b'BLEED: 8.375"w TRIM: 7.875"w SAFETY: 6.875"w CABOMETYXSunitinibto dose reduction of CABOMETYX were: PPE, diarrhea,Differentiated Thyroid Cancerand Nivolumab(n=320) fatigue, hypertension, and increased AST. Adverse reactionsThe safety of CABOMETYX was evaluated in COSMIC-311, Adverse Reaction (n=320) leading to dose interruption occurred in 84% patients receivinga randomized, double-blind, placebo-controlled trial in which CODE_CABOMETYX_RCC_3PG_Efficacy In Balance JournalAd_7.875" x 10.5_A-Size_Page GradesGradesGradesGradesCABOMETYX. Adverse reactions leading to permanent187 patients with advanced differentiated thyroid cancer wereSAFETY: 9.5"hTRIM: 10.5"hBLEED: 11.25"h 1-4 3-4 1-4 3-4 discontinuation of CABOMETYX occurred in 16% of patients.randomized to receive CABOMETYX 60 mg orally once daily Percentage (%) of Patients The most frequent adverse reactions leading to permanent(n=125) or placebo (n=62) with supportive care until disease Infections and Infestations discontinuation of CABOMETYX were PPE (2%), fatigue (2%),progression or unacceptable toxicity. At the time of the primary Upper respiratory tractdecreased appetite (1%), diarrhea (1%), and nausea (1%). efficacy analysis, the median duration of treatment was 4.4 infection k 20 0.3 8 0.3 months (range 0.015.7) for patients receiving CABOMETYX Toxicity was graded per NCI CTCAE v4.Table 6. Adverse Reactions Occurring in 5% ofand 2.3 months (range 0.311.6) for patients receiving placebo. aIncludes abdominal discomfort, abdominal pain lower, abdominalCABOMETYX-Treated Patients in CELESTIAL 1 The median age was 66 years (range 32 to 85 years), 55% wereb pain upper.CABOMETYX Placebofemale, 70% were White, 18% were Asian, 2% were Black, 2% cIncludes gastroesophageal reflux disease.(n = 467) (n = 237)were American Indian or Alaska Native, and 63% received prior dIncludes asthenia.Adverse Reaction All Grade All Grade lenvatinib. Includes hepatotoxicity, ALT increased, AST increased, blood alkaline2 2 Adverse reactions occurring in25% of CABOMETYX-Grades 3-4 Grades 3-4phosphatase increased, gamma-glutamyl transferase increased, autoimmune hepatitis, blood bilirubin increased, drug induced liverPercentage (%) of Patients treated patients, in order of decreasing frequency were: injury, hepatic enzyme increased, hepatitis, hyperbilirubinemia, liverGastrointestinaldiarrhea, PPE, fatigue, hypertension, and stomatitis. Grade function test increased, liver function test abnormal, transaminasesDiarrhea 54 10 19 2 3-4 adverse reactions which occurred in5% of patients were e increased, hepatic failure. Nausea 31 2 18 2 PPE, hypertension, fatigue, diarrhea, and stomatitis. SeriousIncludes mucosal inflammation, aphthous ulcer, mouth ulceration.adverse reactions occurred in 34% of patients who receivedf Includes dermatitis, dermatitis acneiform, dermatitis bullous,Vomiting 26 1 12 3 CABOMETYX. Serious adverse reactions in 2% includedexfoliative rash, rash erythematous, rash follicular, rash macular,Stomatitis 13 2 2 0 diarrhea, pleural effusion, pulmonary embolism and dyspnea. g rash maculo-papular, rash papular, rash pruritic.Dyspepsia 10 0 3 0 Fatal adverse reactions occurred in 1.6% of patients in the ncludes blood pressure increased, blood pressure systolic increased. h I GeneralCABOMETYX arm, including arterial hemorrhage (0.8%) andIncludes primary hypothyroidism. i Includes back pain, bone pain, musculoskeletal chest pain,Fatigue 45 10 30 4 pulmonary embolism (0.8%).musculoskeletal discomfort, myalgia, neck pain, pain in extremity,Asthenia 22 7 8 2 The median average daily dose was 42.0 mg for CABOMETYX. spinal pain.Mucosal inflammation 14 2 2 1 The dose was reduced in 56% of patients receiving CABOMETYX; j k Includes productive cough.Metabolism and22% of patients required a second dose reduction. The mostIncludes nasopharyngitis, pharyngitis, rhinitis Nutritionfrequent adverse reactions (5%) leading to dose reduction Decreased appetite 48 6 18 1 of CABOMETYX were PPE, diarrhea, fatigue, proteinuria, and Table 5. Laboratory Values Worsening from Baseline a Skin anddecreased appetite. Dose interruptions occurred in 72% patients Occurring in 20% of Patients receiving CABOMETYX andSubcutaneous Tissuereceiving CABOMETYX. Adverse reactions requiring dosage Nivolumab-CHECKMATE-9ER Palmar-plantarinterruption in 5% of patients were PPE, diarrhea, dyspnea, erythrodysesthesia46 17 5 0 hypertension, decreased appetite and proteinuria. Adverse CABOMETYXSunitinib Rash 3 21 2 9 1 reactions leading to permanent discontinuation of CABOMETYX Laboratoryand Nivolumab Vascularoccurred in 5% of patients.Abnormality Grades Grades Grades GradesHypertension 4 30 16 6 2 Table 8. Adverse Reactions Occurring in 5% of 1-4 3-4 1-4 1-4 Investigations CABOMETYX-Treated Patients in COSMIC-311 1Percentage (%) of Patients Weight decreased 17 1 6 0Chemistry Nervous SystemCABOMETYX Placebo Increased ALT79 9.8 39 3.5 Dysgeusia 12 0 2 0 Adverse Reaction (N=125) (N=62) Increased AST77 7.9 57 2.6 All GradeAll Grade Hypophosphatemia 69 28 48 10 EndocrineGrades 2 3-4 Grades 2 3-4Hypocalcemia 54 1.9 24 0.6 Hypothyroidism 8 1 1 0 Percentage (%) of PatientsHypomagnesemia 47 1.3 25 0.3 Respiratory, Thoracic,Gastrointestinal Hyperglycemia 44 3.5 44 1.7 and MediastinalDiarrhea 51 7 3 0Hyponatremia 43 11 36 12 Dysphonia 19 1 2 0 Nausea 24 3 2 0Increased lipase 41 14 38 13 Dyspnea 12 3 10 1 Vomiting 14 1 8 0Increased amylase41 10 28 6 Musculoskeletal andStomatitis 3 26 5 3 0Increased alkalineConnective TissueDry mouth 10 1 2 0phosphatase 41 2.8 37 1.6 Pain in extremity 9 1 4 1 General Increased creatinine 39 1.3 42 0.6 1 Muscle spasms 8 1 2 0 Fatigue 4 42 10 23 0 Includes terms with a between-arm difference of5% (all grades)Hyperkalemia 35 4.7 27 1 or2% (Grade 3-4) Metabolism and Hypoglycemia 26 0.8 14 0.4 2NCI CTCAE Version 4.0 Nutrition 3Includes the following terms: rash, rash erythematous, rash generalized,Decreased appetite 23 3 16 0HematologyLymphopenia 42 6.6 45 10 rash macular, rash maculo-papular, rash papular, rash pruritic, rashSkin and Subcutaneous pustular, rash vesicular, dermatitis, dermatitis acneiform, dermatitisTissue Thrombocytopenia 41 0.3 70 9.7 4 contact, dermatitis diaper, dermatitis exfoliative, dermatitis infected Palmar-plantar Anemia 37 2.5 61 4.8Includes the following terms: hypertension, blood pressure diastolic46 10 0 0erythrodysesthesia Leukopenia 37 0.3 66 5.1 increased, blood pressure increased Vascular Neutropenia 35 3.2 67 12 Hypertension 5 30 10 5 3aEach test incidence is based on the number of patients who hadTable7.LaboratoryAbnormalitiesOccurringin5%of Investigationsboth baseline and at least one on-study laboratory measurementCABOMETYX-Treated Patients in CELESTIAL 1available: CABOMETYX and nivolumab group (range: 170 to 317Weight decreased 18 1 5 0patients) and sunitinib group (range: 173 to 311 patients). CABOMETYXPlaceboNervous System LaboratoryN=467 N=237 Dysgeusia 10 0 0 0Hepatocellular CarcinomaAbnormality AllGradeAllGradeHeadache 10 2 2 0The safety of CABOMETYX was evaluated in CELESTIAL,Grades 3-4 Grades 3-4 Respiratory, Thoracic, a randomized, double-blind, placebo-controlled trial in whichPercentage of Patients and Mediastinal 704 patients with advanced hepatocellular carcinoma wereChemistry Dysphonia 10 0 2 0randomized to receive CABOMETYX 60 mg orally once dailyIncreased LDH84 9 29 2 Pulmonary embolism 5 2 0 0(n=467) or placebo (n=237) until disease progression orIncreased ALT73 12 37 6 Renal and Urinaryunacceptable toxicity. The median duration of treatment was 3.8Increased AST73 24 46 19 Proteinuria 15 1 3 0months (range 0.137.3) for patients receiving CABOMETYXHypoalbuminemia 51 1 32 1 1Includes terms that are more frequent in the CABOMETYX arm and 2.0 months (range 0.027.2) for patients receiving placebo. The population exposed to CABOMETYX was 81% male, 56%Increased ALP43 8 38 6 and have a between-arm difference of5% (all grades) or2% White, and had a median age of 64 years.Hypophosphatemia 25 9 8 4 2 (Grade 3-4) NCI CTCAE Version 5.0Adverse reactions occurring in25% of CABOMETYX- treatedHypokalemia 23 6 6 1 3Includes the following terms: mucosal inflammation, stomatitis patients, in order of decreasing frequency were: diarrhea,Hypomagnesemia 22 3 3 0 4Includes the following terms: fatigue, asthenia decreased appetite, PPE, fatigue, nausea, hypertension, andIncreased amylase16 2 9 2 5Includes the following terms: hypertension, blood pressurevomiting. Grade 3-4 adverse reactions which occurred in5%Hypocalcemia 8 2 0 0 increased, hypertensive crisisof patients were PPE, hypertension, fatigue, diarrhea, asthenia,Hematologyand decreased appetite. There were 6 adverse reactionsDecreased platelets54 10 16 1leading to death in patients receiving CABOMETYX (hepaticNeutropenia 43 7 8 1failure, hepatorenal syndrome, esophagobronchial fistula, portalIncreased hemoglobin8 0 1 0vein thrombosis, pulmonary embolism, upper gastrointestinal1hemorrhage). Includes laboratory abnormalities with a between-arm difference of 5% (all grades) or2% (Grade 3-4)The median average daily dose was 35.8 mg for CABOMETYX.ALP,alkalinephosphatase; ALT,alanineaminotransferase; AST, The dose was reduced in 62% of patients receiving CABOMETYX;aspartate aminotransferase; LDH, blood lactate dehydrogenase 33% of patients required a reduction to 20 mg daily. The most frequent adverse reactions or laboratory abnormalities leading 72582_CA-1121-5_Exelixis_Cabometyx_HCP-Brief_7-75x10-75_r1v1jl.indd 3 8/5/22 12:29 PM'