Abstract 6392: Activity of HER2-and TROP2- antibody drug conjugates (ADCs) in small cell lung cancer (SCLC) models with SLFN11 as a predictive biomarker

Abstract Background: Small-cell lung cancer (SCLC) is a highly aggressive malignancy with its few treatment options devoid of biomarker selection, and a 5-year survival rate of less than 7%. Our group previously established four transcriptionally defined subtypes of SCLC, each with distinct cell surface targets (Gay et al, Cancer Cell 2021). Further, we identified SLFN11 (a putative DNA/RNA helicase) as a candidate biomarker of sensitivity to DNA-damaging agents, including topoisomerase inhibitors. Human epidermal growth factor receptor 2 (HER2/ERBB2) expression has been previously described in a subset of SCLCs and has been linked to poor prognosis. HER2 antibody-drug conjugates (ADCs) like trastuzumab deruxtecan (T-DXd) (where the payload is a topoisomerase I inhibitor) have received FDA approval for various solid tumors, highlighting their therapeutic potential. Similarly, TROP2 (TACSTD2) ADC sacituzumab govitecan has shown promising clinical efficacy in a SCLC (TROPiCS-03 basket trial). However, it is unclear what the predictive biomarkers are to these ADCs in SCLC. Methods: Expression of ERBB2 and TACSTD2 mRNA was analyzed using publicly available patient datasets. We also characterized surface expression of HER2 and TROP2 by flow cytometry in SCLC cell lines at baseline and after cisplatin/etoposide treatment. We then assessed the cytotoxicity of T-Dxd and sacituzumab govitecan in a panel of SCLC cell lines representative of each SCLC subtype, as well as SLFN11 status. Results: Analyses of HER2/ERBB2 and TROP2/TACSTD2 in SCLC cell lines and patient datasets showed a range of ERBB2 and TACSTD2 expression with enrichment in the non-neuroendocrine subtypes (SCLC-P and SCLC- I subtypes). We further validated HER2 and TROP2 surface levels by flow cytometry in a subset of SCLC cell lines. Intriguingly, we observed that surface expression of both HER2 and TROP2 increase after frontline chemotherapy cisplatin/etoposide treatment. As expected, T-Dxd and sacituzumab govitecan exhibit cytotoxicity in a subset of SCLC cell lines. We found a strong correlation between the in vitro cytotoxicity (IC50) of sacituzumab govitecan with SLFN11 (rho= 0.74, p=0.015). Importantly, SLFN11 is bimodally distributed in SCLC and we found ERBB2 and TACSTD2 to be enriched in the SLFN11-high group of SCLC patients. We also found ERBB2 and TACSTD2 to be correlated with each other (rho = 0.53, p <0.001). Conclusion: In this study, we demonstrate that HER2/ERBB2 and TROP2/TACSTD2 are enriched in a subset of SCLC. FDA-approved ADCs, T-DXd and sacituzumab govitecan each have preclinical activity in SCLC with SLFN11 as a predictive biomarker of payload cytotoxicity. We also found HER2 and TROP2 target levels increase after frontline chemotherapy (cisplatin/etoposide) in SCLC, which suggest their efficacy may be enhanced in relapsed SCLC where treatment options are extremely limited. Citation Format: Bingnan Zhang, Ali Ibrahim, C.Allison Stewart, Lixia Diao, Qi Wang, Li Shen, Yuann xi, Alejandra Serrano, Luisa M. Solis, Wei-Lien Wang, Kavya Ramkumar, Robert J. Cardnell, Runsheng Wang, Alberto Duarte, Jing Wang, Lauren A. Byers, Carl Gay. Activity of HER2-and TROP2- antibody drug conjugates (ADCs) in small cell lung cancer (SCLC) models with SLFN11 as a predictive biomarker [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 6392.