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

Use of CABOMETYX in pediatric patients aged 12 years and older with DTC and NETs is supported by evidence from adequate and well-controlled studies of CABOMETYX in adults with additional population pharmacokinetic data demonstrating that cabozantinib exposure is within the same range between adults and pediatric patients aged 12 years and older at the recommended dosages

[see

2.2 Recommended Dosage

Administer CABOMETYX on an empty stomach. Administer at least 1 hour before or at least 2 hours after eating

[seeClinical Pharmacology (12.3)]

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

[seeDosage and Administration (2.4,2.5,2.6)]

The recommended dosages of CABOMETYX are presented inTable 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 dailyIf 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	SeverityGraded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0)	CABOMETYX Dosage Modification
Hemorrhage [seeWarnings and Precautions (5.1)]	Grade 3 or 4	Permanently discontinue CABOMETYX
Perforations and Fistulas [seeWarnings and Precautions (5.2)]	Any grade gastrointestinal perforation or Grade 4 fistula	Permanently discontinue CABOMETYX
Thromboembolic Events [seeWarnings 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 [seeWarnings 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 [seeWarnings and Precautions (5.6)]	Grade 2, Grade 3, or Grade 4	Withhold CABOMETYX until ≤Grade 1 Resume at reduced dose
Palmar-Plantar Erythrodysesthesia [seeWarnings and Precautions (5.7)]	Intolerable Grade 2 or Grade 3	Withhold CABOMETYX until ≤Grade 1 Resume at reduced dose
Proteinuria [seeWarnings 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) [seeWarnings and Precautions (5.11)]	Any grade	Withhold CABOMETYX for development of ONJ until complete resolution Resume at reduced dose
Reversible Posterior Leukoencephalopathy Syndrome [seeWarnings and Precautions (5.13)]	Any grade	Permanently discontinue CABOMETYX
Other Adverse Reactions [seeAdverse 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	WithholdConsider corticosteroid therapy for hepatic adverse reactions if CABOMETYX is withheld or discontinued when administered in combination with nivolumabboth CABOMETYX and nivolumab until adverse reactions recoverAfter 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.

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/m²every 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

[seeClinical 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 GradesNational 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 painIncludes 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
RashIncludes 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
HypertensionIncludes 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
AnemiaBased 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

[seeClinical 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 3-4NCI 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
HyponatremiaLaboratory 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
HypertensionIncludes 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

[seeClinical 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)

[seeClinical 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 painIncludes abdominal discomfort, abdominal pain lower, abdominal pain upper.	22	1.9	15	0.3
Vomiting	17	1.9	21	0.3
DyspepsiaIncludes gastroesophageal reflux disease.	15	0	22	0.3
General
FatigueIncludes asthenia.	51	8	50	8
Hepatobiliary
HepatotoxicityIncludes 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
StomatitisIncludes mucosal inflammation, aphthous ulcer, mouth ulceration.	37	3.4	46	4.4
RashIncludes 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
HypertensionIncludes blood pressure increased, blood pressure systolic increased.	36	13	39	14
Endocrine
HypothyroidismIncludes primary hypothyroidism.	34	0.3	30	0.3
Musculoskeletal and Connective Tissue
Musculoskeletal painIncludes 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
CoughIncludes productive cough.	20	0.3	17	0
Dysphonia	17	0.3	3.4	0
Infections and Infestations
Upper respiratory tract infectionIncludes nasopharyngitis, pharyngitis, rhinitis.	20	0.3	8	0.3

Table 9. Laboratory Values Worsening from BaselineEach 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

[seeClinical 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 CELESTIALIncludes 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 GradesNCI 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
RashIncludes 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
HypertensionIncludes 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 CELESTIALIncludes 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

[seeClinical 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-311Includes 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 GradesNCI 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
StomatitisIncludes the following terms: mucosal inflammation, stomatitis	26	5	3	0
Dry mouth	10	1	2	0
General
FatigueIncludes 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
HypertensionIncludes 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-311Includes 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 increasedSponsor-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

[seeClinical 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 14summarizes 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 GradesNCI CTCAE Version 5.0	Grade 3 or 4	All Grades	Grade 3 or 4
	Percentage (%) of Patients
General
FatigueIncludes fatigue, asthenia	79	14	61	6
Vascular
HypertensionIncludes hypertension, blood pressure increased, blood pressure systolic increased, systolic hypertension	67	25	55	16
Thromboembolic eventsIncludes thromboembolic event, pulmonary embolism, embolism, deep vein thrombosis, vena cava thrombosis, embolism venous, embolism arterial	19	11	3.2	0
Gastrointestinal
DiarrheaIncludes diarrhea, colitis	63	6	23	0
StomatitisIncludes stomatitis, aphthous ulcer, mucosal inflammation, cheilitis, glossitis	49	6	10	0
Nausea	37	8	32	3.2
Abdominal painIncludes abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain, abdominal discomfort, hepatic pain	25	3.2	16	6
Vomiting	25	6	16	0
DyspepsiaIncludes dyspepsia, gastroesophageal reflux disease	16	0	6	0
Skin and Subcutaneous Tissue
RashIncludes 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 painIncludes 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
DysgeusiaIncludes dysgeusia, taste disorder, ageusia, anosmia	30	0	6	0
DizzinessIncludes dizziness, vertigo	25	0	3.2	0
Endocrine disorders
HypothyroidismIncludes 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
DyspneaIncludes 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 15summarizes 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 GradesNCI 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
HyperglycemiaIncludes hyperglycemia, blood glucose increased	37	3.2	48	3.2
HypophosphatemiaIncludes hypophosphatemia, blood phosphorus decreased	25	0	6	0
Increased ALPIncludes blood alkaline phosphatase, blood alkaline phosphatase increased	22	3.2	23	0
HypocalcemiaIncludes hypocalcemia, blood calcium decreased, adjusted calcium decreased	17	0	3.2	0
HyponatremiaIncludes hyponatremia, blood sodium decreased	16	1.6	16	0
Blood bilirubin increasedIncludes blood bilirubin increased, hyperbilirubinemia	14	4.8	6	3.2
HyperkalemiaIncludes hyperkalemia, blood potassium increased	14	1.6	10	0
HypoalbuminemiaIncludes hypoalbuminemia, blood albumin decreased	14	0	10	0
HypoglycemiaIncludes hypoglycemia, blood glucose decreased	11	0	6	0
HypomagnesemiaIncludes hypomagnesemia, blood magnesium decreased	11	0	6	0
HypokalemiaIncludes hypokalemia, blood potassium decreased	10	1.6	3.2	0
Hematology
Platelet count decreasedIncludes platelet count decreased, thrombocytopenia	37	0	19	0
Neutrophil count decreasedIncludes neutrophil count decreased, neutropenia	27	1.6	6	0
Hemoglobin decreasedIncludes hemoglobin decreased, anemia	25	1.6	32	0
Lymphocyte count decreasedIncludes lymphocyte count decreased, lymphopenia	22	8	16	0
White blood cell count decreasedIncludes 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

[seeClinical 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 16summarizes 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 GradesNCI CTCAE Version 5.0	Grade 3-4	All Grades	Grade 3-4
	Percentage (%) of Patients
General
FatigueIncludes fatigue, asthenia	73	14	58	9
EdemaIncludes edema, edema peripheral, generalized edema, localized edema, periorbital edema, face edema, eye edema	16	1.5	10	0
Gastrointestinal
DiarrheaIncludes diarrhea, colitis	65	11	42	4.5
StomatitisIncludes stomatitis, aphthous ulcer, mucosal inflammation, cheilitis, glossitis	40	3.8	10	0
Nausea	39	2.3	21	0
Abdominal painIncludes 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
HypertensionIncludes hypertension, blood pressure increased, blood pressure systolic increased, systolic hypertension	64	27	37	6
Skin and Subcutaneous Tissue
RashIncludes 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 painIncludes 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
HypothyroidismIncludes hypothyroidism, blood thyroid stimulating hormone increased	34	0	4.5	0
Metabolism and Nutrition
Decreased appetite	33	1.5	15	1.5
Nervous System
DysgeusiaIncludes dysgeusia, taste disorder, ageusia, anosmia	35	0	1.5	0
DizzinessIncludes dizziness, vertigo	17	0	6	0
Investigations
Weight decreased	27	4.5	8	0
Respiratory, Thoracic, and Mediastinal
CoughIncludes 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 17summarizes 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 GradesNCI 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
HyperglycemiaIncludes hyperglycemia, blood glucose increased	30	0.8	39	1.5
Increased ALPIncludes blood alkaline phosphatase, blood alkaline phosphatase increased	29	4.5	30	6
Blood creatinine increased	23	0	12	1.5
Blood bilirubin increasedIncludes blood bilirubin increased, hyperbilirubinemia	20	3	10	6
HypoalbuminemiaIncludes hypoalbuminemia, blood albumin decreased	20	0.8	9	0
HypocalcemiaIncludes hypocalcemia, blood calcium decreased, adjusted calcium decreased	20	0	4.5	0
HypokalemiaIncludes hypokalemia, blood potassium decreased	20	2.3	10	1.5
HypomagnesemiaIncludes hypomagnesemia, blood magnesium decreased	20	0.8	4.5	0
HypophosphatemiaIncludes hypophosphatemia, blood phosphorus decreased	19	0.8	4.5	0
HyponatremiaIncludes hyponatremia, blood sodium decreased	16	2.3	7	1.5
Hematology
Platelet count decreasedIncludes platelet count decreased, thrombocytopenia	55	1.5	13	1.5
White blood cell count deceasedIncludes white blood cell count decreased, leukopenia	37	3	4.5	0
Neutrophil count decreasedIncludes neutrophil count decreased, neutropenia	36	3	6	0
Hemoglobin decreasedIncludes hemoglobin decreased, anemia	30	2.3	19	0
Lymphocyte count decreasedIncludes lymphocyte count decreased, lymphopenia	28	9	18	1.5

12.3 Pharmacokinetics

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

Absorption

Median time to peak cabozantinib concentrations (T_max) ranged from 3 to 4 hours post-dose. A 19% increase in the C_maxof CABOMETYX compared to a cabozantinib capsule formulation was observed following a single 140 mg dose. A less than 10% difference in the AUC was observed between CABOMETYX and a cabozantinib capsule formulation

[seeDosage and Administration (2.1)]

Food Effect

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

Distribution

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

Elimination

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

Metabolism

Cabozantinib is a substrate of CYP3A4 in vitro.

Excretion

Approximately 81% of the total administered radioactivity was recovered within a 48-day collection period following a single dose of radiolabeled¹⁴C-cabozantinib in healthy subjects. Approximately 54% was recovered in feces and 27% in urine. Unchanged cabozantinib accounted for 43% of the total radioactivity in feces and was not detectable in urine following a 72-hour collection.

Specific Populations

The following patient characteristics did not result in a clinically relevant difference in the pharmacokinetics of cabozantinib: age (32-86 years), sex, race (Whites and non-Whites), or mild to moderate renal impairment (eGFR ≥30 mL/min/1.73 m²as estimated by MDRD (modification of diet in renal disease equation)). The pharmacokinetics of cabozantinib is unknown in patients with eGFR <29 mL/min/1.73m²as estimated by MDRD equation or requiring dialysis.

Pediatric Patients

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

Patients with Hepatic Impairment

Based on a population pharmacokinetic analysis of cabozantinib in healthy subjects and patients with cancer, no clinically significant differences in the mean cabozantinib exposure were observed between subjects with normal liver function (total bilirubin and AST ≤ULN) and those with mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin >1 to 1.5x ULN and any AST value). In a dedicated pharmacokinetic study, cabozantinib exposure (AUC_0-INF) increased by 63% in patients with moderate hepatic impairment (Child-Pugh B). Patients with severe hepatic impairment have not been studied

[seeDosage and Administration (2.6),Use in Specific Populations (8.6)]

Drug Interaction Studies

Clinical Studies

CYP3A4 Inhibitors:

Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), with a cabozantinib capsule formulation to healthy subjects increased single-dose cabozantinib exposure (AUC_0-INF) by 38%.

CYP3A4 Inducers:

Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), with a cabozantinib capsule formulation to healthy subjects decreased single-dose cabozantinib exposure (AUC_0-INF) by 77%.

CYP2C8 Substrates:

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

Gastric Acid Reducing Agents:

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

In vitro Studies

CYP Enzymes:

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

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

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

Transporters:

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

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

and

14.3 Differentiated Thyroid Cancer

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

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

The trial demonstrated a statistically significant improvement in PFS, while it failed to demonstrate a statistically significant improvement in ORR, for patients randomized to CABOMETYX compared with placebo. Efficacy results are summarized inTable 23andFigure 9.

Table 23: Efficacy Results from COSMIC-311
	Primary Analysis		Updated AnalysisNo formal statistical testing was conducted at the time of the updated analysis
	CABOMETYX (n=125)	Placebo (n=62)	CABOMETYX (n=170)	Placebo (n=88)
Progression-Free Survival
_{CI, confidence interval; NR, not reached; NE, not evaluable}
Number of Events, (%)	31 (25)	43 (69)	62 (36)	69 (78)
Median PFS in Months (95% CI)	NR (5.7, NE)	1.9 (1.8, 3.6)	11.0 (7.4, 13.8)	1.9 (1.9, 3.7)
Hazard Ratio (95% CI)Estimated using the Cox proportional-hazard model	0.22 (0.14, 0.35)		0.22 (0.15, 0.31)
p-valueLog-rank test stratified by receipt of prior lenvatinib (yes vs no) and age (≤65 years vs >65 years)	< 0.0001
Overall Response Rate (95% CI)
Overall Response, % (95% CI)All responses were partial responses^,The analysis population overall response rate was the first 100 randomized patients (67 in the CABOMETYX arm, and 33 in the placebo arm)	15% (7%, 26%)	0% (0.0%, 11%)	18% (10%, 29%)	0% (0.0%, 11%)
p-valueFisher’s exact test compared to an alpha boundary of 0.01	0.0281

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

14.4 Neuroendocrine Tumors

Pancreatic Neuroendocrine Tumors

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

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

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

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

Efficacy results are summarized inTable 24andFigure 10.

Table 24: Efficacy Results in Patients with pNET in CABINET
	CABOMETYX (N=66)	Placebo (N=33)
_{CI, confidence interval; NE, not evaluable}
Progression-Free Survival (PFS)
Number of events (%)	33 (50)	26 (79)
Median (95% CI)Kaplan-Meier method, in months	13.8 (8.9, 17.0)	3.3 (2.8, 5.7)
Hazard Ratio (95% CI)Stratified Cox proportional hazards model stratified by concurrent somatostatin analog (SSA) use (yes/no) and prior sunitinib therapy (yes/no)	0.22 (0.12, 0.41)
p-valueStratified log-rank test stratified by concurrent somatostatin analog (SSA) use (yes/no) and prior sunitinib therapy (yes/no) (compared to one-sided alpha=0.001)	<0.0001
Overall Response Rate (ORR)
ORR (95% CI)Clopper-Pearson method, %	18 (10, 30)	0 (0, 11)
Duration of Response (DOR)
Median (95% CI) , in months	11.4 (6.1, NE)	NE

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

Extra-Pancreatic Neuroendocrine Tumors

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

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

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

Efficacy results are summarized inTable 25andFigure 11.

Table 25: Efficacy Results in Patients with epNET in CABINET
	CABOMETYX (N=132)	Placebo (N=67)
_{CI, confidence interval; NE, not evaluable}
Progression-Free Survival (PFS)
Number of events (%)	68 (52)	39 (58)
Median (95% CI)Kaplan-Meier method, in months	8.5 (6.8, 12.5)	4.2 (3.0, 5.7)
Hazard Ratio (95% CI)Stratified Cox proportional hazards model stratified by concurrent somatostatin analog (SSA) use (yes/no) and primary site (midgut GI/unknown vs non-midgut GI/lung/other)	0.40 (0.26, 0.61)
p-valueStratified log-rank test stratified by concurrent somatostatin analog (SSA) use (yes/no) and primary site (midgut GI/unknown vs non-midgut GI/lung/other) (compared to one-sided alpha=0.001)	<0.0001
Overall Response Rate (ORR)
ORR (95% CI)Clopper-Pearson method, %	5 (2.2, 11)	0 (0, 5)
Duration of Response (DOR)
Median (95% CI) , in months	8.3 (4.5, NE)	NE

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

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

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

Juvenile Animal Toxicity Data

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

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