Exelixis’ Partner Ipsen Receives European Commission Approval for CABOMETYX® (cabozantinib) for Patients with Previously Treated Radioactive Iodine-Refractory Differentiated Thyroid Cancer

– Approval is based on COSMIC-311 trial, in which CABOMETYX demonstrated significant improvement in progression-free survival versus placebo –

ALAMEDA, Calif.--(BUSINESS WIRE)-- Exelixis, Inc. (Nasdaq: EXEL) today announced that its partner Ipsen received approval from the European Commission (EC) for CABOMETYX® (cabozantinib) as a monotherapy for the treatment of adult patients with locally advanced or metastatic differentiated thyroid carcinoma (DTC), refractory or not eligible to radioactive iodine (RAI) who have progressed during or after prior systemic therapy. This approval allows for the marketing of CABOMETYX in this indication in all 27 member states of the European Union, Norway, Liechtenstein and Iceland.

“We are excited that CABOMETYX will now be available in Europe for patients with locally advanced or metastatic differentiated thyroid carcinoma who have progressed during or after prior systemic therapy, that previously had no approved standard treatment options,” said Vicki L. Goodman, M.D., Executive Vice President, Product Development and Medical Affairs, and Chief Medical Officer, Exelixis. “The European Commission approval is an additional step in our partnership with Ipsen to provide new treatment options for more eligible patients with difficult-to-treat cancer types.”

The EC approval is based on results from COSMIC-311, the phase 3 pivotal trial that demonstrated significant improvement in progression-free survival (PFS) with CABOMETYX versus placebo in patients with RAI-refractory DTC who progressed after up to two prior VEGFR-targeted therapies. COSMIC-311 was the basis for the U.S. Food and Drug Administration (FDA) approval of CABOMETYX in September 2021 for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic DTC that has progressed following VEGFR-targeted therapy and who are RAI-refractory or ineligible.

CABOMETYX is also approved in the European Union as a monotherapy for the treatment of advanced renal cell carcinoma (RCC) in adults who have received prior VEGFR-targeted therapy, for previously untreated intermediate- or poor-risk advanced RCC and for hepatocellular carcinoma (HCC) in adults who have been previously treated with sorafenib. CABOMETYX in combination with OPDIVO® (nivolumab) is approved as a first-line treatment for advanced RCC.

About COSMIC-311

COSMIC-311 was a multicenter, randomized, double-blind, placebo-controlled phase 3 pivotal trial that enrolled 258 patients at 164 sites globally. Patients were randomized in a 2:1 ratio to receive either CABOMETYX 60 mg or placebo once daily. The primary endpoints were PFS and objective response rate. Exelixis is sponsoring COSMIC-311, and Ipsen is co-funding the trial. More information about this trial is available at ClinicalTrials.gov.

About DTC

In 2020, over 580,000 new cases of thyroid cancer were diagnosed worldwide.1 Approximately 44,000 new cases of thyroid cancer will be diagnosed in the U.S. in 2022. Nearly three out of four of these cases will be in women, and the disease is more commonly diagnosed at a younger age compared with most other adult cancers. While cancerous thyroid tumors include differentiated, medullary and anaplastic forms, differentiated thyroid tumors make up about 90% of cases and includes papillary, follicular and Hürthle cell cancer.2 DTC is typically treated with surgery followed by ablation of the remaining thyroid with RAI, but approximately 5% to 15% of cases are resistant to RAI treatment.3,4 For these patients, life expectancy is only three to six years from the time metastatic lesions are detected.5,6,7

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; 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 DTC that has progressed following prior VEGFR-targeted therapy and who are RAI-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 exclusive rights for the commercialization and further clinical development of cabozantinib outside of the U.S. and Japan. Under the terms of the license agreement with Ipsen, Exelixis is eligible to receive development, regulatory and sales milestone payments from Ipsen and further receive royalties on net sales of cabozantinib by Ipsen 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, 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