Abstract 1323: SWI/SNF complex signature as a novel biomarker for immunotherapy in patients with non-small cell lung cancer

Abstract

Abstract Background: Cancer immunotherapy, especially immune checkpoint inhibitors (ICIs), is remarkably effective in non-small cell lung cancer (NSCLC), but only a small number of patients can derive durable benefits from it. Therefore, more accurate biomarkers are highly needed. The inactivation of subunits of the Switch/Sucrose Non-Fermentable (SWI/SNF) complex was associated with long lasting responses to ICIs in clear cell renal cell carcinoma and soft tissue sarcoma. Although genomic alterations (GAs) of SWI/SNF complex genes were frequently detected by targeted next-generation sequencing (NGS) in NSCLC, their correlation with recognized immune biomarkers and predictive value for ICIs response remains unclear. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor and matched blood samples of 3433 NSCLC patients from OrigiMed were collected for targeted NGS panel sequencing from December 2017 to January 2019. GAs including single nucleotide variations, short and long insertions/deletions, copy number variations, and gene rearrangements were assessed. PD-L1 expression positive was defined as ≥1% of tumor cells with membranous staining (22C3, DAKO). Genomic data and ICIs treatment outcome of 2 cohorts of NSCLC patients were derived from The Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC) databases. Results: We found GAs of the SWI/SNF complex genes in 14.8% (509/3433) of patients in the OrigiMed cohort, including 152 ARID1A GAs, 48 ARID1B GAs, 102 ARID2 GAs, 50 PBRM1 GAs, 189 SMARCA4 and 18 SMARCD1 GAs. Mutation sites were found scattered throughout the genes. Compared with wild-type (WT), ARID1A, ARID1B, ARID2, PBRM1, SMARCA4, and SMARCD1 GAs were associated with a significantly higher tumor mutational burden (TMB) (p<0.001, respectively). PD-L1 expression was detected in 32.4% (1111/3433) of patients. ARID1A and PBRM1 GAs were significantly correlated with higher PD-L1 expression (p<0.001 and p=0.002, respectively). Survival analysis from 2 independent cohorts confirmed that patients with ARID1B GAs had remarkable clinical benefit to ICIs compared with WT in both progression free survival (PFS) (22.43 months vs 3.17 months, respectively, p=0.031) and durable clinical benefit (DCB) (57.1% vs 29.5%, respectively, p=0.2). PBRM1 GAs were an unfavorable prognostic factor for response to ICIs compared with WT in overall survival (OS) (5 months vs 12 months, respectively, p=0.0046; HR: 2.05, 95%CI: 1.2-3.51, p=0.009). Conclusion: Our data revealed that GAs of the SWI/SNF complex genes were associated with an increased TMB in NSCLC patients. ARID1B GAs may be associated with favorable outcome of ICIs while PBRM1 GAs may be an unfavorable prognostic factor for response to ICIs, suggesting that GAs of SWI/SNF complex genes may have implications as biomarkers for guiding ICI treatment. Citation Format: Da Jiang, Ziqiang Tian, Mingjiang Li, Jian Guo, Jie Yang, Yanzhi Cui, Zheng Wang, Yaqing Wu, Shiyue Zhang, Hui Chen, Shaohua Yuan, Ming Yao. SWI/SNF complex signature as a novel biomarker for immunotherapy in patients with non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1323.