Zidesamtinib (NVL-520), a ROS1-selective/TRK-sparing TKI, delivers 40% ORR across non-NSCLC ROS1+ solid tumors

Zidesamtinib is an oral next-generation ROS1 tyrosine kinase inhibitor designed to be highly ROS1-selective and TRK-sparing (to avoid TRK-mediated neurotoxicity), evaluated in the global Phase 1/2 ARROS-1 basket study (NCT05118789) in patients with advanced/metastatic ROS1 fusion–positive solid tumors other than NSCLC after progression on prior therapy (data cut: September 22, 2025). Among 15 efficacy-evaluable patients spanning 10 non-NSCLC histologies (median 2 prior lines; 60% ROS1 TKI–naïve; 40% ROS1 TKI–pretreated), BICR-assessed ORR was 40% (6/15; includes 1 PR pending confirmation) with ongoing responses (DOR range 3.9+–22.8+) and responses reported in cholangiocarcinoma, CRC, gastric, IMT, ovarian, and pancreatic cancer; notably, 2 ROS1 TKI–pretreated patients with baseline ROS1 resistance mutations (G2032R and F2004I/F2004V) both achieved PRs (1 pending). TRAEs ≥15% were ALT increase, CPK increase, and dysgeusia (each in 3 patients); there were no discontinuations for TRAEs and 1 dose reduction—conceptually a tolerability differentiator vs dual ROS1/TRK inhibitors like entrectinib where TRK inhibition contributes to neurologic AEs, while historical ROS1-fusion basket experience with entrectinib showed high activity in a small ROS1-rearranged non-NSCLC solid-tumor cohort (ORR 86% in n=14, early-phase, largely TKI-naïve), underscoring that cross-histology ROS1 dependency can be druggable but that sample size and prior-therapy mix matter for benchmarks.