Cabozantinib versus placebo in patients (pts) with radioiodine-refractory (RAIR) differentiated thyroid cancer (DTC) who progressed after prior VEGFR-targeted therapy: Outcomes in prespecified subgroups based on histology subtypes.

6083 Background: Based on the results of the phase 3 COSMIC-311 trial, the multikinase inhibitor C was recently approved by the FDA for the treatment of RAIR DTC pts who progress after prior VEGFR-targeted therapies, such as lenvatinib (L) or sorafenib (S), and for whom there was no standard of care (Brose et al. Lancet Oncol. 2021). In an extended follow-up of the intent-to-treat (ITT) population, C-treated pts achieved a median (m) progression-free survival (PFS) of 11 months (mo) vs 1.9 mo with P (HR 0.22, 96% CI 0.15–0.32, P <.0001); here we present outcomes for prespecified subgroups who received prior L, S, or both. Methods: Pts were randomized 2:1 to C (60 mg QD) or P. P pts could cross over to open-label C upon disease progression per confirmation by blinded independent radiology committee (BIRC). The primary endpoints were PFS (ITT) and objective response rate (first 100 randomized pts), per RECIST v1.1 by BIRC. Pts must have received L or S and progressed during or after 1–2 prior VEGFR inhibitors. Results: After a median follow-up of 10.1 mo, 258 pts (170 C, 88 P) had been randomized (data cutoff 8 Feb 2021); 96 (̃37%) had received prior S (no L), 102 (̃40%) prior L (no S), and 60 (̃23%) prior S and L. Median PFS was 16.6 for C vs 3.2 mo for P in prior S (no L) (HR 0.13, 95% CI 0.06–0.26); 5.8 vs 1.9 mo in prior L (no S) (HR 0.28, 95% CI 0.16–0.48), and 7.6 vs 1.9 mo in prior S and L (HR 0.27, 95% CI 0.13–0.54). In the C arm, 21% of pts in prior S (no L), 3% in prior L (no S), and 8% in S and L subgroups had confirmed partial response, and 1 pt had a confirmed complete response in prior L (no S); there were no responses with P. Stable disease as best response was 67% for C vs 45% for P in prior S (no L), 68% vs 32% in prior L (no S), and 74% vs 38% in prior S and L. Median duration of C-exposure was 7.0 mo in prior S (no L), 5.6 mo in prior L (no S) and 5.9 mo in prior S and L. Grade 3/4 treatment-emergent adverse events (TEAE) occurred in 63% pts in prior S (no L), 57% in prior L (no S), and 69% in prior S and L. Discontinuations of C due to TEAE occurred in 16% of pts in prior S (no L), 13% in prior L (no S), and 23% in prior S and L. There were no treatment-related deaths. Conclusions: In the extended follow-up, C maintained its superior PFS vs P irrespective of prior L and/or S. AEs in each subgroup were consistent with that of the overall population. This is also the first phase 3 study demonstrating a clinical benefit with C after prior L in RAIR DTC pts. Clinical trial information: NCT03690388.