Velzatinib (IDRX-42) broad-spectrum KIT/PDGFRA TKI drives 19–44% ORR in advanced GIST (ctDNA VAF ↓>99%)

Velzatinib (IDRX-42; subject to USAN approval) is an oral tyrosine kinase inhibitor designed to cover common primary KIT mutations (exons 9/11) and resistance-associated secondary KIT mutations (exons 13/14/17/18). In the Phase 1/1b StrateGIST 1 trial (NCT05489237), 256 patients with advanced/metastatic GIST treated across all therapy lines (data cutoff September 2025) achieved mutation-stratified ORRs of 44% (KIT exon 9) and 19% (exon 11) and, for secondary mutations, 17% (exon 13), 20% (exon 14), and 23% (exon 17); safety (including Grade 3+ AEs) was not reported in this abstract. In ctDNA-evaluable patients (n=180; Guardant360), >99% ctDNA VAF reductions were frequent across exons (67–83%), and baseline ctDNA detectability appeared prognostic: patients without detectable KIT/PDGFRA at baseline (n=46) had lower progression risk (HR=0.41 vs ctDNA-detectable), while among “primary-mutation-only” patients exon 9 had lower progression risk vs exon 11 (reported HR=3.06; directionality in the abstract is internally inconsistent and needs clarification); as a rough benchmark for later-line SOC, ripretinib in ≥4L achieved median PFS 6.3 months vs 1.0 month with placebo (HR 0.15).