A phase I study of the type II ROS1 TRK inhibitor ANS03 in ROS1 fusion-positive lung cancers

Background: ROS1 tyrosine kinase inhibitors (TKIs) are highly effective in ROS1 -positive non-small cell lung cancer (NSCLC), but acquired resistance remains a challenge, particularly solvent front (SF) mutations like G2032R and D2033N, and the central beta sheet (Cbeta6) mutation L2086F. ANS03 is a next generation type II TKI targeting both ROS1 and TRK, possessing a broad spectrum of acquired drug-resistant mutation coverage. In preclinical studies, ANS03 was more potent than repotrectinib against SF mutations and more potent than repotrectinib or zidesamtinib against L2086F. Method: A phase 1 study (NCT06716138) was designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of ANS03 in participants with locally advanced or metastatic solid tumors harboring a ROS1 or NTRK alteration. Dose escalation was determined by Bayesian optimal interval design. Response was assessed by investigators using RECIST V1.1. Results: As of January 6, 2026, the dose escalation study is ongoing. Five dose levels (15mg qd, 30mg qd, 45mg qd, 67.5mg qd and 90mg qd) have been completed. A total of 20 NSCLC patients harboring ROS1/NTRK fusions were enrolled. No dose-limiting toxicities were observed. The most frequently reported treatment related adverse events (TRAE) were low grade, including the elevation of AST/ALT (80%), bilirubin (35%) and LDH (35%). Grade ≥3 TRAE occurred in 25% of patients. Only low grade neurotoxicities (15%) including dizziness, dysgeusia and pain in the limbs occurred. Among 18 efficacy evaluable ROS1 fusion-positive cancers, objective response rates (ORRs) were 38.8% (7/18) for all enrolled patients and 54.5% (6/11) for patients previously received ≥2L systemic therapy and at least 1 prior ROS1 TKI. Of the latter, six patients were pre-treated with 2-4 ROS1 TKIs including lorlatinib, repotrectinib, taletrectinib, and zidesamtinib. Among heavily pretreated patients, one patient posted 5 prior lines of systemic therapy (3 prior TKIs) with an L2086F mutant cancer had a confirmed partial response (PR) with ANS03 at 12 weeks. Two additional patients who received ≥6 prior lines of systemic therapy and ≥4 prior TKIs had a PR at the first tumor assessment and remain on ANS03 therapy. Conclusions: ANS03 had a manageable safety profile with a low incidence of neurotoxicity. In ROS1 fusion-positive NSCLCs, promising preliminary anti-tumor activity was achieved, including against ROS1 L2086F.