Efficacy of velzatinib (IDRX-42) in patients with advanced/metastatic GIST by line of therapy and circulating tumor DNA response in the phase 1/1b StrateGIST 1 trial.

Abstract

11520 Background: Most gastrointestinal stromal tumors (GIST) are driven by mutations in KIT or PDGFRA . Resistance to standard tyrosine kinase inhibitor (TKI) therapy is largely driven by acquisition of secondary mutations in KIT exons 13/14/17/18. Velzatinib (subject to USAN approval) is a broad-spectrum TKI designed to inhibit most common primary KIT mutations (exons 9 and 11) as well as secondary mutations. We present updated circulating tumor DNA (ctDNA) results from StrateGIST 1, a phase 1/1b study evaluating the efficacy and safety of velzatinib across primary and secondary mutations in patients (pts) with advanced/metastatic GIST. Methods: The study design of StrateGIST 1 has been previously described (Schöffski et al. J Clin Oncol 2024). Clinical activity was assessed by mRECIST v1.1. Blood samples for ctDNA analyses (Guardant360 assay) were collected for all pts before and serially during treatment. Data analysis was performed in R and hazard ratios were calculated using Cox proportional hazards regression. Results: As of September 2025, 256 pts received velzatinib across all lines of therapy. Velzatinib showed clinical activity against both primary (Exon 9 ORR: 44% [95% CI: 29.1, 60.1]; Exon 11 ORR: 19% [95% CI: 12.7, 27.6]) and secondary (Exon 13 ORR: 17% [95% CI: 8.6, 27.9]; Exon 14 ORR: 20% [95% CI: 2.5, 55.6]; Exon 17 ORR: 23% [95% CI: 14.6, 33.2]) mutations. Clinical activity is supported by ctDNA analysis (n=180 pts); >99% reduction in ctDNA variant allele frequency (VAF) was observed across a broad spectrum of individual mutations (Exon 9: 80%; Exon 11: 67%; Exon 13: 80%; Exon 14: 80%; Exon 17: 83%). We also evaluated the predictive value of different exon mutations in KIT detected at baseline via ctDNA. Focusing on pts with primary mutations only, KIT exon 9 mutations had 3-fold lower risk of disease progression compared to exon 11 mutations (HR=3.06). No significant difference was observed between major secondary mutations (exon 13 vs exon 17). Additionally, 46 pts without detectable KIT/PDGFRA mutations at baseline showed a lower progression risk (HR=0.41) compared to 180 pts with detectable KIT/PDGFRA mutations, underscoring the prognostic and/or predictive value of ctDNA analysis, even in low-shedding indications such as GIST. Conclusions: Velzatinib has broad activity against clinically relevant KIT mutations in pts with advanced and/or metastatic GIST and can substantially reduce ctDNA levels across a broad spectrum of clinically meaningful KIT mutation profiles. Baseline exon-level KIT mutation status and ctDNA detectability provide potentially useful prognostic and predictive data, justifying further study to discern the relationship between clinical benefit and molecular response. This study (NCT05489237) is funded by GSK. Clinical trial information: NCT05489237 .