PublishedSeptember 29, 2026
JournalNature Medicine
TrialPhase 1, part 1 (RO7589831)

WRN Inhibitor RO7589831 Achieves 74.2% Disease Control but a 10.6% Objective Response Rate in Heavily Pretreated MSI Solid Tumors, in a Phase 1 Trial Without Direct Target-Engagement Evidence

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Article Summary
  • Part 1 of a phase 1 trial of RO7589831 (VVD-133214), a covalent Werner syndrome helicase inhibitor, enrolled 88 patients with MSI and/or dMMR advanced solid tumors who had progressed on standard therapies. Among 66 MSI efficacy-evaluable patients, the disease control rate (DCR) was 74.2% (95% CI 63.9–82.9; 49/66) and the objective response rate (ORR) was 10.6% (7/66, confirmed RECIST v.1.1 partial responses).
  • Median PFS was 6.7 months (95% CI 4.1–8.5) and median OS was 17.6 months (95% CI 17.6–NE). One dose-limiting toxicity (grade 2 nausea) occurred, the maximum tolerated dose was not identified per protocol, and 150 mg and 600 mg BID were selected as recommended phase 2 doses for dose optimization.
  • This was an open-label, first-in-human phase 1 study without a comparator arm. Direct target engagement in tumor tissue could not be demonstrated (only 5 of 26 paired biopsies had sufficient tumor cell content), and the study was described as underpowered to establish tumor-intrinsic predictive biomarkers beyond microsatellite status.

Why This Study Matters

MSI/dMMR is a biomarker of response to immune-checkpoint inhibitors (ICIs), yet some patients do not respond, and others progress after initial benefit. The authors note that approved later-line options are limited and may be associated with low response rates and poor tolerability. Targeted treatments that directly exploit the DNA damage response defect underlying MSI are also lacking. WRN helicase has been identified as a synthetic lethal target in MSI tumors; RO7589831 binds WRN covalently and irreversibly via the Cys 727 residue.

1
DCR 74.2% (95% CI 63.9–82.9; 49/66) among MSI efficacy-evaluable patients.
2
ORR 10.6% (7/66, confirmed RECIST v.1.1 partial responses); median duration of response 10.2+ months (95% CI 3.7–NE).
3
Median PFS 6.7 months (95% CI 4.1–8.5); median OS 17.6 months (95% CI 17.6–NE).
4
One dose-limiting toxicity (grade 2 nausea, 600 mg TID backfill cohort); maximum tolerated dose not identified per protocol; no grade 5 TEAEs.
5
150 mg and 600 mg BID selected as recommended phase 2 doses for dose optimization.

Study Design

NCT06004245 is an open-label, multicenter, first-in-human phase 1 study conducted at 17 centers in 8 countries. Part 1 evaluated escalating oral doses in 21-day cycles, starting at 150 mg once daily, with escalation guided by a modified continual reassessment method with escalation with overdose control. After reviewing dose-escalation data, patients were randomized 1:1:1 (without stratification) into three backfill cohorts: 150 mg QD (n = 14), 200 mg TID (n = 15) and 600 mg TID (n = 14). Primary objectives were safety (including MTD via dose-limiting toxicities) and identification of the RP2D. Secondary objectives included pharmacokinetics and antitumor activity (DCR, ORR, DOR, PFS, OS). Part 2 is enrolling advanced MSI-high or dMMR colorectal cancer (CRC) patients to evaluate two doses of RO7589831 with bevacizumab. Sponsor: initially F. Hoffmann-La Roche; now Vividion Therapeutics.

Patient Population

Between 25 January 2024 and 30 June 2025, 88 patients with MSI and/or dMMR advanced solid tumors who had progressed on standard therapies were enrolled. Median age was 60 years (range 27–86); 50 (56.8%) were male and 77 (87.5%) were white. Sixty-nine (78.4%) had MSI/dMMR confirmed by central laboratory methods. Fifty-seven (64.8%) had advanced CRC and 8 (9.1%) advanced endometrial cancer. The median number of previous lines of therapy was three (range 1–12), and 84 (95.5%) had received at least one previous ICI. At the data cutoff (9 September 2025), 56 had discontinued treatment and 32 were ongoing; median treatment duration was 115 days (range 2–575).

Primary Endpoint Results: Safety and Dose Selection

No DLTs occurred in the dose-escalation cohorts. One DLT of grade 2 nausea occurred in the 600 mg TID backfill cohort (n = 1 of 15; 6.7%); the MTD was not identified per protocol. TEAEs of any grade occurred in 87 (98.9%) patients, grade 3–4 TEAEs in 41 (46.6%), and serious TEAEs in 29 (33.0%). TEAEs led to discontinuation in 3 (3.4%) patients. The 1,000 mg BID schedule was not considered for further development because of tolerability issues, and TID schedules were not proposed for further clinical development. The 150 mg and 600 mg BID doses were selected as RP2Ds for formal dose optimization.

These data suggest that RO7589831 has a manageable safety profile and warrants further clinical testing.
— Yap et al., Nature Medicine abstract

Efficacy

PopulationnDCR (95% CI)Confirmed PRSDPDMedian PFS, mo (95% CI)
MSI efficacy-evaluable6674.2% (63.9–82.9)7 (10.6%)42 (63.6%)17 (25.8%)6.7 (4.1–8.5)
MSI CRC4180.5% (67.5–89.9)3 (7.3%)30 (73.2%)8 (19.5%)7.3 (4.1–9.0)
MSI endometrial666.7% (27.1–93.7)3 (50.0%)1 (16.7%)2 (33.3%)12.7 (0.8–NE)

NE, not estimable. SD includes one patient with an unconfirmed PR in the overall population, as reported in the source. Clinical benefit rate was 54.5% (95% CI 43.7–65.1) at 3 months and 33.3% (95% CI 23.8–44.1) at 6 months. Median OS was 17.6 months (95% CI 17.6–NE) overall and not estimable in CRC and endometrial subgroups; 12-month OS rates were 78.3% (95% CI 55.0–90.5) and 80.0% (95% CI 20.4–96.9) in those subgroups, respectively.

Subgroup Analyses

DCRs were comparable between patients who had (72.7%, 16/22) and had not (75.0%, 33/44) responded to previous ICI; cPR rates were 13.6% (3/22) and 9.1% (4/44). No RECIST v.1.1 responses were observed in seven efficacy-evaluable patients with microsatellite-stable (MSS) tumors per central assessment or nine patients with no evaluable MSI status. The authors report no obvious associations between baseline clinical characteristics and overall response, noting the limited sample size.

Safety Profile

CohortnAny-grade TRAEGrade 3–4 TRAETRAE → dose interruptionTRAE → dose reduction
150 mg QD198 (42.1%)000
150 mg BID43 (75.0%)000
300 mg BID109 (90.0%)01 (10.0%)1 (10.0%)
600 mg BID1412 (85.7%)2 (14.3%)7 (50.0%)5 (35.7%)
1,000 mg BID1111 (100%)5 (45.5%)4 (36.4%)6 (54.5%)
200 mg TID1512 (80.0%)4 (26.7%)2 (13.3%)2 (13.3%)
600 mg TID1514 (93.3%)3 (20.0%)6 (40.0%)7 (46.7%)
All patients8869 (78.4%)14 (15.9%)20 (22.7%)21 (23.9%)

TEAEs occurring in ≥30% were nausea (54.5%, 48/88; grade 3+: 2.3%), diarrhea (43.2%, 38/88; grade 3+: 1.1%), fatigue (39.8%, 35/88; grade 3+: 2.3%), anemia (37.5%, 33/88; grade 3+: 11.4%) and vomiting (30.7%, 27/88; grade 3+: 1.1%). Higher C1D1 Cmax was significantly associated with grade 2+ gastrointestinal toxicity (P = 0.0002).

Interpretation and Broader Context

The authors conclude that WRN inhibition showed evidence of biological activity and disease control in a heavily pretreated population, predominantly as stable disease, with objective responses less frequent (10.6%). Exploratory analyses supported biological activity: reduced metabolic activity on FDG-PET in 81.1% (n = 43) of 53 evaluable patients, and ctDNA molecular response in 63.4% (26/41) of ctDNA-evaluable patients. A similar safety profile and modest ORRs with high DCRs were reported for HRO761, another WRN inhibitor, as cited by the authors.

Limitations

This was an open-label, first-in-human phase 1 study; efficacy outcomes are secondary objectives and are reported without a comparator arm. Direct target engagement in tumor tissue could not be demonstrated: only five (19.2%) of 26 paired biopsies had sufficient tumor cell content. The study was described as underpowered to establish tumor-intrinsic predictive biomarkers beyond microsatellite status, and the authors note a limited sample size when reporting that no obvious associations were found between baseline clinical characteristics and overall response. Subgroups were small (for example, 6 efficacy-evaluable patients with endometrial cancer, with a DCR confidence interval of 27.1–93.7), and median OS was not estimable in the CRC and endometrial subgroups. Disease control was predominantly stable disease, with objective responses in 10.6%.

Trial registration

Primary source: DOI 10.1038/s41591-026-04657-3 · PubMed 42811189

References

  1. Yap TA, Fontana E, Cook N, et al. Werner helicase inhibitor for advanced microsatellite instability solid tumors: a phase 1 trial. Nature Medicine. 2026. DOI: 10.1038/s41591-026-04657-3. PMID: 42811189. ClinicalTrials.gov: NCT06004245.