COSMIC-311 Update: Cabozantinib Sustains PFS Benefit After 10 Months in RAI-DTC

Extended follow-up of patients in COSMIC-311 showed continued survival benefit and tumor reduction with cabozantinib versus placebo in patients with radioactive iodine-refractory differentiated thyroid cancer.

In patients with previously treated radioactive iodine-refractory differentiated thyroid cancer (RAI-DTC), treatment with cabozantinib (Cabometyx) continued to demonstrate significant progression-free survival (PFS) improvement compared with placebo, according to extended follow-up results from the phase 3 COSMIC-311 clinical trial presented during the American Thyroid Association Annual Meeting.1

The PFS benefit of cabozantinib compared with placebo in the previously treated RAI-DTC population was first shown in 2020 after a median follow up of 6.2 months during the primary analysis. The median PFS observed in the intention-to-treat (ITT) population of 187 patients was not reached (96% CI, 5.7 to not estimable [NE]) in the cabozantinib arm compared with 1.9 months (96% CI, 1.8-3.6) in the placebo arm (HR, 0.22; 96% CI, 0.13-0.36; P < .0001).1,2

The agent was considered to be a new treatment option for this patient population after the primary analysis was released and the FDA approved cabozantinib for the treatment of patients 12 years and older with DTC who have progressed following prior therapy (RAI-refractory).1

Extended follow-up of patients in COSMIC-311 was for a median duration of 10.1 months. Investigators assessed efficacy and safety outcomes in 258 patients from the ITT population. Per the study design, all patients enrolled had radiographic progression during or following treatment with 2 or fewer VEGFR multikinase inhibitors, which must have included lenvatinib (Lenvima) or sorafenib (Nexavar). Patients were also required to have an ECOG performance stats of 0 or 1 and be at least 16 years of age.

Randomization in the study was 2:1 to wither the experimental treatment with cabozantinib 60 mg once daily or matching placebo once daily. Treatment continued in the study until patients no longer derived benefit or until unacceptable toxicity. Following RECIST v1.1 criteria, tumors were assessed every 8 weeks for up to a year followed by every 12 weeks. To assess the primary end points of objective response rate (ORR) and PFS, a blinded independent radiology committee (BIRC) was employed. Stratification factors included the age of patients with RAI-DTC receiving cabozantinib and prior treatment with lenvatinib.

After extended follow-up in the ITT population, treatment with cabozantinib achieved a median PFS of 11.0 months (96% CI, 7.4-13.8) compared with only 1.9 months (95% CI, 1.9-3.7) in the placebo arm (HR, 0.22; 96% CI, 0.15-0.32; P <.0001), per BIRC review. Cabozantinib also showed overall survival (OS) benefit during the long-term follow up analysis with a median OS of 19.4 months (95% CI, 15.9-19.4) compared with a non-evaluable (NE) median OS in the placebo arm (HR, 0.76; 95% CI, 0.45-1.3).

In terms of responses, greater tumor reduction from baseline was observed with cabozantinib versus placebo. The ORR in the cabozantinib arm was 11% (95% CI, 6.9%-16.9%), which include 1 complete response and 1 partial responses. In comparison, the ORR observed with placebo was 0% (95% CI, 0.0%-4.1%).

“Eighty percent of patients showed any decrease from baseline in the cabozantinib arm versus only 25% of the placebo arm, demonstrating the benefit of copies and even in patients with stable disease,” stated Marcia S. Brose, MD, PhD, Emeritus Professor CE of Otorhinolaryngology: Head and Neck Surgery at Perelman School of Medicine, University of Pennsylvania, during the ATA presentation.

The BICR further evaluated PFS based on prior exposure to ether lenvatinib, sorafenib, or both. In the subgroup who were previously treated with sorafenib, cabozantinib therapy led to a median PFS of 16.6 months (95% CI, 11.0-NE) compared with 3.2 months (95% CI, 1.8-5.5) with placebo (HR, 0.13; 95% CI, 0.06-0.26). Patients who received lenvatinib as a previous therapy achieved a median PFS of 5.8 months (95% CI, 5.1-9.3) on treatment with cabozantinib compared with 1.9 months (95% CI, 1.7-3.7) in the placebo arm (HR, 0.28; 95% CI, 0.16-0.48). Patients who received both sorafenib and lenvatinib prior to COSMIC-311 had a median PFS of 7.6 months (95% CI, 3.8-13.8) with cabozantinib versus 1.9 months (95% CI, 1.8-3.8) with placebo (HR, 0.27; 95% CI, 0.13-0.54).

Brose stated: “The progression-free survival hazard ratios in all three segments were consistent with that of the intention to treat population overall and ranged from 0.13 to 0.28.” Based on this subgroup analysis, cabozantinib improved PFS in patients with previously treated RAI-DTC irrespective of prior treatment with either sorafenib or lenvatinib.

The safety of cabozantinib during extend follow-up were consistent with the known safety profile of the drug and no new safety signals were observed. The most common any-grade adverse events (AEs) observed with cabozantinib included diarrhea (62%) hand foot skin reaction (47%), and hypertension (32%). The most common grade 3 or higher AEs were hypertension (12%), hand foot skin reaction (10%), and fatigue (9%).

Sixty-seven percent of patients in the cabozantinib arm required dose reduction due to AEs compared with only 5% of the placebo arm. Further, treatment discontinue occurred in 8.8% of the cabozantinib arm versus none of the placebo arm. No grade 5 treatment-related AEs were reported.


1. Brose MS. Cabozantinib versus placebo in patients with radioiodine-refractory differentiated thyroid cancer (DTC) who have progressed after prior VEGFR-targeted therapy: Updated results from the phase 3 cosmic-311 trial and prespecified subgroup analyses based on Prior VEGFR-targeted therapy. Presented at: 90th Annual Meeting of the American Thyroid Association; September 30-October 3, 2021; Virtual. Abstract 25.

2. Brose MS, Robinson B, Sherman SI, et al. Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22(8): 1126-1138. doi: 10.1016/S1470-2045(21)00332-6