FDA Grants Cabozantinib Priority Review in Radioactive Iodine–Refractory Differentiated Thyroid Cancer


Based on results from the phase 3 COSMIC-311 trial, the FDA has accepted an application for cabozantinib use in patients with differentiated thyroid cancer with refractory disease following radioactive iodine therapy.

A supplemental new drug application (sNDA) for cabozantinib (Cabometyx) was accepted and granted priority review by the FDA as treatment for patients 12 years of age and older with radioactive iodine–refractory differentiated thyroid cancer (DTC) following prior therapy, according to the company responsible for the agent, Exelisis, Inc.1

The data supporting the sDNA came from the phase 3 COSMIC-311 trial (NCT03690388), which demonstrated that a statistically significant increase in median progression-free survival (PFS) was possible with cabozantinib vs placebo in this population of patients with no available standard of care.

“The FDA’s acceptance of our sNDA with priority review is an important step toward our goal of bringing Cabometyx to patients with previously treated radioactive iodine–refractory differentiated thyroid cancer,” Michael M. Morrissey, PhD, Exelixis’ president and chief executive officer, said in a press release. “Considering the lack of a standard of care in the treatment of this cancer following anti-VEGFR therapy, the progression-free survival benefit demonstrated in the phase 3 COSMIC-311 pivotal trial means Cabometyx, if approved, could become an important new treatment for these patients.”

The global, multicenter, randomized, double-blind, placebo-controlled trial enrolled 187 patients who were aged 16 years or older with a confirmed DTC diagnosis and measurable disease by RECIST 1.1 criteria.2 In order to enroll, patients need to have undergone or been ineligible for treatment with iodine-131. Patients were randomized in a 2:1 fashion to either the cabozantinib (n = 125) or placebo (n = 62) arms.

Most patients had previously been treated with lenvatinib (lenvatinib; 63%) or sorafenib (Nexavar; 60%), and 24% had previously received both agents. In total, 76% of patients experienced disease progression while receiving either agent as their most recent therapy.

After a median follow-up of 6.2 months (interquartile range [IQR], 3.4-9.2) in the intention-to-treat (ITT) population (n = 187), the median PFS was not reached (96% CI, 5.7 to not estimable) vs 1.9 months (95% CI, 1.8-3.6) with placebo (HR, 0.22; 96% CI, 0.13-0.36; P <.0001). The rate of PFS at the 6-month timepoint was 57% (96% CI, 43%-69%) and 17% (96% CI, 7%-30%), respectively.

Median overall survival was not reached in either arm but the estimated rate at 6 months was 85% in the cabozantinib group (95% CI, 75.0-91.0) and 73% (95% CI, 58.4%-83.7%) in the placebo group. About a third of patients in the placebo group (31%) crossed over to receive open-label cabozantinib. Excluding patients who crossed over, 2% in the cabozantinib cohort and 6% in the placebo cohort went on to receive a subsequent therapy.

In terms of the objective response rate (ORR) for ITT population (n = 100), 67 patients in the cabozantinib group (15%; 99% CI, 5.8%-29.3%) had a confirmed partial response vs 0 patients in the placebo arm (P = .028). Although the results failed to meet the threshold for statistical significance (P-value <.01), median duration of response was not reached at data cutoff and 44 of 58 patients with at least 1 post-baseline target lesion assessment in the cabozantinib group had a reduction in their target lesion versus just 9 out of 31 patients receiving placebo.

At the time of cut-off, 89 patients are continuing masked treatment with cabozantinib and 26 continued to receive placebo. The most common reason for treatment discontinuation across both groups was disease progression. The most common adverse effects (AEs) that led to dose reduction of cabozantinib were palmar-plantar erythrodysaesthesia (19%), diarrhea (10%), and fatigue (7%) vs fatigue (2%), dyspnea (2%), dysphagia (2%), and pruritus (2%) in the placebo group.

The prescription drug user fee act (PDUFA) target action date for this application is December 4, 2021. Cabozantinib was previously granted breakthrough therapy designation in February 2021 for this indication.


1. Exelixis announces U.S. FDA accepts for priority review the supplemental new drug application for Cabometyx (cabozantinib) for patients with previously treated radioactive iodine-refractory differentiated thyroid xancer. News release. August 5, 2021. Accessed August 5, 2021. https://bwnews.pr/3AieHUP

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

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