StrateGIST 3: A randomized, phase 3 study of velzatinib (IDRX-42) versus sunitinib in patients with advanced gastrointestinal stromal tumors after imatinib therapy.

Abstract

TPS11588 Background: Most gastrointestinal stromal tumors (GISTs) are driven by mutations in KIT . Tyrosine kinase inhibitors (TKIs) such as imatinib and sunitinib (first- and second-line therapies for GIST, respectively) are available, but resistance can develop and is primarily mediated by additional KIT mutations in the ATP binding pocket (exon [ex] 13/14) and activation loop (ex 17/18). While sunitinib targets mutations in exon 13/14 in the second-line setting, it has low response rates and short progression-free survival (PFS). Therefore, there is a need for novel therapies with broad mutation coverage, and for patients (pts) with disease progression on, or intolerance to, approved therapies. Velzatinib (subject to USAN approval) is a novel, highly selective, oral KIT TKI that potently and selectively inhibits primary and secondary resistance KIT mutations. In StrateGIST 1, an ongoing, phase 1/1b study in adult pts with advanced GIST, velzatinib exhibited promising clinical activity and favorable safety in 2 nd - and later-line pts at the recommended phase 3 dose of 300-mg QD tablet (or exposure-equivalent 400-mg QD capsule). As of December 15, 2025, median PFS (95% CI) was 13.7 (7.4–18.4) months and confirmed ORR (95% CI) was 33% (19.5–48.0) in 2 nd -line pts (N=46) at the recommended phase 3 dose, supporting the further evaluation of velzatinib in pts with advanced GIST after progression on, or intolerance to, imatinib. Methods: StrateGIST 3 is a phase 3, randomized, multicenter, open-label study (NCT07218926) to evaluate velzatinib vs sunitinib in adult pts with advanced GIST after progression on or intolerance to imatinib. Recruitment for this study opened on December 3, 2025, and the total duration of the study is estimated to be approximately 5 years. Pts must have documented mutation status of KIT and/or PDGFRA , and will be excluded if they have GIST that is wild type for both KIT and PDGFRA or if they have an activating PDGFRA exon 18 mutation. Approximately 450 pts will be randomized (1:1) to receive either velzatinib (300-mg QD tablet, continuous dosing) or sunitinib (50 mg QD, 4 weeks on/2 weeks off). The randomization will be stratified by activating mutation (ex 11 vs ex 9 vs other) and intolerance to first-line imatinib (yes vs no). The primary endpoint is PFS according to modified RECIST for GIST (mRECIST-GIST), by blinded independent central review (BICR). The key secondary endpoint is overall survival, and additional secondary endpoints include PFS per investigator assessment, PFS-2, confirmed objective response rate per BICR and per investigator, time to response per BICR and per investigator, health-related quality of life and functioning, plasma drug concentrations, and safety and tolerability. This trial is now recruiting. This study (NCT07218926) is funded by GSK. Clinical trial information: NCT07218926 .