Abstract CT109: A first-in-human phase 1 study of LY4050784, an oral, potent, and selective SMARCA2 inhibitor, in patients with advanced solid tumors with <i>SMARCA4</i> alterations (Trial in Progress)

Abstract Background: SMARCA4 (BRG1) alterations occur in ∼7% and 10% of all solid tumors and NSCLC, respectively, and are associated with worse overall survival.1, 2 SMARCA4 mutations create a dependency on SMARCA2 (BRM), resulting in synthetic lethality when SMARCA2 is selectively inhibited.3 LY4050784 is an oral, potent, and selective SMARCA2 inhibitor that has demonstrated robust synthetic lethality with single-agent tumor regressions across multiple murine xenograft models of SMARCA4-mutated NSCLC.4 Methods: This is a first-in-human, phase 1a/b open-label, multicenter study of LY4050784, an oral, potent and selective SMARCA2 inhibitor, in patients (pts) with advanced solid tumors with SMARCA4 alterations (NCT06561685). Phase 1a dose escalation is enrolling pts with all tumor types with any alteration in SMARCA4 and is evaluated using a modified toxicity probability interval-2 (mTPI-2) method. Additional pts with known or likely loss of function SMARCA4 alteration or loss of protein expression are allowed to backfill to previously cleared dose levels that demonstrate therapeutically relevant exposures or direct evidence of clinical activity. DLT evaluation is 28 days. In Phase 1b dose expansion, Part A will enroll pts with NSCLC with loss of function SMARCA4 alteration or loss of protein expression and has optional dose randomization in 2 or more dose levels to confirm the optimal dose of LY4050784. Part B will expand enrollment of pts with other advanced solid tumors with eligible SMARCA4 alteration(s). Key objectives are to determine the MTD/RP2D of LY4050784 and assess the safety, PK, and preliminary anti-tumor activity of LY4050784 per RECIST v1.1. Eligible pts (≥18 years) must have a locally advanced or metastatic cancer, measurable or non-measurable disease (Phase 1a dose escalation only) per RECIST v1.1, eligible SMARCA4 alteration, and an ECOG PS 0-1. Pts must have progressed on, ineligible for, or refused all available standard therapies, with no limit on the number of prior therapies; in Phase 1b Part A, pts must have received at least one line of therapy for advanced or metastatic disease. Key exclusion criteria include known loss of function SMARCA2 alteration or malignancy with known association with SMARCA2 alterations, known untreated or uncontrolled CNS metastases, increased risk of prolonged QT or significant arrythmia, significant cardiovascular disease, and active or recently treated second primary malignancy. 1Dagogo-Jack, et al. J Thorac Oncol (2020); 15(5):766-776. 2Alessi JV, et al. J Thorac Oncol (2021); 16(7):1176-1187. 3Hoffman GR, et al. Proc Natl Acad Sci USA (2014); 111(8):3128-3133. 4Lee JY, et al. Poster presented at AACR 2024. Citation Format: Timothy Yap, Alexander Spira, Adam Schoenfeld, Vivek Subbiah, Alexander Philipovskiy, Benjamin O. Herzberg, Gerald Falchook, Ibiayi Dagogo-Jack, Christine M. Bestvina, Shigehisa Kitano, Haruyasu Murakami, Tejas Patil, Gilberto Lopes, Amy E. Chang, Binoj C. Nair, Chunxiao Wang, Tatsuya Yoshida. A first-in-human phase 1 study of LY4050784, an oral, potent, and selective SMARCA2 inhibitor, in patients with advanced solid tumors with SMARCA4 alterations (Trial in Progress) [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 CT109.