Exelixis Announces CABOMETYX® in Combination with OPDIVO® Provides Efficacy Benefits Regardless of Prior Nephrectomy in Patients with Previously Untreated Advanced Renal Cell Carcinoma Based on CheckMate -9ER Analysis Presented at ESMO 2021

– Progression-free survival and objective response rate benefits were observed with combination regimen versus sunitinib regardless of prior nephrectomy status –

ALAMEDA, Calif.--(BUSINESS WIRE)-- Exelixis, Inc. (Nasdaq: EXEL) today announced results demonstrating efficacy benefits regardless of prior nephrectomy status with CABOMETYX® (cabozantinib) in combination with Bristol Myers Squibb’s OPDIVO® (nivolumab) versus sunitinib for patients with previously untreated advanced renal cell carcinoma (RCC). The data, from a post-hoc exploratory analysis of the phase 3 CheckMate -9ER pivotal trial, will be presented as an ePoster available on demand beginning at 8:30 a.m. CEST on Thursday, September 16 during the 2021 European Society of Medical Oncology (ESMO) Congress (abstract 663P).

“Patients with advanced kidney cancer who do not have a prior nephrectomy typically face an even worse prognosis than those who undergo the surgery,” said Camillo Porta, M.D., Full Professor of Medical Oncology at the A. Moro University of Bari, Italy, and presenting author. “It’s critical to gather more data such as this to help us better understand whether recent treatment advancements improve outcomes specifically for these patients. The consistent efficacy benefits demonstrated in the CheckMate -9ER trial regardless of prior nephrectomy status are reassuring as they continue to support the use of CABOMETYX in combination with OPDIVO for a broad range of patients with advanced kidney cancer.”

As previously announced, the phase 3 CheckMate -9ER pivotal trial showed that CABOMETYX in combination with OPDIVO improved overall survival (OS) and doubled median progression-free survival (PFS) and objective response rate (ORR) versus sunitinib in patients with previously untreated advanced RCC. In this new exploratory analysis presented at ESMO 2021, at a median follow-up of 23.5 months, PFS and ORR benefits were observed regardless of prior nephrectomy status. The magnitudes of PFS and ORR benefits associated with CABOMETYX in combination with OPDIVO were greater in the subgroup of patients with prior nephrectomy versus those without prior nephrectomy. See table below for additional details.

“Building on prior subgroup analyses from CheckMate -9ER, we’re pleased to offer physicians these additional data that provide more insights into how the combination regimen may benefit specific subsets of patients with advanced kidney cancer,” said Michael M. Morrissey, Ph.D., President and Chief Executive Officer, Exelixis. “Kidney cancer patients who do not have a prior nephrectomy are an especially difficult-to-treat subset of the patient community that is underserved and faces a particularly poor prognosis. We’re encouraged that these findings show that CABOMETYX in combination with OPDIVO is a valuable first-line treatment option that improves outcomes for these patients.”

Table

In CheckMate -9ER, CABOMETYX in combination with OPDIVO was generally well tolerated and reflected the known safety profiles of the tyrosine kinase inhibitor and immunotherapy components in previously untreated advanced RCC. The most common adverse reactions reported in at least 20% of patients treated with CABOMETYX in combination with OPDIVO were diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough and upper respiratory tract infection. A safety analysis with extended follow-up reported at the 2021 American Society of Clinical Oncology’s Genitourinary Cancers Symposium identified no new safety signals; among patients treated with OPDIVO and CABOMETYX, 6.6% discontinued both agents due to treatment-related adverse events, 9.7% discontinued OPDIVO only and 7.2% discontinued CABOMETYX only.

About CheckMate -9ER

CheckMate -9ER is an open-label, randomized (1:1), multi-national phase 3 trial evaluating patients with previously untreated advanced or metastatic RCC with a clear cell component. A total of 651 patients (22% favorable risk, 58% intermediate risk, 20% poor risk; 25% PD-L1 ≥1%) were randomized to CABOMETYX at a dose of 40 mg once-daily and OPDIVO (n=323) versus sunitinib (n=328). The primary endpoint is PFS; secondary endpoints include OS and ORR. The primary efficacy analysis compares the doublet combination regimen of CABOMETYX and OPDIVO versus sunitinib in all randomized patients. The trial is sponsored by Bristol Myers Squibb and Ono Pharmaceutical Co. and co-funded by Exelixis, Ipsen and Takeda Pharmaceutical Company Limited.

About RCC

The American Cancer Society’s 2021 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 form 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 13%.1 Approximately 32,000 patients in the U.S. and 71,000 worldwide will require systemic treatment for advanced kidney cancer in 2021.3

About 70% of RCC cases are known as “clear cell” carcinomas, based on histology.4 The majority of clear cell RCC tumors have below-normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.5,6 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.7,8,9,10 MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.6,7

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; and for patients with advanced RCC as a first-line treatment in combination with nivolumab. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen 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.

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 and HCC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. 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 36% (17% 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.

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 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 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in