Brose M.S.Keam B.Krajewska J.Hoff A.O.Vaisman F.Lin C.C.Hitre E.Bowles D.W.Robinson B.Sherman S.I.Ngamphaiboon N.Guo X.Simmons A.Williamson D.Andrianova S.Berry N.Capdevila J.Mahidol University2026-04-012026-04-012026-01-01Frontiers in Oncology Vol.16 (2026)https://repository.li.mahidol.ac.th/handle/123456789/115943Background: Cabozantinib is approved for previously treated radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) based on improved progression-free survival (PFS) versus placebo in the COSMIC-311 study. The BRAF^V600E mutation is common in DTC and is associated with poor prognosis. This planned exploratory analysis of COSMIC-311 reports outcomes by BRAF status. Methods: In this exploratory analysis, outcomes by BRAF^wt (wild-type) or BRAF^V600E status were evaluated in the COSMIC-311 phase 3 study in patients with RAIR-DTC who had previously received lenvatinib and/or sorafenib. Results: BRAF status was available for 106 of 258 patients enrolled in COSMIC-311; of these, 74 had BRAF^wt and 27 had BRAF^V600E. Cabozantinib prolonged PFS versus placebo in both the BRAF^wt (hazard ratio [HR] 0.23 [95% CI: 0.12–0.44]; median PFS, 11.1 versus 1.9 months) and BRAF^V600E (HR 0.15 [95% CI: 0.04–0.59]; median PFS, 9.2 versus 1.9 months) subgroups. While no responses were observed with placebo in both BRAF subgroups, objective response rates (ORRs) of 11% and 18% were observed with cabozantinib in the BRAF^wt and BRAF^V600Esubgroups, respectively. Among patients treated with cabozantinib, 68% of the BRAF^wt group and 53% of the BRAF^V600E group reported grade 3/4 treatment-emergent adverse events; the incidences were 17% and 50% in the corresponding groups treated with placebo. Conclusions: In this subgroup analysis of COSMIC-311, cabozantinib improved PFS and ORR versus placebo irrespective of BRAF mutation status. Thus, cabozantinib is an efficacious treatment option with a manageable safety profile for previously treated patients with RAIR-DTC, including those with BRAF^V600E.Biochemistry, Genetics and Molecular BiologyMedicineArticleSCOPUS10.3389/fonc.2026.17485662-s2.0-1050331262142234943X