6001 Background: Cabozantinib (C), an inhibitor of VEGFR2, MET, AXL, and RET, showed clinical activity in patients (pts) with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) in phase 1/2 studies (Cabanillas 2017; Brose 2018). This phase 3 study (NCT03690388) evaluated the efficacy and safety of C vs placebo (P) in pts with RAI-refractory DTC who had progressed during/after prior VEGFR-targeted therapy for whom there is no standard of care. Methods: In this double-blind, phase 3 trial, pts were randomized 2:1 to receive C (60 mg QD) or P, stratified by prior lenvatinib treatment (L; yes, no) and age (≤65, > 65 yr). Pts with RAI-refractory DTC must have received L or sorafenib for DTC and progressed during or following treatment with ≤ 2 prior VEGFR inhibitors. Pts randomized to P could cross over to open-label C upon disease progression per blinded independent radiology committee (BIRC). The primary endpoints were objective response rate (ORR) in the first 100 randomized pts and progression-free survival (PFS) in all randomized pts. PFS and ORR were assessed by BIRC per RECIST v1.1. The study was designed to detect an ORR for C vs P (2-sided α = 0.01) and a hazard ratio (HR) for PFS of 0.61 (90% power, 2-sided α = 0.04). A prespecified interim PFS analysis was planned for the ITT population at the time of the primary ORR analysis. Results: As of 19 Aug 2020,125 vs 62 pts had been randomized to the C and P arms, respectively; median age was 66 yr, 55% were female and 63% received prior L. Median (m) follow-up was 6.2 months (mo). At the planned interim analysis, the trial met the primary endpoint of PFS with C demonstrating significant improvement over P (HR 0.22, 96% CI 0.13–0.36; p < 0.0001). mPFS was not reached for C vs 1.9 mo for P; PFS benefit was observed in all prespecified subgroups including prior L (yes, HR 0.26; no, HR 0.11) and age (≤65 yr, HR 0.16; > 65 yr, HR 0.31). ORR was 15% for C vs 0% for P (p = 0.0281) but did not meet the prespecified criteria for statistical significance (p < 0.01). A favorable OS trend was observed for C vs P (HR 0.54, 95% CI 0.27–1.11). Treatment-emergent adverse events (AEs) of any grade with higher occurrences in the C vs P arm included diarrhea (51% vs 3%), hand-foot skin reaction (46% vs 0%), hypertension (28% vs 5%), fatigue (27% vs 8%), and nausea (24% vs 2%); grade 3/4 AEs were experienced by 57% of pts with C vs 26% with P. Dose reductions due to any grade AEs occurred in 57% of pts with C vs 5% with P. Treatment discontinuations due to AEs not related to disease progression occurred in 5% of pts with C vs 0% with P. No treatment-related deaths occurred in either arm. Conclusions: C showed a clinically and statistically significant improvement in PFS over P in pts with RAI-refractory DTC after prior VEGFR-targeted therapy with no unexpected toxicities. C may represent a new standard of care in pts with previously treated DTC. Clinical trial information: NCT03690388.
Differentiated Thyroid Cancer: Determinants of Disease Progression in Patients <21 Years of Age at Diagnosis
