ALAMEDA, Calif. - Exelixis, Inc. (Nasdaq: EXEL) announced Takeda Pharmaceutical Company Limited (Takeda), its partner responsible for the clinical development and commercialization of CABOMETYX (cabozantinib) in Japan, and Ono Pharmaceutical Co., Ltd. (Ono) received approval from the Japanese Ministry of Health, Labor and Welfare to manufacture and market CABOMETYX in combination with OPDIVO (nivolumab) as a treatment for unresectable or metastatic renal cell carcinoma (RCC).
'We're excited our partner Takeda, along with Ono, will be able to bring CABOMETYX in combination with OPDIVO to patients with advanced kidney cancer in Japan following regulatory approvals as a first-line treatment in the U.S. and EU earlier this year,' said Michael M. Morrissey, Ph.D., Exelixis' President and Chief Executive Officer. 'With approximately 25,000 new cases of kidney cancer diagnosed in Japan annually, we're pleased that this important new treatment option will now be available to Japanese patients in need of new therapies.'
The approval is based on CheckMate -9ER, a phase 3 pivotal trial evaluating CABOMETYX in combination with OPDIVO in previously untreated patients with advanced or metastatic RCC compared with sunitinib. In CheckMate -9ER, CABOMETYX in combination with OPDIVO demonstrated superior overall survival (OS) and doubled median progression-free survival (PFS) and objective response rate (ORR) versus sunitinib, with a favorable safety profile.
Per the terms of Exelixis and Takeda's collaboration and license agreement, Exelixis is eligible to receive a milestone payment of $20 million from Takeda upon the first commercial sale of CABOMETYX in combination with OPDIVO for the treatment of RCC. Exelixis continues to be eligible to receive additional development, regulatory and first-sale milestones for potential future cabozantinib indications and is also eligible for sales revenue milestones and royalties on net sales of cabozantinib in Japan.
Takeda previously received approvals to manufacture and market CABOMETYX in Japan as a treatment for patients with curatively unresectable or metastatic RCC and for patients with unresectable hepatocellular carcinoma (HCC) that has progressed after prior systemic therapy.
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.
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 HCC who have been previously treated with sorafenib; and for patients with advanced RCC as a first-line treatment in combination with OPDIVO. 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