b'CABOMETYXSunitinibleading to dose interruption occurred in 84% patients receivingrandomized to receive CABOMETYX 60 mg orally once daily and Nivolumab(n=320) CABOMETYX. Adverse reactions leading to permanent(n=125) or placebo (n=62) with supportive care until disease Adverse Reaction (n=320) discontinuation of CABOMETYX occurred in 16% of patients.progression or unacceptable toxicity. At the time of the primary GradesGradesGradesGradesThe most frequent adverse reactions leading to permanentefficacy analysis, the median duration of treatment was 4.4 1-4 3-4 1-4 3-4 discontinuation of CABOMETYX were PPE (2%), fatigue (2%),months (range 0.015.7) for patients receiving CABOMETYX Percentage (%) of Patients decreased appetite (1%), diarrhea (1%), and nausea (1%). and 2.3 months (range 0.311.6) for patients receiving placebo. Infections and Infestations The median age was 66 years (range 32 to 85 years), 55% were Table 6. Adverse Reactions Occurring in 5% offemale, 70% were White, 18% were Asian, 2% were Black,Upper respiratory tract1infection k 20 0.3 8 0.3 CABOMETYX-Treated Patients in CELESTIAL2% were American Indian or Alaska Native, and 63% received Toxicity was graded per NCI CTCAE v4.prior lenvatinib.aIncludes abdominal discomfort, abdominal pain lower, abdominal painCABOMETYX PlaceboAdverse reactions occurring in25% of CABOMETYX-treated (n = 467) (n = 237) upper.Adverse Reaction patients, in order of decreasing frequency were: diarrhea, PPE, bIncludes gastroesophageal reflux disease.All 2 Grade All 2 Grade fatigue, hypertension, and stomatitis. Grade 3-4 adverse reactions cIncludes asthenia.Grades 3-4 Grades 3-4 which occurred in5% of patients were PPE, hypertension, d ncludes hepatotoxicity, ALT increased, AST increased, blood alkalinePercentage (%) of Patients fatigue, diarrhea, and stomatitis. Serious adverse reactions Iphosphatase increased, gamma-glutamyl transferase increased,Gastrointestinaloccurred in 34% of patients who received CABOMETYX. Serious autoimmune hepatitis, blood bilirubin increased, drug induced liver injury,Diarrhea 54 10 19 2 adverse reactions in 2% included diarrhea, pleural effusion, hepatic enzyme increased, hepatitis, hyperbilirubinemia, liver function test increased, liver function test abnormal, transaminases increased,Nausea 31 2 18 2 pulmonary embolism and dyspnea. Fatal adverse reactions hepatic failure. Vomiting 26 1 12 3 occurred in 1.6% of patients in the CABOMETYX arm, including eIncludes mucosal inflammation, aphthous ulcer, mouth ulceration.arterial hemorrhage (0.8%) and pulmonary embolism (0.8%). Stomatitis 13 2 2 0f Includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliativeThe median average daily dose was 42.0 mg for CABOMETYX. Dyspepsia 10 0 3 0rash, rash erythematous, rash follicular, rash macular, rash maculo- The dose was reduced in 56% of patients receiving CABOMETYX; g papular, rash papular, rash pruritic.General22% of patients required a second dose reduction. The mostIncludes blood pressure increased, blood pressure systolic increased.Fatigue 45 10 30 4h frequent adverse reactions (5%) leading to dose reduction iIncludes primary hypothyroidism.Asthenia 22 7 8 2 of CABOMETYX were PPE, diarrhea, fatigue, proteinuria, and Includes back pain, bone pain, musculoskeletal chest pain, Mucosal inflammation 14 2 2 1 decreased appetite. Dose interruptions occurred in 72% patients musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain.Metabolism andreceiving CABOMETYX. Adverse reactions requiring dosage j Includes productive cough.Nutritioninterruption in 5% of patients were PPE, diarrhea, dyspnea, kIncludes nasopharyngitis, pharyngitis, rhinitis Decreased appetite 48 6 18 1 hypertension, decreased appetite and proteinuria. Adverse Skin andreactions leading to permanent discontinuation of CABOMETYX Table 5. Laboratory Values Worsening from Baseline a Subcutaneous Tissueoccurred in 5% of patients.Occurring in 20% of Patients receiving CABOMETYX andPalmar-plantar46 17 5 0erythrodysesthesiaTable 8. Adverse Reactions Occurring in 5% of Nivolumab-CHECKMATE-9ER Rash 3 21 2 9 1 CABOMETYX-Treated Patients in COSMIC-311 1CABOMETYX andSunitinib VascularCABOMETYX Placebo LaboratoryNivolumab Hypertension 4 30 16 6 2 (N=125) (N=62) Abnormality Grades Grades Grades GradesInvestigations Adverse Reaction All GradeAll Grade 1-4 3-4 1-4 1-4 Weight decreased 17 1 6 0 Grades 2 3-4 Grades 2 3-4Percentage (%) of Patients Nervous SystemPercentage (%) of PatientsChemistry Dysgeusia 12 0 2 0 Gastrointestinal Increased ALT79 9.8 39 3.5 EndocrineDiarrhea 51 7 3 0Increased AST77 7.9 57 2.6 Hypothyroidism 8 1 1 0 Nausea 24 3 2 0Hypophosphatemia 69 28 48 10 Respiratory, Thoracic,Vomiting 14 1 8 0Hypocalcemia 54 1.9 24 0.6 and MediastinalStomatitis 3 26 5 3 0Hypomagnesemia 47 1.3 25 0.3 Dysphonia 19 1 2 0 Dry mouth 10 1 2 0Hyperglycemia 44 3.5 44 1.7 Dyspnea 12 3 10 1 General Hyponatremia 43 11 36 12 Musculoskeletal andFatigue 4 42 10 23 0Increased lipase 41 14 38 13 Connective TissueMetabolism and Nutrition Increased amylase41 10 28 6 Pain in extremity 9 1 4 1 Decreased appetite 23 3 16 0Increased alkaline41 2.8 37 1.6 1 Muscle spasms 8 1 2 0 Skin and Subcutaneous phosphataseIncludes terms with a between-arm difference of5% (all grades) or Tissue Increased creatinine 39 1.3 42 0.6 22% (Grade 3-4) Palmar-plantar Hyperkalemia 35 4.7 27 1 3NCI CTCAE Version 4.0 erythrodysesthesia46 10 0 0 Includes the following terms: rash, rash erythematous, rash generalized,Hypoglycemia 26 0.8 14 0.4 rash macular, rash maculo-papular, rash papular, rash pruritic, rashVascular Hematology pustular, rash vesicular, dermatitis, dermatitis acneiform, dermatitisHypertension 5 30 10 5 3Lymphopenia 42 6.6 45 10 4 contact, dermatitis diaper, dermatitis exfoliative, dermatitis infected Investigations Includes the following terms: hypertension, blood pressure diastolicThrombocytopenia 41 0.3 70 9.7 increased, blood pressure increased Weight decreased 18 1 5 0Anemia 37 2.5 61 4.8 Nervous System Leukopenia 37 0.3 66 5.1 Table7.LaboratoryAbnormalitiesOccurringin5%ofDysgeusia 10 0 0 0Neutropenia 35 3.2 67 12 CABOMETYX-Treated Patients in CELESTIAL 1 Headache 10 2 2 0aEach test incidence is based on the number of patients who had bothRespiratory, Thoracic,baseline and at least one on-study laboratory measurement available:CABOMETYXPlaceboand Mediastinal CABOMETYX and nivolumab group (range: 170 to 317 patients) andN=467 N=237 Dysphonia 10 0 2 0sunitinib group (range: 173 to 311 patients). Laboratory Abnormality AllGradeAllGradePulmonary embolism 5 2 0 0Hepatocellular CarcinomaGrades 3-4 Grades 3-4 Renal and UrinaryThe safety of CABOMETYX was evaluated in CELESTIAL,Percentage of Patients Proteinuria 15 1 3 0Chemistry 1Includes terms that are more frequent in the CABOMETYX arm and a randomized, double-blind, placebo-controlled trial in which 704 patients with advanced hepatocellular carcinoma wereIncreased LDH84 9 29 2 2 have a between-arm difference of5% (all grades) or2% (Grade 3-4)randomized to receive CABOMETYX 60 mg orally once dailyIncreased ALT73 12 37 6 3NCI CTCAE Version 5.0 Includes the following terms: mucosal inflammation, stomatitis(n=467) or placebo (n=237) until disease progression orIncreased AST73 24 46 19 4 Includes the following terms: fatigue, asthenia unacceptable toxicity. The median duration of treatment was 3.8Hypoalbuminemia 51 1 32 1 5Includes the following terms: hypertension, blood pressure increased,months (range 0.137.3) for patients receiving CABOMETYX andIncreased ALP43 8 38 6 hypertensive crisis2.0 months (range 0.027.2) for patients receiving placebo. TheHypophosphatemia 25 9 8 4population exposed to CABOMETYX was 81% male, 56% White,Table 9. Laboratory Abnormalities Occurring in 10% of and had a median age of 64 years.Hypokalemia 23 6 6 1 CABOMETYX-Treated Patients in COSMIC-311 1Adverse reactions occurring in25% of CABOMETYX- treatedHypomagnesemia 22 3 3 0patients, in order of decreasing frequency were: diarrhea,Increased amylase16 2 9 2 CABOMETYXPlacebo decreased appetite, PPE, fatigue, nausea, hypertension, andHypocalcemia 8 2 0 0 LaboratoryN=125 N=62vomiting. Grade 3-4 adverse reactions which occurred in5%Hematology Abnormality AllGrade AllGradeof patients were PPE, hypertension, fatigue, diarrhea, asthenia,Decreased platelets54 10 16 1 Grades 3 or 4 Grades 3 or 4and decreased appetite. There were 6 adverse reactionsNeutropenia 43 7 8 1 Percentage (%) of Patientsleading to death in patients receiving CABOMETYX (hepaticIncreased hemoglobin8 0 1 0 Chemistryfailure, hepatorenal syndrome, esophagobronchial fistula, portal1Includes laboratory abnormalities with a between-arm difference of5%LDH increased 2 90 10 32 3 vein thrombosis, pulmonary embolism, upper gastrointestinal(all grades) or2% (Grade 3-4) AST increased77 1 18 0hemorrhage).ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartateALT increased66 2 11 0The median average daily dose was 35.8 mg for CABOMETYX.aminotransferase; LDH, blood lactate dehydrogenaseHypocalcemia 36 9 10 2The dose was reduced in 62% of patients receiving CABOMETYX;Differentiated Thyroid Cancer ALP increased34 0 15 033% of patients required a reduction to 20 mg daily. The most frequent adverse reactions or laboratory abnormalities leadingThe safety of CABOMETYX was evaluated in COSMIC-311,GGT increased26 2 21 2to dose reduction of CABOMETYX were: PPE, diarrhea,a randomized, double-blind, placebo-controlled trial in whichHypomagnesemia 25 2 5 0fatigue, hypertension, and increased AST. Adverse reactions187 patients with advanced differentiated thyroid cancer wereHypoalbuminemia 19 1 7 072299_Exelixis_Cabometyx_HCP-Brief_USMedicine_7-875x10-75_r3v1jl.indd 3 11/30/21 10:03 AM'