Cabozantinib Prolongs Progression-Free Survival in Previously Treated Radioiodine-Refractory Differentiated Thyroid Cancer

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As reported in The Lancet Oncology by Marcia S. Brose, MD, Abramson Cancer Center, University of Pennsylvania, and colleagues, the phase III COSMIC-311 trial has shown that cabozantinib produced a numerically higher objective response rate and significantly prolonged progression-free survival vs placebo in patients with previously treated radioiodine-refractory differentiated thyroid cancer.1

Marcia S. Brose, MD

Marcia S. Brose, MD

Study Details

In the double-blind trial, 187 eligible patients aged ≥ 16 years with radioiodine-refractory differentiated thyroid cancer (papillary or follicular and their variants) from sites in 25 countries were randomly assigned 2:1 between February 2019 and August 2020 to receive cabozantinib at 60 mg (n = 125) or placebo (n = 62) once daily until disease progression or unacceptable toxicity. Randomization was stratified by previous lenvatinib treatment and age (≤ 65 vs > 65 years). Both groups also received best supportive care. Patients had to have received previous lenvatinib or sorafenib and experienced disease progression during or after treatment with up to two vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors. Patients receiving placebo could cross over to open-label cabozantinib upon disease progression.

The primary endpoints were an objective response rate on Response Evaluation Criteria in  Solid Tumors version 1.1 in the first 100 randomly assigned patients (objective response rate intention-to-treat population), consisting of 67 patients in the cabozantinib group vs 33 in the placebo group and progression-free survival in the total intention-to-treat population, both assessed by a blinded independent radiology committee. The current report presents the primary objective response rate analysis and a concurrent preplanned interim progression-free survival analysis.

For the cabozantinib vs placebo intention-to-treat groups, the median age was 65 years (range = 56–72 years, 50% ≥ 65 years) vs 66 years (range = 56–72 years, 53% ≥ 65 years), and 54% vs 55% were female. The geographic region was Europe for 52% vs 52%, Asia for 13% vs 21%, North America for 10% vs 15%, and the rest of the world for 25% vs 13%, and 72% vs 66% were White, 16% vs 23% were Asian, and 1% vs 3% were Black. Overall, 37% vs 37% had received sorafenib but not lenvatinib, 38% vs 42% had received lenvatinib but not sorafenib, and 25% vs 21% had received both; 73% vs 77% had received one and 27% vs 23% had been given two VEGFR inhibitors; histologic subtype was papillary in 54% vs 56% and follicular in 50% vs 45%; and 94% vs 97% had metastatic lesions, the most common site being the lungs (70% vs 79%).

Response Rate and Progression-Free Survival

At data cutoff (August 2020) for both analyses, the median follow-up was 8.9 months (interquartile range [IQR] =7.1–10.5 months) in the objective response rate intention-to-treat population and 6.2 months (IQR = 3.4–9.2 months) in the intention-to-treat population.

In the objective response rate intention-to-treat population, objective responses (all partial) were observed in 10 of 67 patients (15%, 99% confidence interval [CI] = 5.8%–29.3%) in the cabozantinib group vs 0 of 33 (0%, 99% CI = 0%–14.8%) in the placebo group (P = .028); the difference did not meet the prespecified significance level (α = .01). Stable disease for at least 16 weeks was observed in 45% vs 27%, yielding disease stabilization rates (response plus stable disease ≥ 16 weeks) of 60% vs 27%. The median duration of response in the cabozantinib group was not reached (95% CI = 4.1 months to not estimable). Among patients with at least one postbaseline target lesion assessment, reductions in target lesions were observed in 44 of 58 (76%) in the cabozantinib group vs 9 of 31 (29%) in the placebo group.

In the total intention-to-treat population, median progression-free survival was not reached (96% CI = 5.7 months to not estimable) in the cabozantinib group vs 1.9 months (96% CI = 1.8–3.6 months) in the placebo group (hazard ratio [HR] = 0.22, 96% CI = 0.13–0.36, P < .0001). The estimated rate at 6 months was 57% vs 17%.

Hazard ratios for progression-free survival favored cabozantinib in all subgroups examined. For stratification subgroups, hazard ratios were 0.16 (95% CI = 0.08–0.33) for 63 vs 30 patients aged ≤ 65 years and 0.31 (95% CI = 0.16–0.60) for 62 vs 32 of those aged > 65 years and 0.26 (95% CI = 0.15–0.44) for 79 vs 39 patients with prior lenvatinib and 0.11 (95% CI = 0.04–0.35) for 46 vs 23 patients without prior lenvatinib.

A total of 19 patients (31%) in the placebo group crossed over to cabozantinib upon disease progression. In addition, subsequent systemic anticancer therapy was received by three patients (2%) in the cabozantinib group and four (6%) in the placebo group.

At data cutoff, death had occurred in 14% of patients in the cabozantinib group vs 23% of patients in the placebo group. Median overall survival was not reached in either group (HR for cabozantinib vs placebo = 0.54, 95% CI = 0.27–1.11); the estimated 6-month rate was 85% vs 73%.


  • Objective response was observed in 15% vs 0% of patients, with the difference not meeting the prespecified significance level; disease stabilization rates were 60% vs 27%.
  • Median progression-free survival was not reached vs 1.9 months.

Adverse Events

Grade 3 or 4 adverse events occurred in 57% of the cabozantinib group vs 26% of the placebo group, with the most common in the cabozantinib group being palmar-plantar erythrodysesthesia (10% vs 0%), hypertension (9% vs 3%), and fatigue (8% vs 0%). Serious treatment-related adverse events occurred in 16% vs 2% of patients. 

Dose reductions due to adverse events occurred in 56% vs 5%. Adverse events led to discontinuation of treatment in 5% vs 0%. Death due to adverse events occurred in four patients in the cabozantinib group, with causes consisting of arterial hemorrhage, cardiorespiratory arrest, pneumonia, and pulmonary embolism in one patient each and in three patients in the placebo group, with causes consisting of cardiac arrest, cerebrovascular accident, and general physical health deterioration in one patient each. No deaths were considered related to treatment.

The investigators concluded: “Our results show that cabozantinib significantly prolongs progression-free survival and might provide a new treatment option for patients with radioiodine-refractory [differentiated thyroid cancer] who have no available standard of care.” 

DISCLOSURE: The study was funded by Exelixis. Dr. Brose has received honoraria from Bayer, Eisai, and Lilly; has served as a consultant or advisor to Bayer, Blueprint Medicines, Eisai, Exelixis, Lilly, and Loxo; and has received institutional research funding from Bayer, Blueprint Medicines, Eisai, Exelixis, Lilly, and Loxo.


1. 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 22:1126-1138, 2021.