Werner helicase inhibitor for advanced microsatellite instability solid tumors: a phase 1 trial

Abstract Werner syndrome helicase (WRN) is a synthetic lethal target for microsatellite instability (MSI) cancers. In part 1 of this ongoing first-in-human, phase 1 trial, escalating doses of RO7589831 (VVD-133214), a first-in-class, WRN covalent inhibitor, were evaluated in 88 patients with MSI and/or deficient DNA mismatch repair advanced solid tumors. RO7589831 was administered once daily (150 mg), twice daily (BID; 150–1,000 mg) or three-times daily (TID; 200–600 mg). Primary objectives were to evaluate safety and tolerability, and identify the recommended phase 2 dose and schedule (RP2D). Secondary objectives included evaluation of antitumor activity (end points: disease control rate (DCR), objective response rate (ORR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS)). One dose-limiting toxicity of grade 2 nausea occurred in the 600-mg TID cohort; however, the maximum tolerated dose was not identified per protocol. Treatment-emergent adverse events (TEAEs) occurring in ≥10% were mostly grade 1–2; events in ≥30% were nausea (54.5%, 48/88; grade 3+: 2.3%, 2/88), diarrhea (43.2%, 38/88; grade 3+: 1.1%, 1/88), fatigue (39.8%, 35/88; grade 3+: 2.3%, 2/88), anemia (37.5%, 33/88; grade 3+: 11.4%, 10/88), and vomiting (30.7%, 27/88, grade 3+: 1.1%, 1/88). TEAEs leading to RO7589831 discontinuation were uncommon (3.4%, 3/88). No grade 5 TEAEs occurred. The DCR among MSI efficacy-evaluable patients was 74.2% (49/66). Seven patients achieved confirmed RECIST v.1.1 partial responses (ORR 10.6%, 7/66); median DOR was 10.2+ months. Among MSI efficacy-evaluable patients, median PFS was 6.7 months (95% CI 4.1–8.5); median OS was 17.6 months (95% CI 17.6–not estimable). Although direct target engagement in tumor tissue could not be demonstrated, exploratory analyses of ctDNA molecular response and FDG-PET metabolic response supported biological activity. The 150-mg and 600-mg BID doses were selected as RP2Ds for dose optimization. These data suggest that RO7589831 has a manageable safety profile and warrants further clinical testing. ClinicalTrials.gov identifier: NCT06004245 .

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Nature Medicine
Published
2026-09-29
DOI
https://doi.org/10.1038/s41591-026-04657-3
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1
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DNA Repair Mechanisms
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article
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article

Werner helicase inhibitor for advanced microsatellite instability solid tumors: a phase 1 trial

Sotirios K. Sotiriou, Elisa Fontana, Oliver Edgar Bechter, John H. Strickler et al.
1 citations
Nature Medicine
DNA Repair Mechanisms
2.43
article

Werner helicase inhibitor for advanced microsatellite instability solid tumors: a phase 1 trial

Sotirios K. Sotiriou, Elisa Fontana, Oliver Edgar Bechter, John H. Strickler, Sophie C. Postel-Vinay, Erica S. Tsang, Matthew P. Patricelli, Matthias Wittwer, Sophia M. Blake, Astrid Heller, Kristoffer Staal Rohrberg, Christina Godfried Sie, Angelika Lahr, Susanna Varkey Ulahannan, Stephen M. Fowler, Hélène Meistermann, Emiliano Calvo, David Dejardin, Neil John Parrott, Bárbara Romagnoli, Marwan Fakih, Timothy Anthony Yap, Adam Sharp, David Lamparter, Natalie Cook, Javier Ros, Piergiorgio Pettazzoni, Jaspreet Singh Grewal, Ignacio Garcia Matos, Christophe Meille, Rajesh Belani, Meredith S. Pelster, Michael Hettich, Nina Henkel, Charlotte Lane, Denise Reeves, Daniel Waterkamp, Ting Liu, Yali Fu, Malaka Ameratunga
article en
1 citations

Abstract

Abstract Werner syndrome helicase (WRN) is a synthetic lethal target for microsatellite instability (MSI) cancers. In part 1 of this ongoing first-in-human, phase 1 trial, escalating doses of RO7589831 (VVD-133214), a first-in-class, WRN covalent inhibitor, were evaluated in 88 patients with MSI and/or deficient DNA mismatch repair advanced solid tumors. RO7589831 was administered once daily (150 mg), twice daily (BID; 150–1,000 mg) or three-times daily (TID; 200–600 mg). Primary objectives were to evaluate safety and tolerability, and identify the recommended phase 2 dose and schedule (RP2D). Secondary objectives included evaluation of antitumor activity (end points: disease control rate (DCR), objective response rate (ORR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS)). One dose-limiting toxicity of grade 2 nausea occurred in the 600-mg TID cohort; however, the maximum tolerated dose was not identified per protocol. Treatment-emergent adverse events (TEAEs) occurring in ≥10% were mostly grade 1–2; events in ≥30% were nausea (54.5%, 48/88; grade 3+: 2.3%, 2/88), diarrhea (43.2%, 38/88; grade 3+: 1.1%, 1/88), fatigue (39.8%, 35/88; grade 3+: 2.3%, 2/88), anemia (37.5%, 33/88; grade 3+: 11.4%, 10/88), and vomiting (30.7%, 27/88, grade 3+: 1.1%, 1/88). TEAEs leading to RO7589831 discontinuation were uncommon (3.4%, 3/88). No grade 5 TEAEs occurred. The DCR among MSI efficacy-evaluable patients was 74.2% (49/66). Seven patients achieved confirmed RECIST v.1.1 partial responses (ORR 10.6%, 7/66); median DOR was 10.2+ months. Among MSI efficacy-evaluable patients, median PFS was 6.7 months (95% CI 4.1–8.5); median OS was 17.6 months (95% CI 17.6–not estimable). Although direct target engagement in tumor tissue could not be demonstrated, exploratory analyses of ctDNA molecular response and FDG-PET metabolic response supported biological activity. The 150-mg and 600-mg BID doses were selected as RP2Ds for dose optimization. These data suggest that RO7589831 has a manageable safety profile and warrants further clinical testing. ClinicalTrials.gov identifier: NCT06004245 .

Nature Medicine
Roche (Switzerland) (CH), City Of Hope National Medical Center (US), The University of Texas MD Anderson Cancer Center (US), Duke University (US), Sarah Cannon Research Institute (GB), Norton Healthcare (US), Universitair Ziekenhuis Leuven (BE), Institut Gustave Roussy (FR), The Alfred Hospital (AU), Princess Margaret Cancer Centre (CA), Rigshospitalet (DK), University of Manchester (GB), Roche Pharma AG (Germany) (DE), Sarah Cannon (US), Vall d'Hebron Institut de Recerca (ES), Roche (United Kingdom) (GB), Vividion Therapeutics (United States) (US), Royal Marsden Hospital (GB), The Christie NHS Foundation Trust (GB), Clinica Universidad de Navarra (ES), University of Oklahoma (US)
Good health and well-being
Openalex Percentile: Top 8%
DNA Repair Mechanisms
2.43
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