Werner helicase inhibitor for advanced microsatellite instability solid tumors: a phase 1 trial.
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Yap Timothy A, Fontana Elisa, Cook Natalie, Fakih Marwan, Bechter Oliver, Tsang Erica S, Calvo Emiliano, Rohrberg Kristoffer S, Ros Javier, Matos Ignacio, Strickler John H, Ameratunga Malaka, Pelster Meredith, Sharp Adam, Grewal Jaspreet, Ulahannan Susanna, Belani Rajesh, Patricelli Matthew P, Blake Sophia M, Dejardin David, Fowler Stephen, Godfried Sie Christina, Heller Astrid, Henkel Nina, Hettich Michael, Lahr Angelika, Lamparter David, Lane Charlotte, Liu Ting, Meistermann Hélène, Meille Christophe, Parrott Neil, Sotiriou Sotirios K, Reeves Denise, Romagnoli Barbara, Pettazzoni Piergiorgio, Waterkamp Daniel, Wittwer Matthias, Fu Yali, Postel-Vinay Sophie
Аннотация
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 .