FDA Approval Decision Pending on Cabozantinib as a New Treatment Option for RR-DTC

Progression-free survival was significantly prolonged with cabozantinib as treatment of patients with radioiodine-refractory differentiated thyroid cancer in the phase 3 COSMIC-311 clinical trial, showing potential as a new treatment option and leading to the filing of a application for FDA approval.

Progression-free survival (PFS) was significantly prolonged with cabozantinib (Cabometyx) as treatment of patients with radioiodine-refractory differentiated thyroid cancer (DTC) in the phase 3 COSMIC-311 clinical trial, showing potential as a new treatment option for patients who have no available standard of care.1

Cabozantinib is an inhibitor of the VEGFR2, AXL, MET, and RET kinases and has also demonstrated the ability to target MET and AXL. The agent is FDA approved for the treatment of multiple advanced solid tumors including for the treatment of metastatic medullary thyroid cancer. For the radioiodine-refractory DTC population, the FDA granted priority review to a supplemental new drug application for cabozantinib based on its achievement of a 78% reduction in the risk of disease progression or death in COSMIC-311 (NCT03690388). The FDA plans to make it decision on the approval of cabozantinib for this indication by December 4, 2021.2

The median PFS by blinded independent central review was not reached (96% CI, 5.7-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). Per investigator assessment, the median PFS was similar. In the cabozantinib arm, the median PFS was NR (95% CI, 5.8-NE) versus 1.9 months (95% CI, 1.8-4.0) in the placebo arm (HR, 0.27; 95% CI, 0.17-0.44; P <.0001).1

“The significant progression-free survival benefit associated with a short follow-up time might indicate that cabozantinib imparted disease stabilization in a patient population who would have otherwise had rapid disease progression, wrote study authors led by Marcia S. Brose, MD, PhD, of the University of Pennsylvania’s Perelman School of Medicine, regarding the PFS results.

In prior phase 1 and 2 studies, the agent had shown clinical activity in radioiodine-refractory DTC, including in patients who had been previously treated with VEGFR therapy. The activity of this agent was further explored COSMIC-311, a global, multicenter, randomized, double-blind, placebo-controlled, phase 3 trial conducted in 164 centers and across 25 countries.

A total of 227 patients with radioiodine-refractory DTC were assessed for eligibility in COSMIC-311. Patients were required to be 16 years of age or older with a confirmed diagnosis of DTC, measurable disease per RECIST v1.1, be previously treated with iodine-131, and deemed ineligible for further iodine therapy, and have experienced radiographic progression on or following treatment with a VEGFR tyrosine kinase inhibitor. Previous treatment with lenvatinib (Lenvima) and sorafenib (Nexavar) was permitted in this study. Patients were also required to have an ECOG performance status of 0 or 1, adequate organ and bone marrow function, prior to thyroxine replacement therapy with serum thyroid-stimulating hormone concentrations below the lower cutoff of the reference range or less than 0.50 mIU/L.

Forty patients were deemed ineligible for the study, leaving 187 to be randomized 2:1 to received either cabozantinib 60 mg once daily or a matching placebo. For the efficacy assessment, patients were stratified by prior treatment with lenvatinib as well as by age.

At baseline, the intention-to-treat (ITT) population had a median age of 66 years (interquartile range [IQR], 56-72). Sixty-three percent of patients had received prior lenvatinib, 60% received prior sorafenib, and 24% previously a combination of lenvatinib and sorafenib. The majority of patients (76%) had developed disease progression while received lenvatinib or sorafenib. The median prior line of therapy was 2 (IQR, 2-3) in both treatment arms.

At a median follow-up of 8.9 months (IQR, 7.1-10.5) in the objective response rate ITT (OITT), population, the ORR by BIRC was 15% (99% CI, 5.8%-29.3%) among those treated with cabozantinib compared with 0% (99% CI, 0%-14.8%) in the placebo arm (P =.28). The difference was not considered to be significant. All responses were partial responses (PRs). Stable disease (SD) was observed in 69% of the cabozantinib arm compared with 42% of the placebo arm, and SD lasting 16 weeks or more was observed in 45% versus 27%, respectively. Six percent of patients in the cabozantinib arm had progressive disease (PD) compared with 55% of the placebo arm.

Overall, cabozantinib achieved a disease control rate (DCR) of 60% (95% CI, 47.0%-71.5%) compared with placebo at 27% (95% CI, 13.3%-45.5%). The median DOR was not reached in the cabozantinib arm, but 9 out of 10 patients maintained their response at data cutoff, and 1 patient experienced disease progression. DOR was not assessed in the placebo arm.

Responses in the OITT population by investigator assessment were similar to those observed by BICR. The ORR was 21% (99% CI, 9.8%-36.3%) in the cabozantinib arm compared with 0% (99% CI, 0%-14.8%) in the placebo arm (P =.0040). All responses were PRs, and 58% of patients achieved SD in both treatment arms. Notably, SD lasting greater than 16 weeks was observed in 425 of the cabozantinib arm compared with 33% of the placebo arm. PD was seen in 10% of the cabozantinib arm and 43% of the placebo arm.

The DCR in the cabozantinib arm per investigator assessment was 63% (95% CI, 50.0%-74.3%) compared with 33% (95% CI, 18.0%-52.8%) in the placebo arm. The median duration of responses was NE in the cabozantinib arm and not assessed in the control arm.

In the ITT population, the BICR-assessed ORR observed with cabozantinib was 9% (95% CI, 4.5%-15.2%) compared with 0% (95% CI, 0%-5.8%) in the placebo arm (P =.017). Per investigator assessment, the ORR was 13% (95% CI, 7.5%-20.05) in the cabozantinib arm compared with 0% (95% CI, 0%-5.8%) in the placebo arm (P =.0016).

Responses to treatment in the study also included a reduction in tumor size from baseline which was observed in 76% of patients in the cabozantinib arm compared with 29% of the placebo arm.

In addition to showing a positive result for the primary end point, treatment with cabozantinib also trended higher than the placebo group. The median OS was not reached in either arm, but the OS rate was estimated to be 85% (95% CI, 75.0%-91.0%) in the cabozantinib arm compared with 73% (95% CI, 58.4%-83.7%) in the placebo arm.

In terms of safety, any-grade AEs were seen in 94% of the cabozantinib arm compared with 93% of the placebo arm. AEs that were grade 3 or 4 in severity occurred in 57% of the cabozantinib arm compared with 26% of the placebo arm. Of the higher-grade AEs, the most common in the cabozantinib arm versus the placebo arm were palmar-plantar erythrodysesthesia (10% vs. 0%), hypertension (9% vs. 3%) fatigue (8% vs. 0%), diarrhea (7% vs. 0%), and hypocalcemia (7% vs. 2%), respectively.

Serious treatment-related AEs were observed in 16% of the cabozantinib arm versus 2% of the placebo. Death occurred in 7% of the cabozantinib arm compared with 11% of the placebo arm. Five of the patients in the experimental arm died due to disease progression and the other 4 died due to grade 5 AEs, which included arterial hemorrhage, cardiorespiratory arrest, pneumonia, and pulmonary embolism. In the placebo arm. The deaths observed were caused by disease progression in 8 patients and grade 5 AEs of cardiac arrest, cerebrovascular accident, and general physical health deterioration in the remaining 3 patients.

Regarding the safety findings, Brose et al wrote “the safety profile was manageable and consistent with the known safety profile of cabozantinib.”

Based on the safety and efficacy results, Brose et al believe cabozantinib can serve an unmet medical need in this patient population.


1. Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22(8): P1126-1138. doi: 10.1016/S1470-2045(21)00332-6

2. 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 cancer. New release. Exelixis, Inc. August 5, 2021. Accessed August 11, 2021.