Bezuclastinib (selective type 1 KIT TKI) + sunitinib (type 2 KIT/VEGFR TKI) halves progression risk in 2L GIST

Bezuclastinib is an oral, selective type 1 KIT tyrosine kinase inhibitor designed to cover common KIT resistance mutations and was paired with sunitinib, a type 2 TKI, to broaden inhibition across primary + secondary KIT variants. In the randomized Phase 3 PEAK trial (NCT05208047) in advanced KIT-mutant GIST after prior imatinib (n=413; bezuclastinib 600mg QD + sunitinib 37.5mg QD n=204 vs sunitinib 37.5mg QD n=209), BICR-assessed mPFS improved to 16.5mo vs 9.2mo (HR 0.50, 95% CI 0.39–0.65; P<0.0001) and ORR improved to 46% vs 26% (risk difference 20%; P<0.0001)—numerically and clinically above historical sunitinib benchmarks post-imatinib where objective responses are typically 7% and median time-to-progression is ~27.3 weeks (6.3mo) in the pivotal placebo-controlled setting. Safety was broadly similar between arms with no new sunitinib-class signals; the combo had higher grade≥3 ALT/AST elevations and anemia, with ALT/AST prompting bezuclastinib dose reductions in 13.2% and discontinuations in 1.5% (all grade 3 hepatic AEs resolved; no grade 4), and few discontinuations >1 patient for neutropenia (2.9%) and diarrhea (1%); OS was immature as of Sep 30, 2025 with allowed crossover at progression.