b'BLEED: 16.75"wTRIM: 15.75"w SAFETY: 14.75"w Superior PFS and ORR results in the ITT population in theEarly and sustained separation of OS curves in the primary analysis 1 primary analysis 1CODE_CABOMETYX_RCC_3PG_Efficacy In Balance JournalAd_15.75" x 10.5_A-Size_Spread Median follow-up time of 18.1 months; range: 10.6-30.6 months 2 SAFETY: 9.5"hTRIM: 10.5"hBLEED: 11.25"hSecondary endpointPrimary endpoint Secondary endpoint 100 40% REDUCTION in risk of death(HR=0.60) CheckMate-9ER study design 1,2,5MEDIAN PFS WAS DOUBLED 1 * ORR WAS DOUBLED 1 * 90A randomized (1:1), open-label, Phase 3 trial 80 vs sunitinib in 651 patients with previously % % untreated aRCC with a clear-cell component. 16.6 vs 8.355.7 vs 27.1 8% CR 4.6%70 The trial evaluated CABOMETYX 40 mg OS (probability)vs 60 (starting dose) PO once daily in combination months HR=0.51months CABOMETYXP0.0001 sunitinib (n=26/323) (n=15/328) 50 Median with OPDIVO 240 mgat dose IV every (95% CI: CABOMETYXsunitinib 2 weeks vs sunitinib 50 mg (starting dose) PO CABOMETYX0.41-0.64) sunitinib + OPDIVO + OPDIVO 40 once daily for 4 weeks, followed by 2 weeks + OPDIVO P0.0001 30 o , per cycle. The primary endpoint was PFS, PR 98.89% CI: 0.40-0.89 and secondary endpoints included OS, ORR, 20 and safety. PFS and ORR were assessed by 48% vs 23%10 P=0.001 CABOMETYX + OPDIVO (n=323) BICR. Quality of life was evaluated as an (95% CI:(95% CI:(95% CI:(95% CI:(n=154/323) (n=74/328) sunitinib (n=328) Median OS not reached in either treatment arm.1 exploratory endpoint using the FKSI-19 scale, 12.5-24.9;7.0-9.7;50.1-61.2;22.4-32.3;CABOMETYXsunitinib 0 and the clinical signi cance is unknown. n=323) n=328) n=323) n=328)+ OPDIVO 0 3 6 9 12 15 18 21 24 27 30 Other exploratory endpoints included biomarkers, PK, immunogenicity, and PFS-2. Months An updated efficacy analysis was conducted * PFS and ORR were assessed by BICR. 1 Patients at risk when 271 events were observed based on 323 308 295 283 259 184 106 55 11 3 0 the pre-speci ed number of events for the 328 296 273 253 223 154 833610 3 0 pre-plannednal analysis of OS.Final analysis of OS (median follow-up: 32.9 months; range: 25.4-45.4 months): Median OS was 37.7 months for CABOMETYX + OPDIVO (95% CI: 35.5-NR;IMPORTANT SAFETY INFORMATION (contd) Approximately 80% (12/15) of patients with adrenal insufficiency1,67WARNINGS AND PRECAUTIONS received hormone replacement therapy, including systemicn=323) compared with 34.3 months for sunitinib (95% CI: 29.0-NR; n=328); HR=0.70 (95% CI: 0.55-0.90).Diarrhea:Diarrhea occurred in 62% of CABOMETYX patients.corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 Grade 3 diarrhea occurred in 10% of CABOMETYX patients.patients. Of the 9 patients in whom CABOMETYX with nivolumab was Monitor and manage patients using antidiarrheals as indicated.withheld for adrenal insufficiency, 6 reinstated treatment afterHypocalcemia: CABOMETYX can cause hypocalcemia. Based onHepatic Impairment: In patients with moderate hepatic impairment, Withhold CABOMETYX until improvement toGrade 1, resume atsymptom improvement; of these, all (n=6) received hormonethe safety population, hypocalcemia occurred in 13% of patientsreduce the CABOMETYX dosage. Avoid CABOMETYX in patients a reduced dose.replacement therapy and 2 had recurrence of adrenal insufficiency. treated with CABOMETYX, including Grade 3 in 2% and Grade 4with severe hepatic impairment.Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 45% ofProteinuria: Proteinuria was observed in 8% of CABOMETYX patients.in 1% of patients. Laboratory abnormality data were not collected CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYXMonitor urine protein regularly during CABOMETYX treatment. Forin CABOSUN. You are encouraged to report negative side e ects of patients. Withhold CABOMETYX until improvement to Grade 1 andGrade 2 or 3 proteinuria, withhold CABOMETYX until improvementIn COSMIC-311, hypocalcemia occurred in 36% of patients treatedprescription drugs to the FDA. Visit www.FDA.gov/medwatchresume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.toGrade 1 proteinuria, resume CABOMETYX at a reduced dose.with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3%or call 1-800-FDA-1088.Hepatotoxicity:CABOMETYX in combination with nivolumab canDiscontinue CABOMETYX in patients who develop nephrotic syndrome. of patients.cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALTOsteonecrosis of the Jaw (ONJ): ONJ occurred in 1% ofMonitor blood calcium levels and replace calcium as necessary duringFor additional safety information, please see Brief Summary and AST elevations compared to CABOMETYX alone. CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis,treatment. Withhold and resume at reduced dose upon recovery orof the Prescribing Information for CABOMETYX on Monitor liver enzymes before initiation of and periodically throughoutosteitis, bone erosion, tooth or periodontal infection, toothache,permanently discontinue CABOMETYX depending on severity. following pages.treatment. Consider more frequent monitoring of liver enzymes thangingival ulceration or erosion, persistent jaw pain, or slow healing ofEmbryo-Fetal Toxicity: CABOMETYX can cause fetal harm. AdviseBICR=blinded independent central review; CR=complete response; ITT=intent to when the drugs are administered as single agents. For elevated liverthe mouth or jaw after dental surgery. Perform an oral examinationpregnant women and females of reproductive potential of thetreat; IV=intravenous; PFS-2=progression-free survival after subsequent therapy; enzymes, interrupt CABOMETYX and nivolumab and considerprior to CABOMETYX initiation and periodically during treatment.potential risk to a fetus. Verify the pregnancy status of females ofPK=pharmacokinetics; PO=by mouth; PR=partial response.administering corticosteroids. Advise patients regarding good oral hygiene practices. Withholdreproductive potential prior to initiating CABOMETYX and advise CABOMETYX for at least 3 weeks prior to scheduled dental surgerythem to use e ective contraception during treatment and forReferences: 1. CABOMETYX (cabozantinib) Prescribing Information. Exelixis With the combination of CABOMETYX and nivolumab, Grades 3 andor invasive dental procedures, if possible. Withhold CABOMETYX for4 months after the last dose. Inc; 2022. 2. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER 4 increased ALT or AST were seen in 11% of patients. ALT or AST 3development of ONJ until complete resolution, resume at aInvestigators. Nivolumab plus cabozantinib versus sunitinib for advanced times ULN (Grade 2) was reported in 83 patients, of whom 23 (28%)reduced dose.ADVERSE REACTIONS renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. 3. Choueiri TK, Powles T, received systemic corticosteroids; ALT or AST resolved to Grades 0-1The most common (20%) adverse reactions are: Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib inrst-line in 74 (89%). Among the 44 patients with Grade 2 increased ALT orImpaired Wound Healing: Wound complications occurred withtreatment for advanced renal cell carcinoma:rst results from the randomized AST who were rechallenged with either CABOMETYX (n=9) orCABOMETYX. Withhold CABOMETYX for at least 3 weeks prior toCABOMETYX as a single agent: diarrhea, fatigue, PPE,phase 3 CheckMate 9ER trial. Presented at The European Society for Medical nivolumab (n=11) as a single agent or with both (n=24), recurrence ofelective surgery. Do not administer CABOMETYX for at least 2 weeksdecreased appetite, hypertension, nausea, vomiting, weightOncology (ESMO) Virtual Congress 2020; September 19-21, 2020. Presentation after major surgery and until adequate wound healing. The safety ofdecreased, constipation.6960. 4. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Grade 2 increased ALT or AST was observed in 2 patients receivingresumption of CABOMETYX after resolution of wound healingCABOMETYX in combination with nivolumab: diarrhea, fatigue,Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma CABOMETYX, 2 patients receiving nivolumab, and 7 patientscomplications has not been established. hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism,[supplementary appendix]. N Engl J Med. 2021;384(9):829-841. 5. Choueiri TK, receiving both CABOMETYX and nivolumab. Withhold and resume atPowles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus a reduced dose based on severity. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS,musculoskeletal pain, decreased appetite, nausea, dysgeusia,cabozantinib versus sunitinib for advanced renal-cell carcinoma [protocol]. Adrenal Insuciency:CABOMETYX in combination with nivolumaba syndrome of subcortical vasogenic edema diagnosed byabdominal pain, cough, and upper respiratory tract infection. N Engl J Med. 2021;384(9):829-841. 6. Motzer RJ, Powles T, Burotto M, et al. characteristicndings on MRI, can occur with CABOMETYX. EvaluateNivolumab plus cabozantinib versus sunitinib inrst-line treatment for can cause primary or secondary adrenal insufficiency. For Grade 2 orfor RPLS in patients presenting with seizures, headache, visualDRUG INTERACTIONS advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up higher adrenal insufficiency, initiate symptomatic treatment, includingdisturbances, confusion, or altered mental function. DiscontinueStrong CYP3A4 Inhibitors: If coadministration with strong CYP3A4results from an open-label, randomised, phase 3 trial. Lancet Oncol. hormone replacement as clinically indicated. Withhold CABOMETYXCABOMETYX in patients who develop RPLS. inhibitors cannot be avoided, reduce the CABOMETYX dosage.2022;23(7):888-898. 7. Data onle. Exelixis, Inc. and/or nivolumab and resume CABOMETYX at a reduced doseThyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism,Avoid grapefruit or grapefruit juice.depending on severity. has been observed with CABOMETYX. Based on the safetyStrong CYP3A4 Inducers:If coadministration with strong CYP3A4 Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCCpopulation, thyroid dysfunction occurred in 19% of patients treatedinducers cannot be avoided, increase the CABOMETYX dosage. who received CABOMETYX with nivolumab, including Grade 3 (2.2%),with CABOMETYX, including Grade 3 in 0.4% of patients. Avoid St. Johns wort.and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led toPatients should be assessed for signs of thyroid dysfunction priorUSE IN SPECIFIC POPULATIONSpermanent discontinuation of CABOMETYX and nivolumab in 0.9%to the initiation of CABOMETYX and monitored for signs and and withholding of CABOMETYX and nivolumab in 2.8% of patientssymptoms of thyroid dysfunction during CABOMETYX treatment.Lactation:Advise women not to breastfeed during CABOMETYX with RCC. Thyroid function testing and management of dysfunction shouldtreat ment and for 4 months after thenal dose.be performed as clinically indicated.DISCOVER MORE AT CABOMETYXhcp.com 2022 Exelixis, Inc.CA-261009/22 OPDIVO and the related logo are registered trademarks of Bristol-Myers Squibb Company.'