Abstract 2928: Combination surface targeting strategies in relapsed small cell lung cancer (SCLC) to overcome intratumoral heterogeneity associated with treatment resistance

Abstract Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy characterized by rapid onset of chemoresistance and poor clinical outcomes. Following decades of, at best, modest clinical advances, the recent FDA approval of tarlatamab, a DLL3 targeting bispecific T-cell engager (BiTE), alongside unprecedented response rates observed with multiple antibody-drug conjugates (ADCs), have ushered in a paradigm shift towards surface targeting strategies in relapsed SCLC patients. These same agents are demonstrating similar efficacy in more rare high-grade neuroendocrine carcinomas, both pulmonary and extrapulmonary; however, they are being largely tested in unselected populations. While providing much-needed optimism for SCLC patients, resistance, both de novo and acquired, is common and must be better characterized to maximize the potential of these new therapeutic classes. We hypothesize that combinatorial targeting of multiple surface proteins using distinct strategies (i.e., BiTEs, ADCs, etc.) represents a novel way to overcome intratumoral heterogeneity common to relapsed SCLC and enhance antitumor immunity engendered by ADC payloads (i.e., topoisomerase 1 [TOP1] inhibitor). To better define the surfaceome of relapsed SCLC, we performed surfaceome mass spectrometry analysis of SCLC cell lines, naïve and relapsed patient derived xenografts (PDXs), and PDXs treated with frontline chemotherapy until relapse occurred, and identified a number of novel and known surface proteins (i.e., TROP2, HER2, B7H3). Surface targeting strategies against HER2, TROP2, and DLL3 are effective in preclinical models (i.e., cell lines and xenograft models) resistant to other common SCLC therapies (i.e., platinum chemotherapy). In particular, ADCs with TOP1 inhibitor payloads were more effective in models with high SLFN11 and target levels, suggesting that sensitivity requires both surface target expression and SLFN11 positivity for greatest response. Notably, single-cell transcriptional profiling of relapsed patient biopsies revealed mutually exclusive expression of surface genes in distinct cell populations, including senescent, drug tolerant persister cells (DTPCs), representing an unique opportunity to target heterogeneous populations. We show that combination targeting against different surface proteins (e.g., DLL3, TROP2, HER2) using both immune (i.e., chimeric antigen receptor T-cells, BiTEs) and payload-based modalities (i.e., ADCs) was more effective than single-agent targeting in resistant, neuroendocrine-low models. Therefore, intratumoral heterogeneity associated with relapsed SCLC, which limits efficacy of single-agent surface targeting strategies, may be exploited with combinatorial therapies to target resistant cell populations, including DTPCs, using payload and immune-based methods. Citation Format: C. Allison Stewart, Kavya Ramkumar, Runsheng Wang, Yan Yang, Bingnan Zhang, Yuanxin Xi, Lixia Diao, Qi Wang, Alberto Duarte, Ping Li, Azusa Tanimoto, Alejandra G. Serrano, Jody Vykoukal, Mukulika Bose, Loukia G. Karacosta, Luisa Solis Soto, Samir Hanash, Jing Wang, John V. Heymach, Lauren Averett Byers, Carl M. Gay. Combination surface targeting strategies in relapsed small cell lung cancer (SCLC) to overcome intratumoral heterogeneity associated with treatment resistance [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 2928.