Abstract 5298: Impact of genomic and clinical factors on therapeutic response to arly-phase epigenetic therapies: An international cohort from two major phase I units

Abstract Introduction: Epigenetic agents—including inhibitors of BET bromodomains, PRMT5, EZH2, and other chromatin regulators—have emerged as promising therapeutic strategies across solid tumors. However, clinical activity remains variable, and robust predictive biomarkers are lacking. We conducted a retrospective two-center analysis to characterize outcomes of patients treated with these compounds in early-phase trials and to evaluate the contribution of next-generation sequencing (NGS) profiles to interpatient variability. Methods: A total of 262 patients treated within phase I trials of epigenetic agents at two academic early-phase drug development units were included. Clinical data (demographics, tumor type, ECOG status, prior therapies) and NGS results (pathogenic variants, VUS, short variants) were harmonized across centers into a unified dataset. Associations with overall survival (OS) were assessed using two-sided univariable Cox proportional hazards models. Hazard ratios (HR), 95% confidence intervals (CI), proportional hazards assumptions, Akaike Information Criteria (AIC), and C-statistics were reported. Results: Median age was 59.9 years (IQR 51-69), and 55% were female. Most patients had metastatic disease (88.2%), ECOG 1 (59.2%), prior chemotherapy (78.5%), and prior immunotherapy (70.9%), with a median of 3 prior systemic lines (IQR 1-4). The median number of metastatic sites was 2 (IQR 1-3). Patients received diverse epigenetic compounds, most commonly BET inhibitors (46.6%), PRMT5 inhibitors (22.5%), HDAC inhibitors (14.1%), and EZH2 inhibitors (8.4%), across tumor types including gastrointestinal (21.4%), thoracic (19.8%), CNS (12.6%), and sarcoma/GIST (12.6%). Best overall response included 10% CR/PR (n=21), 39.7% SD (n=104), and 44.6% PD (n=117), reflecting modest clinical activity.In the clinical Cox model, worse OS was associated with higher metastatic burden (HR 1.19; 95% CI, 1.08-1.32; p<0.001), prior chemotherapy (HR 1.64; 95% CI, 1.17-2.31; p=0.004), and increasing prior lines (HR 1.05; 95% CI, 1.00-1.11; p=0.044). Age was also statistically significant (HR 0.99; 95% CI, 0.98-1.00; p=0.029). In the genomic Cox model, short EGFR variants were significantly associated with worse OS (HR 2.74; 95% CI, 1.36-5.52; p=0.005). Other alterations, including pathogenic EGFR mutations (HR 1.83; p=0.065), ATM (HR 3.00; p=0.066), and ASPM (HR 0.29; p=0.087) variants showed non-significant trends. Conclusions: Epigenetic therapies showed modest activity in this heterogeneous early-phase cohort. Clinical factors—but not individual genomic alterations—were modestly prognostic for survival. These findings underscore the need for integrated biomarker approaches beyond single-gene predictors to optimize patient selection in epigenetic drug development. Citation Format: Manuel Pedregal, Harold Nathan Tan, Mercedes Avedillo, Ignacio Mahillo, Ester Garcia, Bernard Gaston Doger de Spéville, Miriam Dorta, Jordi Rodon Ahnert, Victor Moreno Garcia. Impact of genomic and clinical factors on therapeutic response to arly-phase epigenetic therapies: An international cohort from two major phase I units [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5298.