Abstract CT097: A Phase 1, first-in-human study of the SMARCA2 degrader, PLX-61639, in patients with SMARCA4-mutated, locally advanced or metastatic solid tumors

Abstract Background: SMARCA 4 and SMARCA2 are redundant components of the BAF nucleosome remodeling complex, at least one of which is essential for cell survival. Mutations in the gene encoding SMARCA4, occur in approximately 10 - 15% of epithelial solid tumors, including 10% of NSCLC where they are associated with poor prognosis. Mutations that eliminate SMARCA4 protein or cause Loss of Function (LoF) create a dependency on SMARCA2 for tumor cell survival. PLX-61639 is an oral, monovalent, selective direct degrader of SMARCA2 that has shown anti-tumor activity in SMARCA4-deficient tumor xenografts while sparing SMARCA4 expressing normal tissues. The purpose of this First-in-Humans Phase 1 trial (NCT07284186) is to evaluate the safety and PK of PLX-61639, to define the maximum tolerated or maximum administered dose and recommended expansion dose and to make a preliminary assessment of its anti-tumor activity in patients with relapsed or refractory, SMARCA4-deficient solid tumors. Methods: This is a multi-center, open-label dose escalation study of PLX-61639 conducted in 3 parts: Part 1 Dose Escalation, Part 2 Dose Optimization and Part 3 Expansion. Up to 155 patients will be enrolled across all 3 parts. Eligible patients must have SMARCA4 LoF mutations based on existing genomic profiling or negative IHC staining for SMARCA4 and have failed to respond or have relapsed after standard of care regimens. Patients are required to have adequate liver, bone marrow, coagulation, renal, and cardiopulmonary function, ECOG PS 0 or 1 and measurable disease by RECIST 1.1. Patients with germline SMARCA4 deficiency or tumors with loss of SMARCA2 and SMARCA4 are excluded. Enrolled patients will receive PLX-61639 orally, once daily in 28-day cycles at their assigned dose level until disease progression or unacceptable toxicity. A minimum of 3 patients will be evaluated for Dose-Limiting Toxicity in the first 28-day cycle and the decision to escalate to the next higher dose level, de-escalate or expand at the current dose level will be made by the Safety Review Committee (SRC) using a Bayesian Optimal Interval algorithm. Dose levels that have been deemed tolerated by the SRC will be open for backfill enrollment for patients with NSCLC. Upon completion of Part 1, Part 2 will enroll patients with SMARCA4-deficient NSCLC and randomize patients to one of two dose levels to determine the Recommended Expansion Dose (RED). Part 3 of the trial will comprise an expansion cohort of up to 25 patients with SMARCA4-deficient solid tumors treated at the RED. Key endpoints include the incidence and severity of AEs, including DLTs and anti-tumor activity as measured by RECIST 1.1, volumetric analysis of scans and changes in circulating tumor DNA. This study (NCT7284186) opened for enrollment in December, 2025 and is continuing to enroll. Citation Format: Jorge F. DiMartino, Alexander Spira, Anjali Rohatgi, Muhammad R. Khawaja, Laura Alder, Ibaiyi Dagogo-Jack, Miguel A. Villalona, Drew Rasco, Adam Rock, Afshin Dowlati, Robin Guo. A Phase 1, first-in-human study of the SMARCA2 degrader, PLX-61639, in patients with SMARCA4-mutated, locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT097.