As reported in The Lancet Oncology by Marcia S. Brose, MD, 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.

Marcia S. Brose, MD

Study Details

The double-blind trial included 187 eligible patients aged ≥ 16 years with radioiodine-refractory differentiated thyroid cancer (papillary or follicular and their variants) from sites in 25 countries. Patients 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. Both groups also received best supportive care. Patients must have received previous treatment with lenvatinib or sorafenib and experienced disease progression during or after treatment with up to two VEGFR tyrosine kinase inhibitors. Patients receiving placebo could cross over to open-label cabozantinib at disease progression.

The primary endpoints were 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 [OITT] population)—consisting of 67 patients in the cabozantinib group vs 33 in the placebo group—and progression-free survival in the total ITT 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.

Response Rate and Progression-Free Survival

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

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

In the total ITT population, median progression-free survival was not reached (96% CI = 5.7 months–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). Estimated rates at 6 months were 57% vs 17%.

A total of 19 patients (31%) in the placebo group crossed over to cabozantinib at 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, 14% of patients in the cabozantinib group vs 23% of patients in the placebo group had died. Median overall survival was not reached in either group (HR for cabozantinib vs placebo = 0.54, 95% CI = 0.27–1.11); estimated 6-month rates were 85% vs 73%.

Adverse Events

Grade 3 or 4 adverse events occurred in 57% of patients in 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.”

Dr. Brose, of Abramson Cancer Center, University of Pennsylvania, is the corresponding author for The Lancet Oncology article. 

Disclosure: The study was funded by Exelixis. For full disclosures of the study authors, visit thelancet.com.