Cabozantinib Significantly Improves PFS in Previously Treated, Radioiodine-Refractory Differentiated Thyroid Cancer


December 21, 2020 - Cabozantinib was found to significantly improve progression-free survival compared with placebo in patients with dedifferentiated thyroid cancer who are refractory to radioiodine and have progressed following up to 2 prior VEGF-targeted treatments.

Marcia S. Brose, MD, PhD

Cabozantinib (Cabometyx) was found to significantly improve progression-free survival (PFS) compared with placebo in patients with dedifferentiated thyroid cancer who are refractory to radioiodine (RAI) and have progressed following up to 2 prior VEGF-targeted treatments, meeting the co-primary end point of the phase 3 COSMIC-311 trial (NCT03690388).1

Specifically, results from the planned interim analysis of the trial showed that treatment with the agent led to a 78% reduction in the risk of disease progression or death vs placebo, with a hazard ratio of 0.22 (96% CI, 0.13-0.36; P <.0001).

Based on these data, the independent data monitoring committee for the study advised that the trial stop enrolling patients and that sites and patients be unblinded. Exelixis, Inc. announced their intention to share the study findings and proposed changes to the trial, along with plans for regulatory filing with the FDA in the near future.

“Considering the poor prognosis and lack of progress in the treatment of differentiated thyroid cancer following anti-VEGFR therapy, a significant improvement in PFS is a long-awaited clinical advance,” principal investigator of the trial Marcia S. Brose, MD, PhD, 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, stated in a press release.

“These encouraging results from COSMIC-311 suggest cabozantinib has the potential to become an important new option for these patients,” added Brose. “We look forward to sharing the detailed data from the trial at an upcoming medical meeting.”

In the double-blind, phase 3 trial enrolled patients, investigators sought to evaluate the safety and efficacy of cabozantinib in previously treated patients with RAI-refractory dedifferentiated thyroid cancer who had experienced disease progression following a previous VEGFR-targeted treatment.2

To be eligible for participation, patients needed to have histologically or cytologically confirmed differentiated thyroid cancer; measurable disease per RECIST v1.1 criteria, documented progression after a VEGFR-targeted TKI, either lenvatinib (Lenvima) or sorafenib (Nexavar); and an ECOG performance status of 0-1. Moreover, they had to have received prior treatment with iodine-131 or have been determined to be ineligible for the agent.

Patients could not have received previous treatment with cabozantinib, small-molecule BRAF inhibitors, greater than 2 VEGFR-targeted TKIs, at least 1 immune checkpoint inhibitor, or at least 1 systemic chemotherapy regimen. Additionally, they could not have received previous treatment with a small molecule inhibitor within 2 weeks of study randomization, nor could they have received previous anticancer antibody or systemic treatment within 4 weeks of randomization. Patients with untreated brain metastases or cranial epidural disease were not permitted.

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

In the study, patients were randomized 2:1 to receive either oral cabozantinib at once-daily dose of 60 mg or matching placebo. Patients continued to receive treatment for as long as they experienced clinical benefit per investigator assessment or until they experienced unacceptable toxicity. Patients on the control arm were permitted to crossover to receive cabozantinib in real-time upon progressive disease per investigator assessment and confirmed by BICR.

Patients were stratified based on previous receipt of lenvatinib (yes vs no) and age (65 years or younger vs over 65 years).

The trial aimed to enroll approximately 300 patients spanning 150 clinical sites on a global scale. In February 2020, it was announced that the trial had enrolled its first 100 patients.3

Detailed information will be shared at an upcoming medical meeting, according to Exelixis, Inc.

“We are very pleased that at this early interim analysis of COSMIC-311, cabozantinib has demonstrated a clinically meaningful and statistically significant improvement in PFS for patients with differentiated thyroid cancer who are in need of additional treatment options after prior therapy,” Gisela Schwab, MD, president of product development and medical affairs and chief medical officer of Exelixis, added in the release. “…We intend to discuss the findings with regulatory authorities and look forward to sharing the detailed final COSMIC-311 results when they become available.”


  1. 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 December 21, 2020.
  2. 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
  3. 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. Accessed December 21, 2020.
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