Oliver Bechter

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 .

Multivariate Cox Regression for ctDNA variables

Baseline ctDNA as a prognostic factor in mCRC. A, Association of response (CBOR by RECIST 1.1) with ctDNA values (MTM/mL) at different cycles. Boxplots illustrating ctDNA levels—measured as MTM/mL—stratified by CBOR according to RECIST 1.1. PD patients exhibited significantly higher baseline and early on-treatment ctDNA levels compared with those with SD or PR. CBOR, confirmed best overall response. B, Kaplan–Meier analysis of PFS by baseline cTF (n = 48). PFS stratified by high (>10%) vs. low (≤10%) baseline cTF. A low baseline cTF was highly prognostic for a longer median PFS (284 vs. 59 days; HR = 0.32, P = 0.00051). C, Same analysis, further stratified by prior BRAFi treatment status. PFS analysis demonstrates that whereas prior BRAFi history affects survival, low baseline ctDNA remains a favorable prognostic signal across both treatment cohorts. P values in A were calculated via ANOVA; P values in B and C were determined by the log-rank test. Dashed lines in survival plots indicate mPFS. [Created in BioRender. Godfried Sie, C. (2026) https://BioRender.com/gms7f9h.]

Cox regression models for PFS with clinical and ctDNA variables

Association between ctDNA change from baseline at C1D15 (log MTM/ml) and Mosperafenib dose

Significant associations between clinical and ctDNA variables

Threshold optimization for cTF at baseline

Cox regression forest plot for BRAF V600E allele frequency

Kaplan-Meier analysis of PFS stratified by molecular response