b'CABOMETYXEverolimus CABOMETYX and 3.1 months (range 0.225.5) for patientsCABOMETYX Sunitinib(n=331)1 (n=322) receiving sunitinib. Adverse Reaction (n = 78) (n = 72)Adverse Reaction All GradeAllGradeWithin 30 days of treatment, there were 4 deaths in patients treatedGrade 3-4 1 Grade 3-4 1Grades 2 3-4 Grades 2 3-4 with CABOMETYX and 6 deaths in patients treated with sunitinib.Percentage (%) of PatientsOf the 4 patients treated with CABOMETYX, 2 patients died due to Percentage (%) of Patients gastrointestinal perforation, 1 patient had acute renal failure, andRenal and UrinarySkin and Subcutaneous1 patient died due to clinical deterioration. All Grade 3-4 adverseRenal failure acute 4 1Tissue reactions were collected in the entire safety population. The mostProteinuria 3 1Palmar-plantarfrequent Grade 3-4 adverse reactions (5%) in patients treatedALT, alanine aminotransferase; AST, aspartate aminotransferaseerythrodysesthesia 42 8 6 1 with CABOMETYX were hypertension, diarrhea, hyponatremia,1NCI CTCAE Version 4.0Rash 4 23 1 43 1 hypophosphatemia, PPE, fatigue, increased ALT, decreased2Laboratory abnormalities are reported as adverse reactions and notDry skin 11 0 10 0 appetite, stomatitis, pain, hypotension, and syncope.3 based on shifts in laboratory valuesVascular The median average daily dose was 50.3 mg for CABOMETYX Includes the following term: hypertensionHypertension 5 39 16 8 3 and 44.7 mg for sunitinib (excluding scheduled sunitinib non- CHECKMATE-9ER Investigations dosing days). The dose was reduced in 46% of patients receivingThe safety of CABOMETYX with nivolumab was evaluated in Weight decreased 31 2 12 0 CABOMETYX and in 35% of patients receiving sunitinib. The doseCHECKMATE-9ER, a randomized, open-label study in patients Nervous System was held in 73% of patients receiving CABOMETYX and in 71%with previously untreated advanced RCC. Patients received Dysgeusia 24 0 9 0 of patients receiving sunitinib. Based on patient disposition, 21%CABOMETYX 40 mg orally once daily with nivolumab 240 mg Headache 11 1 12 1 of patients receiving CABOMETYX and 22% of patients receivingover 30 minutes every 2 weeks (n=320) or sunitinib 50 mg Dizziness 11 0 7 0 sunitinib discontinued due to an adverse reaction.daily, administered orally for 4 weeks on treatment followed Endocrine Table 3. Grade 3-4 Adverse Reactions Occurring in1%by 2 weeks off (n=320). CABOMETYX could be interrupted or Hypothyroidism 21 0 1 1 Patients Who Received CABOMETYX in CABOSUN 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 Respiratory, Thoracic,CABOMETYX Sunitinib CABOMETYX and nivolumab-treated patients. In this trial, 82% of and Mediastinal Adverse Reaction (n = 78) (n = 72) patients in the CABOMETYX and nivolumab arm were exposed Dysphonia 20 1 4 0 Grade 3-4 1 Grade 3-4 1 to treatment for 6 months and 60% of patients were exposed to Dyspnea 19 3 29 4 Percentage (%) of Patients treatment for 1 year. Cough 18 1 33 1 Patients with any Grade68 65 Serious adverse reactions occurred in 48% of patients receiving Blood and Lymphatic 3-4 Adverse Reaction CABOMETYX and nivolumab. Anemia 17 5 38 16 The most frequent (2%) serious adverse reactions were Musculoskeletal andGastrointestinal diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary Connective Tissue Diarrhea 10 11 tract infection, and hyponatremia. Fatal intestinal perforations Pain in extremity 14 1 8 1 Stomatitis 5 6 occurred in 3 (0.9%) patients. Muscle spasms 13 0 5 0 Nausea 3 4 Adverse reactions leading to discontinuation of either CABOMETYX Arthralgia 11 1 14 1 Vomiting 1 3 or nivolumab occurred in 20% of patients: 8% CABOMETYX only, Renal and Urinary Constipation 1 0 7% nivolumab only, and 6% both drugs due to the same adverse Proteinuria 12 2 9 1 General reaction at the same time. Adverse reactions leading to dose 1One subject randomized to everolimus received cabozantinib. interruption or reduction of either CABOMETYX or nivolumab 2Fatigue 6 17National Cancer Institute (NCI) Common Terminology Criteria foroccurred in 83% of patients: 46% CABOMETYX only, 3% nivolumab Adverse Events (CTCAE) Version 4.0 Pain 5 0 only, and 21% both drugs due to the same adverse reaction at the 3Includes the following terms: abdominal pain, abdominal pain upper, andMetabolism and Nutrition same time, and 6% both drugs sequentially.4abdominal pain lower Hyponatremia 2 9 8 The most common adverse reactions reported in 20% of patients Includes the following terms: rash, rash erythematous, rash follicular,2Hypophosphatemia 9 7 treated with CABOMETYX and nivolumab were diarrhea, fatigue, rash macular, rash papular, rash pustular, rash vesicular, genital rash, intermittent leg rash, rash on scrotum and penis, rash maculo-papular,Decreased appetite 5 1 hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, rash pruritic, contact dermatitis, dermatitis acneiform Dehydration 4 1 musculoskeletal pain, decreased appetite, nausea, dysgeusia, 5Includes the following terms hypertension, blood pressure increased,2 abdominal pain, cough, and upper respiratory tract infection.Hypocalcemia 3 0hypertensive crisis, blood pressure fluctuation Hypomagnesemia 2 3 0 Table 4. Adverse Reactions in 15% of Patients receiving Other clinically important adverse reactions (all grades) that wereHyperkalemia 2 1 3 CABOMETYX and Nivolumab-CHECKMATE-9ERreported in 10% of patients treated with CABOMETYX included:Skin and SubcutaneousCABOMETYXSunitinib wound complications (2%), convulsion (1%), pancreatitis (1%),Tissueand Nivolumab(n=320)osteonecrosis of the jaw (1%), and hepatitis cholestatic (1%). Palmar-plantar8 4 Adverse Reaction (n=320)erythrodysesthesia GradesGradesGradesGrades Table 2. Laboratory Abnormalities Occurring in25%Skin ulcer 3 0 1-4 3-4 1-4 3-4Patients Who Received CABOMETYX in METEOR Vascular Percentage (%) of PatientsCABOMETYXEverolimus Hypertension 3 28 21 Gastrointestinal Laboratory Abnormality(n=331) (n=322) Hypotension 5 1 Diarrhea 64 7 47 4.4AllGradeAllGradeAngiopathy 1 1 Nausea 27 0.6 31 0.3Grades 3-4 Grades 3-4 Investigations Abdominal Pain a 22 1.9 15 0.3Percentage (%) of Patients Increased ALT 2 5 0 Vomiting 17 1.9 21 0.3Chemistry Weight decreased 4 0 Dyspepsia b 15 0 22 0.3Increased AST74 3 40 1 Increased AST 2 3 3 General Increased ALT68 3 32 1 Increased blood cIncreased creatinine58 1 71 0 creatinine 2 3 3 Fatigue 51 8 50 8Increased triglycerides53 4 73 13 Lymphopenia 2 1 6 Hepatobiliary dHypophosphatemia 48 8 36 5 Thrombocytopenia 2 1 11 Hepatotoxicity 44 11 26 5Hyperglycemia 37 2 59 8 Nervous System Skin and Subcutaneous Tissue Hypoalbuminemia 36 2 28 1 Syncope 5 0 Palmar-plantar40 8 41 8erythrodysesthesiaIncreased ALP35 2 29 1 Respiratory, Thoracic, andStomatitis e 37 3.4 46 4.4Hypomagnesemia 31 7 4 1 Mediastinal Rash f 36 3.1 14 0Hyponatremia 30 8 26 6 Dyspnea 1 6 Pruritis 19 0.3 4.4 0Increased GGT27 5 43 9 Dysphonia 1 0 Vascular Hematology Blood and Lymphatic Hypertension g 36 13 39 14Leukopenia35 1 31 1 Anemia 1 3 Endocrine Neutropenia31 2 17 1 Psychiatric Hypothyroidism h 34 0.3 30 0.3Anemia 1 31 4 71 17 Depression 4 0 Musculoskeletal and Connective Tissue Lymphopenia 25 7 39 12 Confusional state 1 1 Musculoskeletal pain i 33 3.8 29 3.1Thrombocytopenia 25 1 27 1 Infections Arthralgia 18 0.3 9 0.3ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartateLung infection 4 0 Metabolism and Nutrition aminotransferase; GGT, gamma glutamyl transferase.Musculoskeletal and NCI CTCAE, Version 4.0 Connective Tissue Decreased appetite 28 1.9 20 1.31Based on laboratory abnormalities Back pain 4 0 Nervous System Disorders Bone pain 3 1 Dysgeusia 24 0 22 0CABOSUNPain in extremity 3 0 Headache 16 0 12 0.6The safety of CABOMETYX was evaluated in CABOSUN, aArthralgia 1 0 Respiratory, Thoracic, and Mediastinal randomized, open-label trial in patients with advanced renal cellCough j 20 0.3 17 0carcinoma, in which 78 patients received CABOMETYX 60 mgDysphonia 17 0.3 3.4 0once 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. The median duration of treatment was 6.5 months (range 0.228.7) for patients receiving 72299_Exelixis_Cabometyx_HCP-Brief_USMedicine_7-875x10-75_r3v1jl.indd 2 11/30/21 10:03 AM'