ADVERSE 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) ]

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 ²every 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)
Adverse Reaction	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	<1
Vomiting	32	2	14	<1
Stomatitis	22	2	24	2
Constipation	25	<1	19	<1
Abdominal pain Includes the following terms: abdominal pain, abdominal pain upper, and abdominal pain lower	23	4	13	2
Dyspepsia	12	<1	5	0
General
Fatigue	56	9	47	7
Mucosal inflammation	19	<1	23	3
Asthenia	19	4	16	2
Metabolism and Nutrition
Decreased appetite	46	3	34	<1
Skin and Subcutaneous Tissue
Palmar-plantar erythrodysesthesia	42	8	6	<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	<1	43	<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	<1	12	<1
Dizziness	11	0	7	0
Endocrine
Hypothyroidism	21	0	<1	<1
Respiratory, Thoracic, and Mediastinal
Dysphonia	20	<1	4	0
Dyspnea	19	3	29	4
Cough	18	<1	33	<1
Blood and Lymphatic
Anemia	17	5	38	16
Musculoskeletal and Connective Tissue
Pain in extremity	14	1	8	<1
Muscle spasms	13	0	5	0
Arthralgia	11	<1	14	1
Renal and Urinary
Proteinuria	12	2	9	<1

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

Table 6. Laboratory Abnormalities Occurring in ≥ 25% Patients Who Received CABOMETYX in METEOR
Laboratory Abnormality	CABOMETYX (n=331)		Everolimus (n=322)
Laboratory Abnormality	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	<1
Increased ALT	68	3	32	<1
Increased creatinine	58	<1	71	0
Increased triglycerides	53	4	73	13
Hypophosphatemia	48	8	36	5
Hyperglycemia	37	2	59	8
Hypoalbuminemia	36	2	28	<1
Increased ALP	35	2	29	1
Hypomagnesemia	31	7	4	<1
Hyponatremia	30	8	26	6
Increased GGT	27	5	43	9
Hematology
Leukopenia	35	<1	31	<1
Neutropenia	31	2	17	<1
Anemia Based on laboratory abnormalities	31	4	71	17
Lymphopenia	25	7	39	12
Thrombocytopenia	25	<1	27	<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 [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.

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 [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.

Table 8. Adverse Reactions in >15% of Patients Receiving CABOMETYX and Nivolumab - CHECKMATE-9ER
Adverse Reaction	CABOMETYX and Nivolumab (n=320)		Sunitinib (n=320)
Adverse Reaction	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
Laboratory Abnormality	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 [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%).

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)
Adverse Reaction	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	<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	<1
Metabolism and Nutrition
Decreased appetite	48	6	18	<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	<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	<1	<1	0
Respiratory, Thoracic, and Mediastinal
Dysphonia	19	1	2	0
Dyspnea	12	3	10	<1
Musculoskeletal and Connective Tissue
Pain in extremity	9	<1	4	1
Muscle spasms	8	<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)
Laboratory Abnormality	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)
Adverse Reaction	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)
Laboratory Abnormality	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)
Adverse Reaction	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 <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)
Laboratory Abnormality	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 [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 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)
Adverse Reaction	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 <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)
Laboratory Abnormality	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

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

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