FDA Grants Breakthrough Therapy Designation to Cabozantinib for Radioactive Iodine–Refractory Differentiated Thyroid Cancer

Gisela Schwab, MD

The FDA has granted a breakthrough therapy designation to cabozantinib (Cabometyx) as a potential therapeutic option for patients with differentiated thyroid cancer (DTC) that has progressed after previous therapy and who are refractory to radioactive iodine (RAI).¹

The decision was based on data from the phase 3 COSMIC-311 trial (NCT03690388), where treatment with cabozantinib resulted in a significant improvement in progression-free survival (PFS) over placebo in patients with DTC who are RAI and have progressed after up to 2 VEGF-targeted therapies.² Specifically, the agent reduced the risk of disease progression or death by 78% compared with placebo (HR, 0.22; 95% CI, 0.13-0.36; P <.0001), meeting the primary end point of the trial.

“Receiving breakthrough therapy designation is a testament to both the urgent need for effective treatments for patients with DTC who progressed after prior therapy and the promising data demonstrating cabozantinib significantly improved PFS for these patients,” Gisela Schwab, MD, president of Product Development and Medical Affairs and chief medical officer of Exelixis, stated in a press release.

The multicenter, double-blind, placebo-controlled phase 3 COSMIC-311 trial examined the safety and efficacy of cabozantinib in patients with histologically or cytologically confirmed DTC who had measurable disease per RECIST v1.1 criteria.³

Patients had to have documented progression following treatment with a VEGF TKI, specifically lenvatinib (Lenvima) or sorafenib (Nexavar). They also needed to have an ECOG performance status of 0 or 1 had previously received iodine-131 or had been determined to be ineligible for the agent.

The co-primary end points of the trial were overall response rate and PFS, both per RECIST v1.1 criteria and blinded independent review committee (BIRC). Secondary end points included overall survival, safety and tolerability, pharmacokinetics, biomarkers, and health-related quality of life.

Study participants was randomized in a 2:1 ratio to receive either cabozantinib at a dose of 60 mg or placebo once daily. Stratification factors included previous receipt of lenvatinib (yes vs no) and age (65 years or younger vs over 65 years).

Investigators sought to enroll about 300 patients at 150 sites worldwide. In February 2020, the trial had enrolled its first 100 patients.⁴ Based on the data from the planned interim analysis of the trial, in December 2020, an independent data monitoring committee for the study recommended that the trial stop enrolling patients and that the sites and patients be unblinded.

“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,” added Schwab in the release.

In the United States, cabozantinib is indicated for use in patients with advanced renal cell carcinoma (RCC), for use in combination with nivolumab (Opdivo) as a frontline treatment for patients with advanced RCC, and for use in patients with hepatocellular carcinoma who previously received sorafenib.

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 25, 2021. http://bit.ly/37KKthq

2. Exelixis announces cabozantinib significantly improved progression-free survival of 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 25, 2021. http://bit.ly/37BxCOG

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 VEGF-targeted therapy. J Clin Oncol. 2019;37(suppl 15):TPS6097. doi:10.1200/JCO.2019.37.15_suppl.TPS6097

4. Exelixis announces first 100 patients enrolled in phase 3 COSMIC-311 pivotal trial of cabozantinib in relapsed radioiodine-refractory dedifferentiated thyroid cancer. News release. Exelixis, Inc. February 25, 2020. February 25, 2021. http://bit.ly/2Kgmcat