Abstract CT194: First-in-human, phase 1/2 study of GSK4418959, an oral Werner DNA helicase inhibitor, alone or combined with other anticancer agents in adults with advanced mismatch repair-deficient or microsatellite instability-high solid tumors (SY

Abstract Background: Werner syndrome helicase (WRN) is a RecQ helicase family member that plays an important role in genome stability, primarily through its involvement in DNA repair processes such as nonhomologous end-joining and homologous recombination. Upregulation of WRN in mismatch repair (MMR)-deficient or microsatellite instability-high (MSI-H) tumor cells facilitates DNA damage repair and, thus, cell survival. In these cells, WRN inhibition induces double-strand DNA breaks, leading to cell death. Therefore, WRN has emerged as a novel, promising synthetic lethality target in MMR-deficient/MSI-H solid tumors, particularly endometrial and colorectal cancers, which exhibit MMR-deficiency/MSI-H in approximately 20%-30% and 5%-15% of cases, respectively. GSK4418959, a WRNi, is a distinct, oral small molecule that uniquely binds to an allosteric site in the WRN helicase domain, exhibiting synthetic lethality in MMR-deficient/MSI-H tumor cells. It showed potent antitumor activity in in vitro and in vivo preclinical models by selectively inducing DNA damage and, consequently, death of MSI-H cancer cells. Methods: The SYLVER first-in-human, open-label, multicenter, phase 1/2 trial (NCT06710847) opened on December 9, 2024 and aims to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK4418959, as monotherapy or in combination with a programmed cell death protein-1 (PD-1) inhibitor. The trial comprises WRNi monotherapy dose escalation (part 1), WRNi monotherapy dose expansion (part 2), and dose escalation of WRNi + PD-1 inhibitor (part 3). Key eligibility criteria include age ≥18 years, an advanced MMR-deficient/MSI-H solid tumor, an ECOG PS score of 0-1, and having exhausted standard of care (parts 1 and 3) or received 1-3 lines of systemic therapy, including ≥1 immune checkpoint inhibitor therapy (part 2). Patients who have not recovered from treatment-associated adverse events, have uncontrolled hypertension, or have received prior treatment with a WRNi are ineligible. Primary endpoints are safety during the dose-limiting toxicity observation period (ie, first 21 days; parts 1 and 3) and objective response rate (part 2). Secondary endpoints include overall safety (parts 1-3), pharmacokinetics (parts 1-3), progression-free survival (part 2), and duration of response (part 2). Tumor responses will be assessed per RECIST 1.1. Planned enrollment is approximately 133 patients in the US, Australia, Japan, South Korea, Spain, Belgium and the Netherlands, with potential to expand to additional countries for later stages of the study. Disclosures: This study (NCT06710847) is sponsored by GSK. NCT number: NCT06710847 Third-party medical writing support: Writing and editorial support, funded and coordinated by GSK, was provided by Tafara T.R. Kunota, PhD, and Mary C. Wiggin of Ashfield MedComms, an Inizio company. Citation Format: Vivek Samnotra, Natalia Ramos-Hernandez, Thomas Faitg, Meenakshi Srinivasan, Tania Roy, Andrew Liu, Tomasz Zaremba, Clare Holford, Rachel Smith, Jason T. Henry, Jeanne Tie, Noboru Yamamoto, Gul Serbest. First-in-human, phase 1/2 study of GSK4418959, an oral Werner DNA helicase inhibitor, alone or combined with other anticancer agents in adults with advanced mismatch repair-deficient or microsatellite instability-high solid tumors (SYLVER) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT194.