xs">[see Clinical Studies (14.2) ]</span> . 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%).

Table

10.

Adverse Reactions

Occurring in ≥ 5% of CABOMETYX-Treated Patients in CELESTIAL Includes terms with a between-arm difference of ≥ 5% (all grades) or ≥ 2% (Grade 3-4)

Adverse

Reaction CABOMETYX (n=467) Placebo (n=237)

All

Grades NCI CTCAE Version

4.0 Grade 3-4 All Grades Grade 3-4 Percentage (%) of Patients Gastrointestinal Diarrhea 54 10 19 2 Nausea 31 2 18 2 Vomiting 26 &lt;1 12 3 Stomatitis 13 2 2 0 Dyspepsia 10 0 3 0 General Fatigue 45 10 30 4 Asthenia 22 7 8 2 Mucosal inflammation 14 2 2 &lt;1 Metabolism and Nutrition Decreased appetite 48 6 18 &lt;1 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia 46 17 5 0 Rash 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 21 2 9 &lt;1 Vascular Hypertension Includes the following terms: hypertension, blood pressure diastolic increased, blood pressure increased 30 16 6 2 Investigations Weight decreased 17 1 6 0 Nervous System Dysgeusia 12 0 2 0 Endocrine Hypothyroidism 8 &lt;1 &lt;1 0 Respiratory, Thoracic, and Mediastinal Dysphonia 19 1 2 0 Dyspnea 12 3 10 &lt;1 Musculoskeletal and Connective Tissue Pain in extremity 9 &lt;1 4 1 Muscle spasms 8 &lt;1 2 0 Table 11.

Laboratory Abnormalities

Occurring in ≥5% of CABOMETYX-Treated Patients in CELESTIAL Includes laboratory abnormalities with a between-arm difference of ≥5% (all grades) or ≥2% (Grade 3-4)

Laboratory

Abnormality CABOMETYX (n=467) Placebo (n=237)

All Grades Grade

3-4 All Grades Grade 3-4 Percentage (%) of Patients ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDH, blood lactate dehydrogenase Chemistry Increased LDH 84 9 29 2 Increased ALT 73 12 37 6 Increased AST 73 24 46 19 Hypoalbuminemia 51 1 32 1 Increased ALP 43 8 38 6 Hypophosphatemia 25 9 8 4 Hypokalemia 23 6 6 1 Hypomagnesemia 22 3 3 0 Increased amylase 16 2 9 2 Hypocalcemia 8 2 0 0 Hematology Decreased platelets 54 10 16 1 Neutropenia 43 7 8 1 Increased hemoglobin 8 0 1 0 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.

Table

12.

Adverse Reactions

Occurring in ≥5% of CABOMETYX-Treated Patients in COSMIC-311 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)

Adverse

Reaction CABOMETYX (N=125) Placebo (N=62)

All

Grades NCI CTCAE Version

5.0 Grade 3-4 All Grades Grade 3-4 Percentage of Patients Gastrointestinal Diarrhea 51 7 3 0 Nausea 24 3 2 0 Vomiting 14 1 8 0 Stomatitis Includes the following terms: mucosal inflammation, stomatitis 26 5 3 0 Dry mouth 10 1 2 0 General Fatigue Includes the following terms: fatigue, asthenia 42 10 23 0 Metabolism and Nutrition Decreased appetite 23 3 16 0 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia 46 10 0 0 Vascular Hypertension Includes the following terms: hypertension, blood pressure increased, hypertensive crisis 30 10 5 3 Investigations Weight decreased 18 1 5 0 Nervous System Dysgeusia 10 0 0 0 Headache 10 2 2 0 Respiratory, Thoracic, and Mediastinal Dysphonia 10 0 2 0 Pulmonary embolism 5 2 0 0 Renal and Urinary Proteinuria 15 1 3 0 Table 13.

Laboratory Abnormalities

Occurring in ≥10% of CABOMETYX-Treated Patients in COSMIC-311 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)

Laboratory

Abnormality CABOMETYX (N=125) Placebo (N=62)

All Grades Grade

3 or 4 All Grades Grade 3 or 4 Percentage of Patients ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyl transferase; LDH, blood lactate dehydrogenase Chemistry LDH increased Sponsor-defined grades for LDH were as follows: Grade 1 (> ULN to ≤2 × ULN), Grade 2 (>2 × ULN to ≤3 × ULN), Grade 3 (>3 × ULN). 90 10 32 3 AST increased 77 1 18 0 ALT increased 66 2 11 0 Hypocalcemia 36 9 10 2 ALP increased 34 0 15 0 GGT increased 26 2 21 2 Hypomagnesemia 25 2 5 0 Hypoalbuminemia 19 1 7 0 Hypokalemia 18 1 3 0 Hyponatremia 15 0 10 2 Hyperbilirubinemia 12 0 5 0 Hematology Leukocytes decreased 38 2 7 2 Neutrophils decreased 31 2 5 2 Platelets decreased 26 0 5 0 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

14 summarizes the adverse reactions in patients with pNET in CABINET.

Table

14.

Adverse

Reactions (≥15%) in Patients with pNET Who Received CABOMETYX in CABINET Adverse Reaction CABOMETYX (N=63) Placebo (N=31)

All

Grades NCI CTCAE Version

5.0 Grade 3 or 4 All Grades Grade 3 or 4 Percentage (%) of Patients General Fatigue Includes fatigue, asthenia 79 14 61 6 Vascular Hypertension Includes hypertension, blood pressure increased, blood pressure systolic increased, systolic hypertension 67 25 55 16 Thromboembolic events Includes thromboembolic event, pulmonary embolism, embolism, deep vein thrombosis, vena cava thrombosis, embolism venous, embolism arterial 19 11 3.2 0 Gastrointestinal Diarrhea Includes diarrhea, colitis 63 6 23 0 Stomatitis Includes stomatitis, aphthous ulcer, mucosal inflammation, cheilitis, glossitis 49 6 10 0 Nausea 37 8 32

3.2 Abdominal pain Includes abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain, abdominal discomfort, hepatic pain 25 3.2 16 6 Vomiting 25 6 16 0 Dyspepsia Includes dyspepsia, gastroesophageal reflux disease 16 0 6 0 Skin and Subcutaneous Tissue Rash 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 57 11 23 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 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 41 1.6 19 0 Nervous System Dysgeusia Includes dysgeusia, taste disorder, ageusia, anosmia 30 0 6 0 Dizziness Includes dizziness, vertigo 25 0 3.2 0 Endocrine disorders Hypothyroidism Includes hypothyroidism, blood thyroid stimulating hormone increased 25 0 3.2 0 Metabolism and Nutrition Decreased appetite 25 3.2 19 0 Investigations Weight decreased 19 3.2 10 0 Respiratory, Thoracic, and Mediastinal Dyspnea Includes dyspnea, dyspnea exertional 16 0 3.2 0 Clinically relevant adverse reactions in &lt;15% of patients who received CABOMETYX included peripheral neuropathy, hemorrhage, cardiac arrhythmia, hypotension, alopecia, and hair color changes.

Table

15 summarizes the laboratory abnormalities in patients with pNET in CABINET.

Table

15: Select Laboratory Abnormalities (≥10%) Reported as Adverse Reactions in Patients with pNET Who Received CABOMETYX in CABINET Laboratory Abnormality CABOMETYX (N=63) Placebo (N=31)

All

Grades NCI CTCAE Version 5.0 (%)

Grade

3 or 4 (%)

All

Grades (%)

Grade

3 or 4 (%)

Chemistry

Increased AST 76 1.6 48 0 Increased ALT 75 1.6 39

3.2 Hyperglycemia Includes hyperglycemia, blood glucose increased 37 3.2 48

3.2 Hypophosphatemia Includes hypophosphatemia, blood phosphorus decreased 25 0 6 0 Increased ALP Includes blood alkaline phosphatase, blood alkaline phosphatase increased 22 3.2 23 0 Hypocalcemia Includes hypocalcemia, blood calcium decreased, adjusted calcium decreased 17 0 3.2 0 Hyponatremia Includes hyponatremia, blood sodium decreased 16 1.6 16 0 Blood bilirubin increased Includes blood bilirubin increased, hyperbilirubinemia 14 4.8 6

3.2 Hyperkalemia Includes hyperkalemia, blood potassium increased 14 1.6 10 0 Hypoalbuminemia Includes hypoalbuminemia, blood albumin decreased 14 0 10 0 Hypoglycemia Includes hypoglycemia, blood glucose decreased 11 0 6 0 Hypomagnesemia Includes hypomagnesemia, blood magnesium decreased 11 0 6 0 Hypokalemia Includes hypokalemia, blood potassium decreased 10 1.6 3.2 0 Hematology Platelet count decreased Includes platelet count decreased, thrombocytopenia 37 0 19 0 Neutrophil count decreased Includes neutrophil count decreased, neutropenia 27 1.6 6 0 Hemoglobin decreased Includes hemoglobin decreased, anemia 25 1.6 32 0 Lymphocyte count decreased Includes lymphocyte count decreased, lymphopenia 22 8 16 0 White blood cell count decreased Includes white blood cell count decreased, leukopenia 19 1.6 3.2 0 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 <span class="opacity-50 text-xs">[see Clinical Studies (14.4) ]</span> . 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

16 summarizes the adverse reactions in patients with epNET in CABINET.

Table

16.

Adverse

Reactions (≥15%) in Patients with epNET Who Received CABOMETYX in CABINET Adverse Reaction CABOMETYX (N=132) Placebo (N=67)

All

Grades NCI CTCAE Version

5.0 Grade 3-4 All Grades Grade 3-4 Percentage (%) of Patients General Fatigue Includes fatigue, asthenia 73 14 58 9 Edema Includes edema, edema peripheral, generalized edema, localized edema, periorbital edema, face edema, eye edema 16 1.5 10 0 Gastrointestinal Diarrhea Includes diarrhea, colitis 65 11 42

4.5 Stomatitis Includes stomatitis, aphthous ulcer, mucosal inflammation, cheilitis, glossitis 40 3.8 10 0 Nausea 39 2.3 21 0 Abdominal pain Includes abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain, abdominal discomfort, hepatic pain 29 9 43 8 Vomiting 17 2.3 10

1.5 Vascular Hypertension Includes hypertension, blood pressure increased, blood pressure systolic increased, systolic hypertension 64 27 37 6 Skin and Subcutaneous Tissue Rash 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 50 3.0 10 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 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 36 8 33

1.5 Endocrine System Hypothyroidism Includes hypothyroidism, blood thyroid stimulating hormone increased 34 0 4.5 0 Metabolism and Nutrition Decreased appetite 33 1.5 15

1.5 Nervous System Dysgeusia Includes dysgeusia, taste disorder, ageusia, anosmia 35 0 1.5 0 Dizziness Includes dizziness, vertigo 17 0 6 0 Investigations Weight decreased 27 4.5 8 0 Respiratory, Thoracic, and Mediastinal Cough Includes cough, upper-airway cough syndrome, productive cough 17 0 10 0 Clinically relevant adverse reactions in &lt;15% of patients who received CABOMETYX included cardiac arrhythmia, hemorrhage, thromboembolic events, kidney injury, proteinuria, hypotension, peripheral neuropathy, reversible posterior leukoencephalopathy syndrome, alopecia, hair color changes, and cardiac failure.

Table

17 summarizes the laboratory abnormalities in patients with epNET in CABINET.

Table

17: Select Laboratory Abnormalities (≥10%) Reported as Adverse Reactions in Patients with epNET Who Received CABOMETYX in CABINET Laboratory Abnormality CABOMETYX (N=132) Placebo (N=67)

All

Grades NCI CTCAE Version 5.0 (%)

Grade

3 or 4 (%)

All

Grades (%)

Grade

3 or 4 (%)

Chemistry

Increased AST 70 3.8 21

1.5 Increased ALT 63 0.8 18

1.5 Hyperglycemia Includes hyperglycemia, blood glucose increased 30 0.8 39

1.5 Increased ALP Includes blood alkaline phosphatase, blood alkaline phosphatase increased 29 4.5 30 6 Blood creatinine increased 23 0 12

1.5 Blood bilirubin increased Includes blood bilirubin increased, hyperbilirubinemia 20 3 10 6 Hypoalbuminemia Includes hypoalbuminemia, blood albumin decreased 20 0.8 9 0 Hypocalcemia Includes hypocalcemia, blood calcium decreased, adjusted calcium decreased 20 0 4.5 0 Hypokalemia Includes hypokalemia, blood potassium decreased 20 2.3 10

1.5 Hypomagnesemia Includes hypomagnesemia, blood magnesium decreased 20 0.8 4.5 0 Hypophosphatemia Includes hypophosphatemia, blood phosphorus decreased 19 0.8 4.5 0 Hyponatremia Includes hyponatremia, blood sodium decreased 16 2.3 7

1.5 Hematology Platelet count decreased Includes platelet count decreased, thrombocytopenia 55 1.5 13

1.5 White blood cell count deceased Includes white blood cell count decreased, leukopenia 37 3 4.5 0 Neutrophil count decreased Includes neutrophil count decreased, neutropenia 36 3 6 0 Hemoglobin decreased Includes hemoglobin decreased, anemia 30 2.3 19 0 Lymphocyte count decreased Includes lymphocyte count decreased, lymphopenia 28 9 18 1.5

6.2 Postmarketing Experience 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

AND PRECAUTIONS Hemorrhage: Do not administer CABOMETYX if recent history of hemorrhage. ( 5.1 ) Perforations and Fistulas: Monitor for symptoms. Discontinue CABOMETYX for Grade 4 fistula or perforation. ( 5.2 )

Thromboembolic

Events: Discontinue CABOMETYX for myocardial infarction or serious venous or arterial thromboembolic events. ( 5.3 ) Hypertension and Hypertensive Crisis: Monitor blood pressure regularly. Interrupt for hypertension that is not adequately controlled with anti-hypertensive therapy. Discontinue CABOMETYX for hypertensive crisis or severe hypertension that cannot be controlled with anti-hypertensive therapy. ( 5.4 )

Cardiac

Failure: Monitor patients for signs and symptoms of cardiac failure throughout treatment. ( 5.5 ) Diarrhea: May be severe. Interrupt CABOMETYX until diarrhea resolves or decreases to ≤Grade 1, resume at reduced dose. Recommend standard antidiarrheal treatments. ( 5.6 ) Palmar-Plantar Erythrodysesthesia (PPE): Interrupt CABOMETYX treatment until PPE resolves or decreases to Grade 1. ( 5.7 ) Hepatotoxicity: When used in combination with nivolumab, higher frequencies of Grade 3 and 4 ALT and AST elevation may occur than with CABOMETYX alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider withholding CABOMETYX and/or nivolumab, initiating corticosteroid therapy, and/or permanently discontinuing the combination for severe or life- threatening hepatotoxicity. ( 5.8 )

Adrenal

Insufficiency: When used in combination with nivolumab, primary or secondary adrenal insufficiency may occur.

For Grade

2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab depending on severity. ( 5.9 ) Proteinuria: Monitor urine protein. Interrupt CABOMETYX until proteinuria resolves to ≤ Grade 1, resume CABOMETYX at a reduced dose. Discontinue for nephrotic syndrome. ( 5.10 ) Osteonecrosis of the jaw (ONJ): Withhold CABOMETYX for at least 3 weeks prior to invasive dental procedures and for development of ONJ. ( 5.11 )

Impaired Wound

Healing: Withhold CABOMETYX for at least 3 weeks before elective surgery. Do not administer for at least 2 weeks following major surgery and adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established. ( 5.12 )

Reversible Posterior Leukoencephalopathy

Syndrome (RPLS): Discontinue CABOMETYX. ( 5.13 )

Thyroid

Dysfunction: Monitor thyroid function before and during treatment with CABOMETYX. ( 5.14 ) Hypocalcemia: Withhold CABOMETYX and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity. ( 5.15 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.16 , 8.1 , 8.3 )

5.1 Hemorrhage 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) , Warnings and Precautions (5.11 , 5.12) ]</span> .

5.2 Perforations and Fistulas CABOMETYX can cause gastrointestinal (GI) perforations and fistulas. Fistulas, including fatal cases, occurred in 1% of CABOMETYX-treated patients <span class="opacity-50 text-xs">[see [see Adverse Reactions (6.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.3 Thromboembolic Events 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 thromboembolic events occurred in CABOMETYX-treated patients <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.4 Hypertension and Hypertensive Crisis CABOMETYX can cause hypertension, including hypertensive crisis <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span>. Hypertension was reported in 37% (16% Grade 3 and &lt;1% Grade 4) of CABOMETYX-treated patients. In CABINET (n=195) <span class="opacity-50 text-xs">[see Clinical Studies (14.4) ]</span> , 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.5 Cardiac Failure CABOMETYX can cause severe and fatal cardiac failure <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Cardiac failure occurred in 0.5% of patients treated with CABOMETYX as a single agent, including fatal cardiac failure in 0.1% of patients. Median time to onset of cardiac failure was 73 days (range: 44 days to 159 days). Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Withhold and resume at a reduced dose upon recovery or permanently discontinue CABOMETYX depending on the severity <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.6 Diarrhea 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 (2.3) ] .

5.7 Palmar-Plantar Erythrodysesthesia CABOMETYX can cause palmar-plantar erythrodysesthesia (PPE). PPE occurred in 45% of patients treated with CABOMETYX <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> .

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 (2.3) ] .

5.8 Hepatotoxicity 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . ALT or AST &gt;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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.9 Adrenal Insufficiency 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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 (2.3) ] .

5.10 Proteinuria CABOMETYX can cause proteinuria. Proteinuria was observed in 8% of patients receiving CABOMETYX <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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 (2.3) ] .

5.11 Osteonecrosis of the Jaw CABOMETYX can cause osteonecrosis of the jaw (ONJ). ONJ occurred in &lt;1% of patients treated with CABOMETYX <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.12 Impaired Wound Healing CABOMETYX can cause impaired wound healing <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Withhold CABOMETYX for at least 3 weeks prior to elective surgery <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.1 , 2.3 )]</span> .

5.13 Reversible Posterior Leukoencephalopathy Syndrome 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.14 Thyroid Dysfunction 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.15 Hypocalcemia 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Laboratory abnormality data were not collected in CABOSUN and CABINET. In COSMIC-311 (n=125) <span class="opacity-50 text-xs">[see Clinical Studies (14.3) ]</span> , 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.16 Embryo-Fetal Toxicity 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) , Clinical Pharmacology (12.1) ]</span> .

INTERACTIONS Strong CYP3A4 Inhibitors: Reduce the COMETRIQ dosage. ( 2.2 , 7.1 ) Strong CYP3A4 Inducers: Increase the COMETRIQ dosage. ( 2.2 , 7.2 )

7.1 Effect of CYP3A4 Inhibitors 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 )]</span> . Avoid ingestion of foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 while taking COMETRIQ.

7.2 Effect of CYP3A4 Inducers 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 )]</span>.

7.3 Effect of MRP2 Inhibitors 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .