Exelixis Announces Cabozantinib in Combination with Nivolumab and Ipilimumab Significantly Improved Progression-Free Survival in Phase 3 COSMIC-313 Pivotal Trial in Patients with Previously Untreated Advanced Kidney Cancer

– Exelixis intends to discuss the results with the U.S. FDA to determine next steps toward a potential regulatory submission –

– Trial to continue until the next analysis of the secondary endpoint of overall survival –

ALAMEDA, Calif.--(BUSINESS WIRE)-- Exelixis, Inc. (Nasdaq: EXEL) today announced that COSMIC-313 met its primary endpoint, demonstrating significant improvement in progression-free survival (PFS) at the primary analysis. COSMIC-313 is an ongoing phase 3 pivotal trial evaluating the combination of cabozantinib (CABOMETYX®), nivolumab and ipilimumab versus the combination of nivolumab and ipilimumab in patients with previously untreated advanced intermediate- or poor-risk renal cell carcinoma (RCC). At a prespecified interim analysis for the secondary endpoint of overall survival (OS), the combination of cabozantinib, nivolumab and ipilimumab versus the combination of nivolumab and ipilimumab did not demonstrate a significant benefit. Therefore, the trial will continue to the next analysis of OS.

“As the treatment landscape continues to evolve, resulting in more options for advanced kidney cancer, there is still a need for additional effective first-line treatment options for patients with intermediate- or poor-risk disease,” said Toni Choueiri, M.D., Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School. “These initial findings from COSMIC-313 suggest that the triplet combination of cabozantinib, nivolumab and ipilimumab may have potential to serve as an additional option for this patient population.”

In the primary analysis of PFS per Response Evaluation Criteria in Solid Tumors version 1.1, as assessed by Blinded Independent Radiology Committee, cabozantinib in combination with nivolumab and ipilimumab significantly reduced the risk of disease progression or death compared with the combination of nivolumab and ipilimumab (hazard ratio: 0.73; 95% confidence interval: 0.57-0.94; P=0.01). The safety profile observed in the trial was reflective of the known safety profiles for each single agent, as well as the combination regimens used in this study. No new safety signals were identified.

Exelixis intends to discuss the results with the U.S. Food & Drug Administration (FDA) to determine next steps toward a potential regulatory submission for the combination regimen for patients with previously untreated advanced intermediate- or poor-risk RCC. Detailed findings will be submitted for presentation at a future medical meeting.

“COSMIC-313 is the first trial to show that a tyrosine kinase inhibitor added to dual checkpoint inhibition can improve progression-free survival in patients with advanced kidney cancer,” said Vicki L. Goodman, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis. “With these findings in hand, we look forward discussing the results with the FDA and presenting the data at a future medical meeting.”

About COSMIC-313 COSMIC-313 is a multicenter, randomized, double-blinded, controlled phase 3 pivotal trial that enrolled 855 patients at 177 sites globally. Patients were randomized 1:1 into the experimental or control arms of the study. Patients in the experimental arm received cabozantinib (40 mg, once daily) in combination with nivolumab (3 mg/kg infusion, once every 3 weeks for 4 doses total) and ipilimumab (1 mg/kg infusion, once every 3 weeks for 4 doses total) followed by cabozantinib (40 mg, once daily) and nivolumab (480 mg/kg flat dose infusion, once every 4 weeks for up to 2 years). Patients in the control arm received cabozantinib-matched placebo in combination with nivolumab (3 mg/kg infusion, once every 3 weeks for 4 doses total) and ipilimumab (1 mg/kg infusion, once every 3 weeks for 4 doses total) followed by cabozantinib-matched placebo and nivolumab (480 mg/kg flat dose infusion, once every 4 weeks for up to 2 years). The primary endpoint is PFS; the secondary endpoint is OS. Exelixis is funding the trial, and Bristol Myers Squibb is providing nivolumab and ipilimumab for use in this trial. More information about this trial is available at ClinicalTrials.gov.

About RCC The American Cancer Society’s (ACS) 2022 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common type of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 14%.1 Approximately 33,000 patients in the U.S. and over 71,000 worldwide will require systemic treatment for advanced kidney cancer in 2022, with over 15,000 patients in need of a first-line treatment in the U.S.3

About CABOMETYX® (cabozantinib) In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC; for the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib; for patients with advanced RCC as a first-line treatment in combination with nivolumab; and for adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen Pharma SAS exclusive rights for the commercialization and further clinical development of cabozantinib outside of the U.S. and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the U.S.

CABOMETYX in combination with nivolumab and ipilimumab is not indicated as a treatment for previously untreated advanced RCC.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and 3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab. Withhold and resume at a reduced dose based on severity.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in