Phase 1/2 study of the novel Werner helicase inhibitor EIK1005 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors, including MSI-H or dMMR tumors.

Abstract

TPS3170 Background: Cancers with deficient mismatch repair (dMMR) have high microsatellite instability (MSI-H) and are reported to be sensitive to inhibition of the Werner syndrome helicase (WRN) via synthetic lethality. WRN inhibition in MSI-H cells leads to loss of genomic integrity and ultimately cell death while not affecting microsatellite stable (MSS) and healthy cells. Standard of care for patients (pts) with MSI-H tumors includes surgery and immunotherapy (checkpoint inhibitors [CPIs] like pembrolizumab [pembro]). While these are viable treatment options, depending on the indication, ~30 to 50% do not respond to first-line immune CPIs, or acquire resistance. A critical unmet medical need exists for new therapies for such patients (pts). EIK1005 is a novel, potent, high-affinity and selective WRN inhibitor (WRNi) with the potential for targeted antitumor activity in MSI-H or dMMR solid tumors. In vitro studies demonstrated sustained target engagement leading to cell death in MSI-H cells while sparing MSS and healthy cells. In a Phase 1 single ascending dose study in healthy participants, EIK1005 was well tolerated at the doses evaluated. Methods: EIK1005-002 (NCT#07262619) is a multicenter, multi-part, Phase 1/2 study of EIK1005 monotherapy and combination with pembro, in participants with advanced solid tumors including MSI-H and dMMR tumors. The study has three parts; Part 1A (monotherapy dose escalation [DE]): EIK1005 will be evaluated at ~ three dose levels (DL) in participants without alternative therapeutic options (n~40). Preference is given to pts with MSI-H or dMMR cancer for whom prior CPI therapy has failed, or with MSS cancer who progressed after ≥1 regimen of platinum, alkylating or topoisomerase chemotherapy as evidence suggests MMR alterations and MSI induction in previously MSS cancer. Part 1B (combination DE): participants with MSI-H or dMMR tumors (n~40) will receive EIK1005 + pembro (Q3W). Part 2 (dose optimization [DO]): participants (n~80) with MSI-H and dMMR tumors and slowly progressive disease are randomized 1:1 to receive EIK1005 at one of two doses from Part 1A. Key eligibility criteria: participants ≥18 years, life expectancy ≥3 months, unresectable and/or metastatic solid tumor, measurable disease at baseline (RECIST v1.1), progression after or intolerance to ≥ 1 advanced-setting standard treatment regimen (Part 1A), has MSI-H or dMMR tumor (Parts 1B and 2) and slowly progressive disease (Part 2). Primary objectives: safety and tolerability of EIK1005 monotherapy and + pembro to determine the MTD (Part 1) and to inform DO (Part 2). Secondary objectives: preliminary antitumor activity, characterize plasma PK profile of EIK1005 monotherapy and + pembro. This study began in December 2025. Clinical trial information: NCT07262619 .