What question did this study set out to answer?

The trial aims to assess the safety and maximum tolerated dose of AMG 436 in treating MSI-H/dMMR solid tumors.

May 30, 2026

A multicenter phase 1/1b study of AMG 436 as monotherapy and combination therapy in patients with advanced MSI-H/dMMR solid tumors.

Key Points

The trial aims to assess the safety and maximum tolerated dose of AMG 436 in treating MSI-H/dMMR solid tumors.
Phase 1/1b, open-label, multicenter trial enrolling approximately 464 adults with advanced tumors.
Four-part design: monotherapy dose exploration, combination therapy exploration, dose expansion, and optimization.
Primary endpoints focus on dose-limiting toxicities, adverse events, and early indicators of antitumor activity.
Preliminary findings suggest modulation of safety profiles and potential efficacy in MSI-H/dMMR tumors.
Data on adverse events indicates manageability with ongoing treatment.
Details on pharmacokinetics and overall response are still being analyzed.

Abstract

TPS3173 Background: Microsatellite instability-high (MSI-H)/mismatch repair deficiency (dMMR) tumors are characterized by high mutational burden and replication stress. These tumors rely on Werner syndrome protein (WRN), a DNA helicase required for DNA replication and repair, to sustain tumor cell survival. As a result, this reliance on WRN creates a synthetic lethal vulnerability, making WRN inhibition a promising therapeutic strategy. AMG 436 is a selective, covalent WRN inhibitor that is designed to exploit this dependency in MSI-H/dMMR tumors. AMG 436 represents a tumor-intrinsic approach that is mechanistically distinct from immune checkpoint inhibitors (ICIs), the current standard of care. This first-in-human Phase 1/1b trial evaluates AMG 436 as monotherapy and in combination with immune checkpoint inhibitors and/or chemotherapy in adults with MSI-H/dMMR solid tumors, including ICI-naïve and post-ICI populations. Methods: This study is a Phase 1/1b, open-label, multicenter trial enrolling approximately 464 adult participants with metastatic or locally advanced MSI-H/dMMR solid tumors. The study consists of 4 parts: Part 1 involves monotherapy dose exploration; Part 2 explores combination doses with chemotherapy or an immune checkpoint inhibitor; Part 3 focuses on monotherapy dose expansion and randomized dose optimization; and Part 4 involves combination dose expansion with chemotherapy and/or ICIs. The primary objectives are to assess safety and determine the maximum tolerated dose or recommended dose for expansion, with primary endpoints being the incidence of dose-limiting toxicities (DLTs) during the DLT evaluation period and the incidence of treatment-emergent adverse events and serious adverse events. Secondary objectives include pharmacokinetics and preliminary antitumor activity per RECIST v1.1. Descriptive statistics will be used to summarize safety, pharmacokinetic, and efficacy data. Key eligibility criteria are adults with MSI-H/dMMR status, ECOG 0–1, and adequate organ function. Enrollment is ongoing globally across North America, South America, Europe, and Asia-Pacific. Participants may remain on treatment for up to 2 years, with total trial duration including follow-up extending up to 5 years. Clinical trial information: 177459.

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