WRN inhibitor RO7589831 shows early activity in advanced MSI solid tumors

Werner syndrome helicase (WRN) is a synthetic lethal target in microsatellite instability (MSI) cancers. Part 1 of an ongoing first-in-human phase 1 trial evaluated the covalent WRN inhibitor RO7589831 (VVD-133214) in 88 patients with advanced MSI and/or mismatch repair-deficient solid tumors. Escalating once-, twice- and three-times-daily regimens were assessed, primarily for safety, tolerability and recommended phase 2 dosing; antitumor activity was a secondary objective.

Among 66 MSI efficacy-evaluable patients, disease control occurred in 49 (74.2%), and seven achieved confirmed partial responses, giving an objective response rate of 10.6%. Median response duration was reported as 10.2+ months. Median progression-free survival was 6.7 months (95% CI 4.1–8.5), and median overall survival was 17.6 months (95% CI 17.6–not estimable).

Common treatment-emergent adverse events included nausea (54.5%), diarrhea (43.2%), fatigue (39.8%), anemia (37.5%) and vomiting (30.7%). Grade 3 or higher anemia occurred in 11.4%. Three patients (3.4%) discontinued treatment because of adverse events; no grade 5 events occurred. One dose-limiting event, grade 2 nausea, occurred at 600 mg three times daily; a maximum tolerated dose was not identified.

Doses of 150 mg and 600 mg twice daily were selected for further optimization. These early findings support additional testing rather than establish clinical benefit. Direct target engagement in tumor tissue was not demonstrated, although exploratory circulating tumor DNA and FDG-PET responses supported biological activity.