Velzatinib (IDRX-42) as 1L or 2L therapy for advanced gastrointestinal stromal tumors (GISTs) by <i>KIT</i> mutation status: A subset analysis of the phase 1/1b StrateGIST 1 study.

Abstract

11501 Background: Most GISTs present with activating KIT mutations (exons 9/11) initially responsive to imatinib, but many progress due to diverse KIT resistance mutations (largely in exons 13/14/17/18). Velzatinib (subject to USAN approval), a novel selective KIT inhibitor, has broad mutation coverage and robust in vitro/vivo preclinical activity in models with mutations relevant to 1 st - (1L) and 2 nd -line (2L) GIST. We present results from StrateGIST 1 evaluating the safety and efficacy of velzatinib in patients (pts) with advanced GIST as 1L or 2L therapy by KIT mutation status. Methods: The study design of StrateGIST 1 has been previously described (Schöffski et al. J Clin Oncol 2024). We present updated safety and efficacy data for 1L and 2L pts by KIT mutation status treated with velzatinib at the recommended phase 1b dose (RP1bD) of 300-mg tablet or exposure-equivalent 400-mg capsule. Results: As of December 15, 2025, 18 pts in 1L and 46 pts in 2L received velzatinib at the RP1bD and were evaluable for the efficacy analysis. In 2L pts, median follow-up (mFU) was 14.7 (95% CI: 12.9, 18.4) mo and median progression-free survival (mPFS) was 13.7 (95% CI: 7.4, 18.4) mo. In 1L, the mFU was 6.4 (95% CI: 1.8, 11) mo, and all pts (18/18) had a reduction in tumor volume, of whom 11 (61%) experienced unconfirmed responses, including 1 complete and 10 partial responses (Table 1). As of the cutoff date, 17 1L pts remained on study treatment. Treatment was well tolerated, with low rates of dose reductions (1L: 0%; 2L: 6%) and withdrawals (1L: 0%; 2L: 4%) due to AEs. Conclusions: Velzatinib exhibited promising activity and tolerable safety as 1L and 2L therapy across clinically relevant KIT mutations for pts with advanced GIST. These data support further study of velzatinib, including in 1L pts, to address the need for therapeutic options with broad coverage of clinically relevant GIST mutations. This study (NCT05489237) is funded by GSK. Clinical trial information: NCT05489237 . Clinical activity and response by mutation status per mRECIST v1.1. a 1Ltotal(n=18) 2Ltotal(n=46) 2LEx 9mutation only(n=8) 2LEx 11mutation only(n=14) 2LEx 11+ATP-binding pocket resistance mutation (13/14)(n=14) 2LEx 11+activation loop resistance mutation (17/18)(n=3) 2LOther(including ≥2 resistance mutations)(n=7) Best overall response, n (%) Complete response 1 (6) 2 (4) 0 1 (7) 0 0 1 (14) Partial response 10 (56) 14 (30) 5 (62) 2 (14) 5 (36) 1 (33) 1 (14) Stable disease 7 (39) 25 (54) 3 (38) 8 (57) 8 (57) 2 (67) 4 (57) Progressive disease 0 5 (11) 0 3 (21) 1 (7) 0 1 (14) Not evaluable 0 0 0 0 0 0 0 Objective response rate, n (%)(95% CI) 11 (61)(35.7, 82.7) 16 (35)(21.4, 50.2) 5 (62)(24.5, 91.5) 3 (21)(4.7, 50.8) 5 (36)(12.8, 64.9) 1 (33)(0.8, 90.6) 2 (29)(3.7, 71) a In an efficacy-evaluable population defined as all pts with ≥1 postbaseline disease assessment or prior clinical progression or death.