Exelixis Announces U.S. FDA Accepts for Priority Review the Supplemental New Drug Application for CABOMETYX® (cabozantinib) for Patients with Previously Treated Radioactive Iodine-Refractory Differentiated Thyroid Cancer

– U.S. Food and Drug Administration assigned a Prescription Drug User Fee Act action date of December 4, 2021 –

– The supplemental New Drug Application is based on the phase 3 COSMIC-311 pivotal trial, which demonstrated significant improvement in progression-free survival with CABOMETYX versus placebo –

ALAMEDA, Calif.--(BUSINESS WIRE)-- Exelixis, Inc. (NASDAQ: EXEL) today announced that the U.S. Food and Drug Administration (FDA) has accepted the company’s supplemental New Drug Application (sNDA) for CABOMETYX® (cabozantinib) as a treatment for patients 12 years and older with differentiated thyroid cancer (DTC) who have progressed following prior therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate). The FDA granted Priority Review designation and assigned a Prescription Drug User Fee Act (PDUFA) target action date of December 4, 2021.

“The FDA’s acceptance of our sNDA with Priority Review is an important step toward our goal of bringing CABOMETYX to patients with previously treated radioactive iodine-refractory differentiated thyroid cancer,” said Michael M. Morrissey, Ph.D., Exelixis’ President and Chief Executive Officer. “Considering the lack of a standard of care in the treatment of this cancer following anti-VEGFR therapy, the progression-free survival benefit demonstrated in the phase 3 COSMIC-311 pivotal trial means CABOMETYX, if approved, could become an important new treatment for these patients.”

The sNDA is based on the results of COSMIC-311, a phase 3 pivotal trial evaluating CABOMETYX versus placebo in patients with radioactive iodine-refractory DTC who progressed after up to two prior vascular endothelial growth factor receptor (VEGFR)-targeted therapies. At a planned interim analysis, CABOMETYX met one of the trial’s primary endpoints, demonstrating a significant improvement in progression-free survival versus placebo. In February 2021, the FDA granted Breakthrough Therapy Designation to CABOMETYX as a potential treatment for patients with DTC that has progressed following prior therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate) based on these results. Detailed study findings were presented at the 2021 American Society of Clinical Oncology Annual Meeting and were published by The Lancet Oncology in July 2021.

About COSMIC-311

COSMIC-311 is a multicenter, randomized, double-blind, placebo-controlled phase 3 pivotal trial that aimed to enroll approximately 300 patients at 150 sites globally. Patients were randomized in a 2:1 ratio to receive either cabozantinib 60 mg or placebo once daily. The primary endpoints are progression-free survival and objective response rate. More information about this trial is available at ClinicalTrials.gov.

About Differentiated Thyroid Cancer

Approximately 44,000 new cases of thyroid cancer will be diagnosed in the U.S. in 2021.1 Nearly three out of four of these cases will be in women, and the disease is more commonly diagnosed at a younger age compared to most other adult cancers.1 While cancerous thyroid tumors include differentiated, medullary and anaplastic forms, differentiated thyroid tumors make up about 90 percent of cases.1 These include papillary, follicular and Hürthle cell cancer.1 Differentiated thyroid cancer is typically treated with surgery followed by ablation of the remaining thyroid tissue with radioiodine, but approximately 5% to 15% of cases are resistant to radioiodine treatment. 2,3 For these patients, life expectancy is only three to five years from the time metastatic lesions are detected.4,5,6

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 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 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 for radioactive iodine-refractory differentiated thyroid cancer.

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