Cabozantinib Lands Breakthrough Therapy Designation in RAI-Refractory Differentiated Thyroid Cancer

The FDA has granted Breakthrough Therapy Designation to cabozantinib (Cabometyx) for the potential treatment of patients with differentiated thyroid cancer (DTC) that has progressed following prior therapy and who are radioactive iodine-refractory if eligible for radioactive iodine, according to a press release from Exelixis, Inc.¹

"Receiving Breakthrough Therapy Designation is a testament to both the urgent need for effective treatments for patients with differentiated thyroid cancer who progressed after prior therapy and the promising data demonstrating cabozantinib significantly improved progression-free survival for these patients,” said Gisela Schwab, MD, president, Product Development and Medical Affairs and chief medical officer, Exelixis, in a statement.

Development of cabozantinib and the review of any applications submitted to the FDA will be expedited now that the agent has been granted this designation.

“We look forward to submitting our regulatory application in 2021 and to working closely with the FDA during the review process, with the goal of bringing cabozantinib to this patient population with a high unmet medical need for whom there is currently no available standard of care,” Schwab said, in the press release.

The BTD for cabozantinib comes on the heels of news that the pivotal phase 3 COSMIC-311 clinical trial of cabozantinib versus placebo (NCT03690388), met its primary end point of significant progression-free survival (PFS) improvement. Cabozantinib reduced the risk of disease progression or death by 78% with a hazard ratio of 0.22 (96% CI, 0.13-0.36; P < .0001) compared with placebo.²

The safety profile for the agent was also consistent with prior reports of cabozantinib.

COSMIC-311 is a randomized, double-blind, placebo-controlled study conducted for patients with radioactive iodine-refractory DTC who progressed after prior VEGFR-targeted therapy. In addition to PFS, a coprimary end point in the study is objective response rate. The patient population of the study included those with histologically or cytologically confirmed disease, measurable disease per RECIST v1.1, and an ECOG performance status of 0 or 1.

More than 300 patients who were enrolled to the study were randomized in a 2:1 ratio to receive either cabozantinib 60 mg or a matching placebo once daily. Patients are stratified by prior treatment with lenvatinib and age (≤ 65 years vs > 65 years). Those randomized to the placebo arm may be eligible for crossover to cabozantinib if they develop disease progression. The trial is being conducted at 150 sites worldwide.

COSMIC-311 was launched to address the unmet medical need for patients with RAI-refractory DTC that is resistant to VEGFR-targeted therapy, for whom treatment options are limited. In preclinical studies, cabozantinib shows clinical activity in this patient population. The agent inhibits receptor tyrosine kinases including VEGFR2, MET, AXL, and RET, which are all found in DTC.³

_References:

_{1. Exelixis announces Breakthrough Therapy Designation granted to Cabozantinib for the treatment of patients with previously treated radioactive iodine-refractory differentiated thyroid cancer. News release. Exelixis. Inc. February 25, 2021. Accessed February 26, 2021. https://bit.ly/3dNLf0T}

_{2. Exelixis Announces cabozantinib significantly improved progression-free survival in cosmic-311 phase 3 pivotal trial in patients with previously treated radioiodine-refractory differentiated thyroid cancer. News release. Exelixis. Inc. December 21, 2020. Accessed February 26, 2021. https://bit.ly/2NI7ieH}

_{3. Brose MS, Robinson B, Bermingham C, et al. A phase 3 (COSMIC-311), randomized, double-blind, placebo-controlled study of cabozantinib in patients with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) who have progressed after prior VEGFR-targeted therapy. J Clin Oncol. 2019;37(suppl 15):TPS6097. doi:10.1200/JCO.2019.37.15_suppl.TPS6097}