Abstract 3279: Smoking burden is associated with immunotherapy resistance in extensive stage small cell lung cancer

Abstract Small cell lung cancer (SCLC) remains the deadliest histologic lung cancer subtype with a median survival of only ∼12 months among patients with extensive stage (ES) disease. SCLC is strongly associated with heavy tobacco use, yet the effect of tobacco use on therapeutic outcomes remains understudied. Recent data from our group showed that the subtype of SCLC with inflammatory gene signatures (SCLC-I) responds better to immunotherapy (IO) than the other subtypes. Given the association between smoking and inflammation, we hypothesized that heavy smoking may correlate with better IO responses and enrichment in the SCLC-I subtype. To investigate this, we evaluate the outcomes of ES-SCLC patients treated at MD Anderson between 2017-2024 (N=521) and compared those who received chemotherapy plus IO (N=263) to those who received chemo alone (N=258). Transcriptional changes were evaluated across different tobacco pack-year cohorts using the GEMINI bulk RNAseq database of MD Anderson SCLC tumors (N=81). The median overall survival (mOS) for all ES-SCLC patients was 13.3 months. Immunotherapy provided an added 1-month benefit in mOS over chemotherapy alone, extending mOS from 12.1 to 13.1-months (HR=0.88; p=0.21); consistent with historic cohorts. Patients were then stratified by the cohort pack-year median of 40. For patients with ≤ 40 pack-year smoking histories, the addition of IO improved mOS by 3.7-months from 11.5 to 14.3-months (HR=0.74; p=0.03). However, those with >40 pack-year smoking histories demonstrated no benefit from added IO (13.0 to 12.2-months (HR=1.06; p=0.70). Further analysis by pack-year tertiles (0-24, 25-49, 50+) showed mOS benefits of 5.4 months (HR: 0.67, P=0.05), 1.6m (HR:0.91, P=0.62), and 0.7m (HR=1.01, P=0.679) respectively, for chemo plus IO vs chemo alone. Despite better IO outcomes among patients with 0-40 pack-years, the SCLC-I subtype was underrepresented in the 0-40 pack-year group compared to expectation using the GEMINI RNAseq database (chi-squared 8.2; p=0.04). Tobacco exposure positively correlated with absolute immune cell infiltration by CIBERSORTx (R=0.24; p=0.03), although driven by higher immunosuppressive T cell signatures. Tumors from the 50+ pack-year (upper smoking tertile) group also demonstrated elevated chronic inflammatory GSEA signatures and genes associated with microenvironment immune suppression compared to the 0-24 (lower smoking tertile) pack-year group. The discovery that smoking is linked to immunotherapy resistance in SCLC represents a novel contribution to our understanding of the disease and its treatment. By identifying immunosuppressive cellular infiltrates and immunosuppressive gene signatures among patients with heavy vs light smoking histories, we have identified potentially targetable mechanisms of immune evasion. This represents a new lens through which to study immunotherapy resistance in SCLC. Citation Format: Kyle Concannon, Benjamin Morris, Lixia Diao, Moushumi Sahu, Whitney Lewis, Xiaowen Sun, Simon Heeke, Bingnan Zhang, Hai Tran, Lingzhi Hong, Waree Rinsurongkawong, Minh Nguyen, Kang Qin, Hui Li, Jainjun Zhang, Jack Lee, Jing Wang, Robert Cardnell, Carl Gay, John Heymach, Lauren Byers. Smoking burden is associated with immunotherapy resistance in extensive stage small cell lung cancer [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 3279.