Abstract 675: Targeting Bcl-2/Bcl-xl for small cell lung cancer treatment with LP-118

Abstract Small cell lung cancer (SCLC) is an aggressive form neuroendocrine carcinoma with limited treatment options and poor prognosis, and novel approaches are urgently needed for the treatment of this disease. Bcl-2 and Bcl-xl are aberrantly expressed in 60-70% SCLC and have been considered as promising therapeutic targets for SCLC. However, navitoclax (ABT-263), a Bcl-2/Bcl-xl dual inhibitor, demonstrated limited efficacy in SCLC while induced sever adverse events, such as thrombocytopenia due to the platelet toxicity mediated by Bcl-xl inhibition. Therefore, agents with novel mechanisms of action and safety profile are to be developed for the treatment of SCLC with Bcl-2/Bcl-xl dependency. LP-118 is a new generation and super potent Bcl-2 inhibitor with moderate Bcl-xl activity, and it is being evaluated in Phase1 clinical trials in solid tumors and hematological cancers (NCT05025358, NCT04771572). In this preclinical study, we aimed to evaluate the single agent activity of LP-118 in a panel of 9 SCLC cell lines and to further determine if LP-118 can enhance the efficacies of Standard of Cares (SOC) in vitro and in vivo. The results show that LP-118 has high in vitro activity in a subset of SCLC cell lines, and it is particularly potent in Bcl-2-depended cell lines, such as NCI-H889, with the IC50 of 0.15 nM. LP-118 is also very potent in NCI-H1963, a Bcl-xl dependent cell line (IC50: 5nM), and NCI-H526, a Bcl-2/Bcl-xl co-dependent cell line (IC50: 4-5.1 nM). Overall, LP-118 is more potent than ABT-263 in Bcl-2 or Bcl-2/Bcl-xl co-dependent cell lines, and it is relatively less active in Bcl-2/Bcl-xl/Mcl-1 co-dependent cell lines, such as NCI-H69 (IC50: 169.7 nM). In addition, combinations of LP-118 and SN-38 (the active metabolite of irinotecan), topotecan, or etoposide, induced strong synergist effects in both NCI-H69 and NCI-H146 cell lines, suggesting that LP-118 could enhance the cytotoxicity of these drugs. Consistent with the in vitro data, treatment with LP-118 alone induced complete tumor remissions in NCI-H889-derived xenograft models (10/10), whereas no complete tumor remission was observed in the ABT-263-treated group. Moreover, LP-118 plus carboplatin or topotecan dramatically inhibited tumor growth of NCI-H526 xenograft models and has significantly better efficacy than either carboplatin or topotecan alone. Importantly, no significant body weight loss was observed in mice treated with LP-118 single agent or the combinations, indicating such regimens were well tolerated. In summary, LP-118, a new generation Bcl-2/Bcl-xl dual inhibitor, is highly active, as single agent or in combination with SOCs, in a large subset of SCLC cell lines. Clinical trials are ongoing to further evaluate the safety and efficacy of LP-118 in hematological cancers and solid tumors, including SCLC. Additional studies are also underway to develop predictive biomarkers for facilitating patient stratification in the clinic. Citation Format: Ling-Ling Lee, Huan Chen, Cong Zhu, Yao Chen, Brianna Feldmeier, Yue Shen, Yu Chen, Stephen P. Anthony, Fenlai Tan, Yi Chen, Bing Dai. Targeting Bcl-2/Bcl-xl for small cell lung cancer treatment with LP-118 [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 675.