Exelixis and Ipsen Announce Cabozantinib in Combination with an Immune Checkpoint Inhibitor Significantly Improved Progression-Free Survival in Phase 3 COSMIC-312 Pivotal Trial in Patients with Previously Untreated Advanced Liver Cancer

ALAMEDA, Calif. & PARIS--(BUSINESS WIRE)-- Regulatory News:

Exelixis, Inc. (NASDAQ: EXEL) and Ipsen (Euronext: IPN; ADR: IPSEY) today announced that COSMIC-312, the ongoing phase 3 pivotal trial evaluating cabozantinib (CABOMETYX®) in combination with atezolizumab versus sorafenib in patients with previously untreated advanced hepatocellular carcinoma (HCC) met one of the primary endpoints, demonstrating significant improvement in progression-free survival (PFS) at the planned primary analysis. A prespecified interim analysis for the second primary endpoint of overall survival (OS), conducted at the same time as the primary analysis for PFS, showed a trend favoring the combination of cabozantinib and atezolizumab, but did not reach statistical significance. Based on the preliminary OS data, Exelixis anticipates that the probability of reaching statistical significance at the time of the final analysis is low. The trial will continue as planned to the final analysis of OS; results are anticipated in early 2022.

In the analysis of the primary endpoint of PFS in the PFS intent-to-treat population, cabozantinib in combination with atezolizumab significantly reduced the risk of disease progression or death by 37% compared with sorafenib (hazard ratio [HR]: 0.63; 99% confidence interval [CI]: 0.44-0.91; P=0.0012). Safety for the combination appeared to be consistent with the known safety profiles of the individual medicines, and no new safety signals were identified. Exelixis plans to discuss the trial results and next steps for a potential regulatory filing with the U.S. Food and Drug Administration (FDA).

“While we are encouraged by the data supporting the potential for the combination of cabozantinib and atezolizumab to reduce the risk of disease progression or death, we are disappointed by the interim result of lack of significant improvement on overall survival versus the comparator arm,” said Michael M. Morrissey, Ph.D., Exelixis’ President and Chief Executive Officer. “As these data continue to mature, we are working to understand the potential impact of various contributing factors on the results, including patient demographics, subsequent anti-cancer therapy and the impact of COVID-19 on the trial. We anticipate presenting the results at a future medical conference.”

About COSMIC-312

COSMIC-312 is a global, multicenter, randomized, controlled phase 3 pivotal trial that aimed to enroll approximately 840 patients at up to 200 sites globally. Patients were randomized approximately 2:1:1 to one of three arms: cabozantinib (40 mg) in combination with atezolizumab, sorafenib, or cabozantinib (60 mg). Exelixis is sponsoring COSMIC-312, and Ipsen is co-funding the trial. Genentech, a member of the Roche Group, is providing atezolizumab for use in this trial. More information about COSMIC-312 is available at ClinicalTrials.gov.

About HCC

More than 900,000 new cases of liver cancer, 90% of which are HCC, are diagnosed worldwide each year.1,2 HCC is a leading cause of cancer-related death, expected to cause 1 million global deaths annually by 2030.3 In the U.S., HCC is the fastest-rising cause of cancer-related death.4 Median survival for patients with symptomatic advanced HCC who are treated with systemic therapies is just 1 to 1.5 years.2

About CABOMETYX® (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced renal cell carcinoma (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 nivolumab. Outside of the U.S., CABOMETYX is approved in 58 countries, including in the European Union, the U.K., Norway, Iceland, Australia, New Zealand, Switzerland, South Korea, Canada, Brazil, Taiwan, Hong Kong, Singapore, Macau, Jordan, Lebanon, Russian Federation, Ukraine, Turkey, United Arab Emirates, Saudi Arabia, Serbia, Israel, Mexico, Chile, Peru, Panama, Guatemala, Dominican Republic, Ecuador, Thailand and Malaysia for the treatment of advanced RCC in adults who have received prior VEGF-targeted therapy; in the European Union, the U.K., Norway, Iceland, Canada, Australia, Brazil, Taiwan, Hong Kong, Singapore, Lebanon, Jordan, Russian Federation, Ukraine, Turkey, United Arab Emirates, Saudi Arabia, Israel, Mexico, Chile, Peru, Panama, Guatemala, Dominican Republic, Ecuador, Thailand and Malaysia for previously untreated intermediate- or poor-risk advanced RCC; and in the European Union, the U.K., Norway, Iceland, Canada, Australia, New Zealand, Switzerland, Saudi Arabia, Serbia, Israel, Taiwan, Hong Kong, South Korea, Singapore, Jordan, Russian Federation, Ukraine, Turkey, Lebanon, United Arab Emirates, Peru, Panama, Guatemala, Chile, Dominican Republic, Ecuador, Thailand and Malaysia for HCC in adults who have previously been treated with sorafenib. In the European Union, CABOMETYX is also approved in combination with nivolumab as first line treatment for patients living with advanced RCC. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States 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 United States.

CABOMETYX is not indicated as a treatment for previously untreated advanced HCC.

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