– New findings demonstrate the significant progression-free survival benefit seen in the intent-to-treat population was also consistent across subgroups –
– Results from COSMIC-311 served as basis for Exelixis’ recent supplemental New Drug Application to U.S. Food and Drug Administration –
– Data are in press to be published in The Lancet Oncology –
ALAMEDA, Calif. & PARIS--(BUSINESS WIRE)-- Exelixis, Inc. (NASDAQ: EXEL) and Ipsen (Euronext:IPN; ADR:IPSEY) today announced detailed results from the phase 3 COSMIC-311 pivotal trial of cabozantinib (CABOMETYX®) in patients with previously treated radioactive iodine-refractory differentiated thyroid cancer (DTC). Results from the trial, which met the co-primary endpoint of significant improvement in progression-free survival (PFS) assessed by blinded independent radiology committee (BIRC), are in press to be published in The Lancet Oncology and have been submitted to the U.S. Food and Drug Administration (FDA). The data are being presented during the Oral Abstract Session: Head and Neck Cancer at 11:45 a.m. PT on Monday, June 7 at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting (abstract #6001).
“Following disease progression on anti-VEGFR therapy, patients with radioactive iodine-refractory differentiated thyroid cancer currently have no standard of care available to them, making the positive results of the COSMIC-311 trial an important clinical advance for this community in need of additional treatment options,” said Marcia S. Brose, M.D., Ph.D., Full Professor of Otorhinolaryngology: Head and Neck Surgery and Director of the Center for Rare Cancers and Personalized Therapy at the Abramson Cancer Center of the University of Pennsylvania, and principal investigator of COSMIC-311. “The significant improvement in progression-free survival and favorable trend for overall survival suggest cabozantinib could be an important new option for these patients.”
Results from COSMIC-311 served as the basis for the supplemental New Drug Application that Exelixis has submitted to the FDA, seeking an expanded indication for CABOMETYX for patients 12 and older with DTC that has progressed following prior therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).
As previously announced, at a planned interim analysis, cabozantinib demonstrated a significant reduction in the risk of disease progression or death of 78% versus placebo (hazard ratio [HR]: 0.22; 96% confidence interval [CI]: 0.13-0.36; P65; prior treatment with lenvatinib (yes vs. no), and number of prior vascular endothelial growth factor receptor (VEGFR)-targeting therapies (1 vs. 2).
The results for the co-primary endpoint of objective response rate in the first 100 randomized patients after six months favored cabozantinib at 15% versus 0% for placebo, although this difference was not statistically significant (P=0.028). In the ITT population, a reduction in target lesion size was found in 76% of patients receiving cabozantinib versus 29% of patients receiving placebo; median overall survival was not reached in either treatment arm but favored cabozantinib (HR: 0.54; 95% CI: 0.27-1.11).
The safety profile was consistent with that previously observed for cabozantinib and adverse events (AEs) were managed with dose modifications. The discontinuation rate due to treatment-emergent AEs was 5% for cabozantinib versus 0% for placebo. The most common (≥5%) all-causality grade 3 or 4 AEs with cabozantinib were palmar-plantar erythrodysesthesia (10%), hypertension (9%), fatigue (8%), diarrhea (7%) and hypocalcemia (7%). There were no treatment-related deaths per investigator.
In February 2021, the U.S. FDA granted Breakthrough Therapy Designation to cabozantinib 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).
“We’re excited to offer a more detailed picture of results from the COSMIC-311 trial following the previous announcements that the trial met its co-primary endpoint of PFS, and that we received Breakthrough Therapy Designation for cabozantinib earlier this year,” said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. “The submission of our regulatory application for CABOMETYX to the FDA is an important step toward our goal of addressing an urgent treatment need for this patient community as soon as possible.”
“The results from the COSMIC-311 phase 3 trial have been highly anticipated, with the current survival time for people living with this uncommon form of differentiated thyroid cancer at just three to five years from the time metastatic lesions are detected,” said Howard Mayer, M.D., Executive Vice President and Head of Research and Development, Ipsen. “We’re delighted to share these data at ASCO together with Exelixis, highlighting our continued commitment to exploring the potential of cabozantinib across a range of hard-to-treat cancers. We look forward to working with regulatory authorities in our territories with the aim of bringing a meaningful new treatment option to a patient population in critical need.”
About COSMIC-311 COSMIC-311 is a global, 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 co-primary endpoints are PFS and ORR, both assessed by BIRC. Patients randomized to placebo were eligible to cross over to open label cabozantinib upon BIRC-confirmed disease progression. Exelixis is sponsoring COSMIC-311, and Ipsen is co-funding the trial. 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.2 While cancerous thyroid tumors include differentiated, medullary and anaplastic forms, differentiated thyroid tumors make up about 90 percent of cases.2 These include papillary, follicular and Hürthle cell cancer.2 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 the treatment of 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