Abstract 7142: Mutations in PBAF, especially in PBRM1, enhance immune checkpoint inhibitor response in lung adenocarcinoma

Abstract Introduction: The SWI/SNF chromatin remodeling complex plays a pivotal role in regulating gene expression and maintaining genomic integrity, with three distinct complexes identified: BAF, PBAF, and ncBAF (also known as GBAF). Each complex contributes uniquely to cellular processes and cancer development. Within the PBAF complex, PBRM1, a key component, has garnered significant interest for its potential to influence the efficacy of immune checkpoint inhibitors (ICIs) in Non-Small Cell Lung Cancer (NSCLC). Despite the critical implications, there remains considerable controversy regarding whether mutations in PBRM1 and other components of the SWI/SNF complexes enhance or impair responses to ICIs. This study seeks to resolve these conflicting perspectives by elucidating the impact of mutations in these key components on the outcomes of ICI therapy in patients with NSCLC, especially lung adenocarcinoma. Methods: We conducted a retrospective analysis of 4, 166 NSCLC patients treated with ICIs at Samsung Medical Center. Among these, 745 met strict inclusion criteria including pre-treatment biopsy and complete RECIST and clinical data. Whole-exome sequencing was performed on 514 patients, focusing on mutations in all the SWI/SNF complex subunits such as ARID1A, ARID1B, ARID2, BRD7, SMARCA4, and PBRM1. Survival analysis techniques were employed to evaluate the association between these mutations and ICI therapy outcomes, calculating median progression-free survival (mPFS) and overall survival (mOS) using hazard ratios (HRs) and log-rank tests. Results: In the lung adenocarcinoma subset, PBAF complex mutations were significantly associated with improved ICI outcomes, with an mPFS of 3.8 months (HR: 0.71, 95% CI: 0.52-0.98, p = 0.034) and an mOS of 19.4 months (HR: 0.69, 95% CI: 0.50-0.95, p = 0.022). PBRM1 mutations, in particular, resulted in favorable outcomes, with an mPFS of 4.2 months (HR: 0.58, 95% CI: 0.35-0.94, p = 0.018) and an mOS of 24.7 months (HR: 0.54, 95% CI: 0.33-0.91, p = 0.026). These associations were not significant in lung squamous cell carcinoma and other NSCLC subsets. Conclusion: This study provides evidence that PBAF complex mutations, especially in PBRM1, are associated with improved ICI outcomes in lung adenocarcinoma patients. These findings suggest the potential utility of these mutations as predictive biomarkers for personalizing immunotherapy in this subset of NSCLC patients. Prospective studies are needed to validate these observations and explore the underlying biological mechanisms. Citation Format: Sung Feel Kim, Hong Sook Kim, Hongui Cha, Hyemin Kim, Yeong Hak Bang, Cheolyong Joe, Jun-Gi Jeong, Eunjoo Oh, Na-Eun Lee, Hyun Ae Jung, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Sehhoon Park, Se-hoon Lee. Mutations in PBAF, especially in PBRM1, enhance immune checkpoint inhibitor response in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7142.