Exelixis, Inc. announced that the US Food and Drug Administration (FDA) approved Cabometyx (cabozantinib) for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior vascular endothelial growth factor receptor (VEGFR)-targeted therapy and who are radioactive iodine-refractory or ineligible.

The FDA granted Breakthrough Therapy designation and Priority Review to Cabometyx and its approval comes more than two months ahead of the Prescription Drug User Fee Act (PDUFA) target action date of December 4, 2021. DTC is the most common type of thyroid cancer in the US, and patients who are resistant to radioactive iodine treatment face a poor prognosis.

“Before today, patients with radioactive iodine-refractory differentiated thyroid cancer who have progressed following prior VEGFR-targeted therapy were facing aggressive disease and no standard treatment option,” said Marcia S. Brose, M.D., Ph.D., Chief, Cancer Center Operation Sidney Kimmel Cancer Center at Jefferson Torresdale Hospital, Co-Director, Community Based Clinical Trials, Sidney Kimmel Cancer Center at Thomas Jefferson University, and principal investigator of COSMIC-311. “In the COSMIC-311 pivotal phase 3 trial, Cabometyx extended the time patients live without progression of their cancer. The FDA approval of Cabometyx is an important advancement for these patients who are badly in need of new treatment options.”

The approval is based on results from 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 VEGFR-targeted therapies. At a planned interim analysis, Cabometyx significantly reduced the risk of disease progression or death versus placebo (p<0.0001) in the intent-to-treat population. At a follow-up analysis with a median follow-up of 10.1 months, the median progression-free survival (PFS) as assessed by blinded independent radiology committee was 11.0 months for patients treated with Cabometyx (n=170) compared with 1.9 months for patients treated with placebo (n=88); hazard ratio (HR): 0.22; 95% confidence interval (CI): 0.15–0.31. These results will be presented at the 2021 European Society of Medical Oncology (ESMO) Congress this month.

“This approval of Cabometyx builds on our existing legacy of delivering transformational medicines for patients with difficult-to-treat forms of cancer,” said Michael M. Morrissey, Ph.D., president and chief executive officer, Exelixis. “We would like to thank the clinical trial participants, the physicians and their staff who participated in the COSMIC-311 trial and to acknowledge the team at the FDA for their collaboration during the quick review of our application.”

The most common adverse events (AEs) reported in at least 25% of patients treated with Cabometyx were diarrhea, palmar-plantar erythrodysesthesia, fatigue, hypertension and stomatitis. Grade 3/4 AEs that occurred in at least 5% of patients were palmar-plantar erythrodysesthesia, hypertension, fatigue, diarrhea and stomatitis. Serious AEs occurred in 34% of patients who received Cabometyx, and the most common serious AEs reported in at least 2% of patients included diarrhea, pleural effusion, pulmonary embolism and dyspnea. Fatal AEs occurred in 1.6% of patients treated with Cabometyx arm, including arterial hemorrhage (0.8%) and pulmonary embolism (0.8%). Dose reductions were required in 56% of patients treated with Cabometyx, and 22% of patients required a second dose reduction. AEs leading to discontinuation of Cabometyx occurred in 5% of patients.

“Patients with differentiated thyroid cancer who have progressed following prior therapy and are radioactive iodine-refractory often face a poor prognosis and have limited treatment options,” said Gary Bloom, executive director of ThyCa: Thyroid Cancer Survivors’ Association. “We are excited about the latest approval of Cabometyx, which will offer hope for patients with this type of thyroid cancer.”

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.

In the US, Cabometyx tablets are approved for the treatment of patients with advanced RCC; for the treatment of patients with hepatocellular carcinoma 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 radioactive iodine-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 US 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 US