Abstract 6551: Comprehensive genomic and transcriptomic analyses capture the effects of epigenetic therapy priming on immune checkpoint blockade response in non-small cell lung cancer

Abstract Introduction: Emergence of resistance to immune checkpoint blockade (ICB) mandates the development of strategies for ICB sensitization. Here we employed a multi-omic approach to understand the effects of epigenetic priming in re-shaping the tumor microenvironment, together with genomic drivers of therapeutic response of epigenetic therapy followed by ICB in non-small cell lung cancer (NSCLC). Methods: We performed whole exome sequencing (WES) on 39 baseline tumors and bulk RNA sequencing (RNAseq) on 18 serial tumors across 42 patients with metastatic immunotherapy-naïve NSCLC, who received azacitidine and entinostat followed by nivolumab (NCT01928576). WES was utilized to assess co-mutations, mutation signatures and genome-wide structural changes. RNAseq was utilized for gene and gene set enrichment analysis (GSEA) and repeat element analysis. Response after nivolumab initiation was assessed using RECIST 1.1 criteria. Patients who were progression-free at 6 months or alive at 2 years after initial treatment were defined as exceptional responders. Results: We found an enrichment in inactivating mutations in homologous recombination genes in radiographic responders (Fisher’s exact, p=0.0007). Higher germline and somatic HLA class II diversity (Mann-Whitney U-test, p=0.05 and p=0.03 respectively), and an enrichment of smoking and DNA damage mutational signatures were noted in radiographic responders (Mann-Whitney U-test, p=0.03 and p=0.15 respectively). Radiographically responding tumors harbored a higher number of mutations in genomic regions that were haploid or present in multiple copies (persistent tumor mutation burden; Mann-Whitney U-test, p=0.018). GSEA revealed an upregulation of inflammatory response gene sets post-epigenetic therapy in patients attaining an exceptional response. Antigen presentation, interferon-alpha, and interferon-gamma related gene sets were upregulated in exceptional responders post epigenetic priming (FDR-adjusted p=0.005, p=0.009, and p=0.011 respectively). Additionally, we observed an enrichment in interferon-alpha, cancer testis antigens, and interferon-gamma related gene sets in patients with a longer progression-free survival (FDR-adjusted p=0.007, p=0.011, and p=0.013 respectively). Repeat element analysis showed an increase in long terminal repeats on-therapy in exceptional responders, suggesting induction of repeat element expression with epigenetic therapy. A higher expression of MAGE family tumor associated antigens (MAGEA10, MAGEB1, MAGEB2) was noted post-epigenetic therapy in exceptional responders. Conclusions: Genomic and transcriptomic analyses reveal the potential of epigenetic-priming to re-shape the tumor microenvironment and highlight patients that could benefit from combination epigenetic therapy with immunotherapy. Citation Format: Blair V. Landon, Kristen A. Marrone, Michael J. Topper, Akshaya Annapragada, Hua-Ling Tsai, Archana Balan, Noushin Niknafs, Christopher Cherry, James R. White, Gavin Pereira, Vilmos Adleff, Chen Hu, Joanne Riemer, Margaret Fitzpatrick, Patrick Forde, Christine L. Hann, Ronan J. Kelly, David S. Ettinger, Benjamin Levy, Jorge Nieva, James Herman, Victor E. Velculescu, Stephen Baylin, Julie Brahmer, Valsamo Anagnostou. Comprehensive genomic and transcriptomic analyses capture the effects of epigenetic therapy priming on immune checkpoint blockade response in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6551.