AbstractBackgroundAt an interim analysis (median follow‐up, 6.2 months; n = 187), the phase 3 COSMIC‐311 trial met the primary end point of progression‐free survival (PFS): cabozantinib improved PFS versus a placebo (median, not reached vs. 1.9 months; p < .0001) in patients with previously treated radioiodine‐refractory differentiated thyroid cancer (RAIR‐DTC). The results from an exploratory analysis using an extended datacut are presented.MethodsPatients 16 years old or older with RAIR‐DTC who progressed on prior lenvatinib and/or sorafenib were randomized 2:1 to oral cabozantinib tablets (60 mg/day) or a placebo. Placebo patients could cross over to open‐label cabozantinib upon radiographic disease progression. The objective response rate (ORR) in the first 100 randomized patients and the PFS in the intent‐to‐treat population, both according to Response Evaluation Criteria in Solid Tumors version 1.1 by blinded, independent review, were the primary end points.ResultsAt the data cutoff (February 8, 2021), 258 patients had been randomized (cabozantinib, n = 170; placebo, n = 88); the median follow‐up was 10.1 months. The median PFS was 11.0 months (96% confidence interval [CI], 7.4–13.8 months) for cabozantinib and 1.9 months (96% CI, 1.9–3.7 months) for the placebo (hazard ratio, 0.22; 96% CI, 0.15–0.32; p < .0001). The ORR was 11.0% (95% CI, 6.9%–16.9%) versus 0% (95% CI, 0.0%–4.1%) (p = .0003) with one complete response with cabozantinib. Forty placebo patients crossed over to open‐label cabozantinib. Grade 3/4 treatment‐emergent adverse events occurred in 62% and 28% of the cabozantinib‐ and placebo‐treated patients, respectively; the most common were hypertension (12% vs. 2%), palmar–plantar erythrodysesthesia (10% vs. 0%), and fatigue (9% vs. 0%). There were no grade 5 treatment‐related events.ConclusionsAt extended follow‐up, cabozantinib maintained superior efficacy over a placebo in patients with previously treated RAIR‐DTC with no new safety signals.