b'BALANCE OF DAT+ A A CheckMate-9ER study designERIOP nitini RU vs su b 1-4 * O S A randomized (1:1), open-label, Phase 3 trial Svs sunitinib in 651 patients with previously untreated aRCC with a clear-cell component. The trial evaluated CABOMETYX 40 mg (starting dose) PO once daily in combination with OPDIVO 240 mg flat dose IV every 2 weeks vs sunitinib 50 mg (starting dose) PO once daily for 4 weeks, followed by 2 weeks 1L aRCC treatment that off, per cycle. The primary endpoint was PFS, and secondary endpoints included OS, OFFERS A BALANCE OF DATA: ORR, and safety. 1,3,4,7T Ssuperior OS,* safety & tolerability,O A National L F NCCN Comprehensive Y6R T TEpatient-reported quality of life CATEGORY 1 Cancer Network 1-6 EI E PREFERRED (NCCN)A Y L I FA A L (OPDIVO) is a 1L combination with aB Cabozantinib (CABOMETYX) + nivolumab I UI D Q F IMDC risk groups in clear-cell aRCC 84 L N Category 1, preferred designation across all * vs sunitinib in patients with previously untreated aRCC.Y Ohe primary endpoint was PFS (16.6 months with CABOMETYX + OPDIVO vs 8.3 months with sunitinib; HR=0.51; 95% CI: 0.41-0.64; P0.0001). T T 1,5The secondary endpoints included OS (40% reduction in risk of death with CABOMETYX + OPDIVO vs sunitinib; HR=0.60; 98.89% CI: 0.40-0.89;= P0.001; 1,4 NCCN makes no warranties of any kind whatsoever regarding their median OS was not reached in either arm), ORR, and safety. content, use or application and disclaims any responsibility for their application or use in any way. Quality of life was evaluated as an exploratoryINDICATIONS endpoint using the FKSI-19 scale, and the clinical CABOMETYX (cabozantinib), in combination with nivolumab, is indicated for the first-line treatment of patients with advanced renal cellsignificance is unknown.4,6carcinoma (RCC). CABOMETYX is indicated for the treatment of patients with advanced RCC.development of ONJ until complete resolution, resume at a reduced dose . CABOMETYXincombinationwithnivolumab:diarrhea,fatigue, IMPORTANT SAFETY INFORMATION treatment. Consider more frequent monitoring of liver enzymes than when theImpairedWoundHealing:Woundcomplicationsoccurredwithhepatotoxicity,PPE,stomatitis,rash,hypertension,hypothyroidism, WARNINGS AND PRECAUTIONS drugs are administered as single agents. For elevated liver enzymes, interruptCABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to electivemusculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX.CABOMETYX and nivolumab and consider administering corticosteroids. surgery. Do not administer CABOMETYX for at least 2 weeks after majorpain, cough, and upper respiratory tract infection.The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYXWith the combination of CABOMETYX and nivolumab, Grades 3 and 4surgeryanduntiladequatewoundhealing.Thesafetyofresumption DRUG INTERACTIONSpatients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Gradeincreased ALT or AST were seen in 11% of patients. ALT or AST 3 times ULNof CABOMETYX after resolution of wound healing complications has notStrongCYP3A4Inhibitors:IfcoadministrationwithstrongCYP3A4 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer(Grade 2) was reported in 83 patients, of whom 23 (28%) received systemicbeen established. inhibitorscannotbeavoided,reducetheCABOMETYXdosage.Avoid CABOMETYXtopatientswhohavearecenthistoryofhemorrhage,corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among theReversiblePosteriorLeukoencephalopathySyndrome(RPLS): RPLS,agrapefruit or grapefruit juice.including hemoptysis, hematemesis, or melena.44 patients with Grade 2 increased ALT or AST who were rechallengedsyndromeofsubcorticalvasogenicedemadiagnosedbycharacteristicStrongCYP3A4Inducers:IfcoadministrationwithstrongCYP3A4 Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% ofwith either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or withfindings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patientsinducers cannot be avoided, increase the CABOMETYX dosage. AvoidCABOMETYX patients. Gastrointestinal (GI) perforations, including fatalboth (n=24), recurrence of Grade 2 increased ALT or AST was observed inpresenting with seizures, headache, visual disturbances, confusion, or alteredSt. Johns wort.cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7mental function. Discontinue CABOMETYX in patients who develop RPLS.and symptoms of fistulas and perforations, including abscess and sepsis.patients receiving both CABOMETYX and nivolumab. Withhold and resumeThyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, hasUSE IN SPECIFIC POPULATIONSDiscontinue CABOMETYX in patients who experience a Grade 4 fistula orat a reduced dose based on severity. been observed with CABOMETYX. Based on the safety population, thyroidLactation: Advise women not to breastfeed during CABOMETYX treat-a GI perforation.Adrenal Insufficiency: CABOMETYXincombinationwithnivolumabcandysfunction occurred in 19% of patients treated with CABOMETYX, includingment and for 4 months after the final dose.Thrombotic Events: CABOMETYX increased the risk of thrombotic events.cause primary or secondary adrenal insufficiency. For Grade 2 or higherGrade 3 in 0.4% of patients. HepaticImpairment:Inpatientswithmoderatehepaticimpairment, Venousthromboembolismoccurredin7%(including4%pulmonaryadrenalinsufficiency,initiatesymptomatictreatment,includinghormonePatients should be assessed for signs of thyroid dysfunction prior to thereduce the CABOMETYX dosage. Avoid CABOMETYX in patients with embolism) and arterial thromboembolism in 2% of CABOMETYX patients.replacement as clinically indicated. Withhold CABOMETYX and/or nivolumabinitiation of CABOMETYX and monitored for signs and symptoms of thyroidsevere hepatic impairment.Fatal thrombotic events occurred in CABOMETYX patients. Discontinueand resume CABOMETYX at a reduced dose depending on severity. dysfunction during CABOMETYX treatment. Thyroid function testing and CABOMETYX in patients who develop an acute myocardial infarction orAdrenal insufficiency occurred in 4.7% (15/320) of patients with RCC whomanagement of dysfunction should be performed as clinically indicated. 1L=first-line; aRCC=advanced renal cell carcinoma; CI=confidence interval; FKSI-19= Functional Assessment of Cancer Therapy-Kidney Symptom Index 19; HR=hazard ratio; serious arterial or venous thromboembolic events that require medicalreceived CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safetyIMDC=International Metastatic RCC Database Consortium; IV=intravenous; ORR=overall intervention. (1.9%)adversereactions.Adrenalinsufficiencyledtopermanentpopulation,hypocalcemiaoccurredin13%ofpatientstreatedwithresponse rate; OS=overall survival; PFS=progression-free survival; PO=orally.HypertensionandHypertensiveCrisis:CABOMETYXcancausediscontinuation of CABOMETYX and nivolumab in 0.9% and withholding ofCABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients.References: 1. CABOMETYX (cabozantinib) Prescribing Information. Exelixis, Inc, 2021 . hypertension, including hypertensive crisis. Hypertension was reported inCABOMETYX and nivolumab in 2.8% of patients with RCC. Laboratory abnormality data were not collected in CABOSUN. 2. Data on file. Topline 9ER. Exelixis, Inc3. . Motzer RJ, Choueiri TK, Powles T, et al. Nivolumab 37% (16% Grade 3 and 1% Grade 4) of CABOMETYX patients. Do not initiateIn COSMIC-311, hypocalcemia occurred in 36% of patients treated withpluscabozantinibversussunitinibforadvancedrenalcellcarcinoma:outcomesby CABOMETYX in patients with uncontrolled hypertension. Monitor bloodApproximately 80% (12/15) of patients with adrenal insufficiency receivedCABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients. sarcomatoid histology and updated trial results with extended follow-up of CheckMate pressure regularly during CABOMETYX treatment. Withhold CABOMETYXhormone replacement therapy, including systemic corticosteroids. Adrenal9ER.Posterpresentedat:GenitourinaryCancersSymposium;February11-13,2021 . insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients inMonitorbloodcalciumlevelsandreplacecalciumasnecessaryduring4. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus for hypertension that is not adequately controlled with medical management;whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6treatment.Withholdandresumeatreduceddoseuponrecoveryorcabozantinibversussunitinibforadvancedrenal-cellcarcinoma. NEnglJMed. whencontrolled,resumeatareduceddose.Permanentlydiscontinuereinstated treatment after symptom improvement; of these, all (n=6) receivedpermanently discontinue CABOMETYX depending on severity. 2021;384(9):829-841. 5. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib CABOMETYX for severe hypertension that cannot be controlled with anti- versus sunitinib in first-line treatment for advanced renal cell carcinoma: first results from hypertensive therapy or for hypertensive crisis.hormone replacement therapy and 2 had recurrence of adrenal insufficiency. Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnantthe randomized phase 3 CheckMate 9ER trial. Presented at: European Society for Medical Proteinuria: Proteinuriawasobservedin8%ofCABOMETYXpatients.women and females of reproductive potential of the potential risk to a fetus.Oncology (ESMO) Virtual Congress 2020; September 19-21, 2020. Presentation 6960 . Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrheaMonitor urine protein regularly during CABOMETYX treatment. For Grade 2Verify the pregnancy status of females of reproductive potential prior to6. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus occurred in 10% of CABOMETYX patients. Monitor and manage patients usingor 3 proteinuria, withhold CABOMETYX until improvement toGrade 1initiating CABOMETYX and advise them to use effective contraceptioncabozantinibversussunitinibforadvancedrenal-cellcarcinoma[supplementary antidiarrheals as indicated. Withhold CABOMETYX until improvement toproteinuria,resumeCABOMETYXatareduceddose.Discontinueduring treatment and for 4 months after the last dose. appendix]. N Engl J Med. 2021;384(9):829-841. 7. Apolo AB, Powles T, Burotto M, et al. Grade 1, resume at a reduced dose.Nivolumab plus cabozantinib versus sunitinib for advanced renal cell carcinoma: outcomes CABOMETYX in patients who develop nephrotic syndrome . by baseline disease characteristics in the phase 3 CheckMate 9ER trial. Poster presented at: Palmar-PlantarErythrodysesthesia(PPE):PPEoccurredin45%ofOsteonecrosis of the Jaw (ONJ): ONJ occurred in 1% of CABOMETYXADVERSE REACTIONS AmericanSocietyofClinicalOncology(ASCO)AnnualMeeting;June4-8,202 1. CABOMETYXpatients.Grade3PPEoccurredin13%ofCABOMETYXpatients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion,The most common (20%) adverse reactions are: 8. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology patients. Withhold CABOMETYX until improvement to Grade 1 and resumetooth or periodontal infection, toothache, gingival ulceration or erosion,CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite,(NCCNGuidelines)forKidneyCancerV1.2022.NationalComprehensiveCancer at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE . persistent jaw pain, or slow healing of the mouth or jaw after dental surgery.hypertension, nausea, vomiting, weight decreased, constipation.Network, Inc. 2021. All rights reserved. Accessed July 27, 2021. To view the most recent and Hepatotoxicity: CABOMETYXincombinationwithnivolumabcancausePerform an oral examination prior to CABOMETYX initiation and periodicallycomplete version of the guideline, go online to NCCN.org.hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and ASTduring treatment. Advise patients regarding good oral hygiene practices.For additional safety information, please see Brief Summary of elevations compared to CABOMETYX alone. WithholdCABOMETYXforatleast3weekspriortoscheduleddentalthe Prescribing Information for CABOMETYX on adjacent pages.Monitorliverenzymesbeforeinitiationofandperiodicallythroughoutsurgery or invasive dental procedures, if possible. Withhold CABOMETYX forDiscover more at You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatchCABOMETYXhcp.comor call 1-800-FDA-1088. 2021 Exelixis, Inc.CA-1750-2 09/21OPDIVO and the related logo is a registered trademark of Bristol-Myers Squibb Company.72299_CA-1750-2_RCC_2_Page_Journal_Ad_USMedicine_7-875x10-75_r2v1jl.indd All Pages 11/30/21 10:10 AM'