Abstract 1381: BCL-2 selective inhibitor venetoclax combined with topoisomerase I inhibitor irinotecan is effective in small cell lung cancer (SCLC)

Abstract Background: Lung cancer is the third most common cancers globally, and small cell lung cancer (SCLC) accounts for 10-15% of all lung cancer cases. Extensive stage (ES)-SCLC has an overall five-year survival rate of ∼5%. Although ES-SCLC initially responds well to platinum-based combination chemotherapy, it almost invariably develops resistance over time. Immunotherapy can induce some responses in ES-SCLC, and arlatamab-dlle, a DLL3 targeted bi-specific T-cell engager, was recently given advanced approval to treat relapsed ES-SCLC. However, ES-SCLC remains a dismal prognosis. Venetoclax is a Bcl-2 selective inhibitor that induces apoptosis by binding to the hydrophobic groove of BCL-2. We previously demonstrated that venetoclax is effective in SCLC with high BCL-2 expression (Lochmann et al., Clinical Cancer Research 2018). Irinotecan is an antineoplastic enzyme inhibitor that blocks the topoisomerase I-DNA complex, preventing DNA repair and causing double-strand breaks that lead to cell death. It is often given in the relapsed setting as second-line therapy for ES-SCLC. Aims: We aimed to determine if venetoclax could enhance responses to irinotecan in SCLC preclinical models, and vice versa. Methods: Venetoclax was combined with irinotecan and SCLC cell viability was evaluated including CellTiter-Glo (CTG), immunoblotting, and in mouse models, including patient-derived xenografts, in vivo. Results: Our data showed that combining the BCL-2 selective inhibitor venetoclax with irinotecan demonstrated in many SCLC models, enhanced activity over single-agent alone. In vivo, the combination enhanced survival compared to either single-agent. Conclusion: We demonstrate that combining the BCL-2 selective inhibitor venetoclax with irinotecan could enhance responses and survival in the refractory SCLC setting. Citation Format: Yanli Xing, Krista M. Dalton, Jane L. Roberts, Anthony C. Faber. BCL-2 selective inhibitor venetoclax combined with topoisomerase I inhibitor irinotecan is effective in small cell lung cancer (SCLC) [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 1381.