FDA Approves Cabozantinib for Previously Treated Radioactive Iodine-Refractory Differentiated Thyroid Cancer


The FDA has approved cabozantinib for the treatment of adult and pediatric patients aged 12 years and older with locally advanced or metastatic differentiated thyroid cancer that has progressed after prior VEGF-targeted therapy and who are radioactive iodine–refractory or ineligible.



The FDA has approved cabozantinib (Cabometyx) for the treatment of adult and pediatric patients aged 12 years and older with locally advanced or metastatic differentiated thyroid cancer that has progressed after prior VEGF-targeted therapy and who are radioactive iodine–refractory or ineligible.1

The regulatory decision is supported by findings from the phase 3 COSMIC-311 trial (NCT03690388), in which cabozantinib significantly reduced the risk of disease progression or death vs placebo, meeting one of the primary end points of the trial.2 The median progression-free survival (PFS) with cabozantinib had not yet been reached (95% CI, 5.7–not evaluable [NE]) vs 1.9 months (95% CI, 1.8-3.6) with placebo (HR, 0.22; 95% CI, 0.13-0.36; P < .0001).

Results from the follow-up analysis, which will be presented during the 2021 ESMO Congress, showed that with a median follow-up of 10.1 months, the agent was reported to result in a median progression-free survival of 11.0 months per blinded independent radiology committee (BIRC) assessment vs 1.9 months with placebo (HR, 0.22; 95% CI, 0.15-0.31).

“Before today, patients with radioactive iodine-refractory differentiated thyroid cancer who have progressed following prior VEGFR-targeted therapy were facing aggressive disease and no standard treatment option,” Marcia S. Brose, MD, PhD, chief of the Cancer Center Operation Sidney Kimmel Cancer Center at Jefferson Torresdale Hospital, co-Director of Community Based Clinical Trials at Sidney Kimmel Cancer Center at Thomas Jefferson University, and principal investigator of COSMIC-311, stated in a press release. “In the COSMIC-311 pivotal phase 3 trial, [cabozantinib] extended the time patients live without progression of their cancer. The FDA approval of [cabozantinib] is an important advancement for these patients who are badly in need of new treatment options.”

COSMIC-311 enrolled a total of 300 patients with locally advanced or metastatic differentiated thyroid cancer who were radioactive iodine refractory or ineligible, and who experienced radiographic progression during or after treatment with up to 2 prior VEGFR multikinase inhibitors that must have included lenvatinib (Lenvima) or sorafenib (Nexavar).

Patients also needed to be at least 16 years of age, have an ECOG performance status of 0 or 1, and a serum thyroid stimulating hormone of less than 0.5 mIU/L.

Patients were randomized 2:1 to receive either cabozantinib at a once-daily dose of 60 mg (n = 125) or placebo (n = 62). Participants were stratified based on prior receipt of lenvatinib (yes vs no) and age (≤65 years vs >65 years). Crossover was allowed at the time of BIRC–confirmed progression per RECIST v1.1 criteria.

The co-primary end points of the trial were PFS and ORR in the intent-to-treat population per RECIST v1.1 criteria and BIRC assessment. Other end points of interest included overall survival (OS) and safety.

The median age of patients across the arms was 65.5 years, 54.5% were female, 69% were White, 52% were from Europe, 47.5% had an ECOG performance status of 0, and 55% had papillary disease. Additionally, 37% of patients received prior sorafenib but not lenvatinib, 40% had prior lenvatinib but not sorafenib, and 23% had previously received both agents. Seventy-five percent of patients had received 1 prior VEGFR multikinase inhibitor. Moreover, 44.5% of patients had metastatic lesions in the bone, 16% had them in the liver, 74.5% had them in the lung, and 86.5% had then in another area of the body.

The PFS benefit reported with cabozantinib over placebo was observed across all prespecified subgroups, which included age, number of prior VEGFR TKIs received, and prior sorafenib, lenvatinib, or both.

Additional findings from the trial presented during the 2021 ASCO Annual Meeting showed that the disease control rate achieved with cabozantinib was 60% vs 27% with placebo. The duration of response had not been reached (95% CI, 4.1–NE) in the investigative arm.

Moreover, the median OS had not yet been reached in either arm (HR, 0.54; 95% CI, 0.27-1.11). At 6 months of minimum follow-up, cabozantinib reduced target lesions by 76% vs 29% with placebo.

The most common toxicities experienced by at least 25% of patients treated with cabozantinib included diarrhea, palmar-plantar erythrodysesthesia, fatigue, hypertension and stomatitis. Grade 3/4 toxicities that were reported in at least 5% of patients included palmar-plantar erythrodysesthesia, hypertension, fatigue, diarrhea and stomatitis. Serious AEs were experienced by 34% of patients who received the agent, and the most common serious toxicities reported in at least 2% of patients included diarrhea, pleural effusion, pulmonary embolism and dyspnea.

Fatal AEs occurred in 1.6% of those on the investigative arm and included arterial hemorrhage (0.8%) and pulmonary embolism (0.8%). Dose reductions were needed in 56% of patients treated with cabozantinib; 22% of patients needed a second dose reduction. Toxicities that led to discontinuation of cabozantinib were reported in 5% of patients.

“This approval of [cabozantinib] builds on our existing legacy of delivering transformational medicines for patients with difficult-to-treat forms of cancer,” said Michael M. Morrissey, PhD, president and chief executive officer at Exelixis. “We would like to thank the clinical trial participants, the physicians and their staff who participated in the COSMIC-311 trial and to acknowledge the team at the FDA for their collaboration during the quick review of our application.”


  1. Exelixis announces US FDA approval of CABOMETYX (cabozantinib) for patients with previously treated radioactive iodine-refractory differentiated thyroid cancer. News release. Exelixis. September 17, 2021. Accessed September 17, 2021. https://bit.ly/3kiaxa8
  2. Brose MS, Robinson B, Sherman SI, et al. Cabozantinib versus placebo in patients with radioiodine-refractory differentiated thyroid cancer who have progressed after prior VEGFR-targeted therapy: results from the phase 3 COSMIC-311 trial. J Clin Oncol. 2021;39(suppl 15):6001. doi:10.1200/JCO.2021.39.15_suppl.6001
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