Abstract 5330: Antitumor activity of potent and selective CDK2 inhibitors as monotherapy and in combination with chemotherapy in models of small cell lung cancer

Background: A molecular hallmark of small cell lung cancer (SCLC) is the high frequency of inactivating mutations in the retinoblastoma 1 (Rb1) gene, leading to loss of functional Rb expression and dysregulated G1-S phase progression. Analysis of publicly available DepMap data shows that Rb-mutant SCLC cell lines exhibit a genetic dependency on cyclin-dependent kinase 2 (CDK2), suggesting aberrant CDK2 activity may be essential in regulating cell cycle progression in the absence of CDK4/6-Rb signaling. BLU-222 is an investigational, potent, highly selective, orally bioavailable CDK2 inhibitor currently in Phase I/II clinical trials (NCT05252416). Here, we report on the activity of BLU-222 and BLU-956, a next-generation CDK2 inhibitor, in pre-clinical models of SCLC. Using in vitro cell line screening, we identified specific biomarkers predictive of response to BLU-222 and BLU-956. Methods: The in vitro antiproliferative effect of BLU-222 and BLU-956 alone or in combination with cisplatin was assessed by CyQuant in a panel of SCLC cell lines. In vivo antitumor activity of BLU-222 or BLU-956 as single agents or in combination with cisplatin was measured in biomarker positive cell line-derived xenograft (CDX) models. Results: Both BLU-222 and BLU-956 demonstrated strong anti-proliferative activity in Rb-null SCLC cell lines. Biomarker analysis identified high levels of SKP2 expression as a predictive biomarker for CDK2 inhibitor sensitivity. Further, co-expression of high SKP2, high CDKN2A, and high CCNE1 expression was associated with the strongest responses to BLU-222 or BLU-956 in Rb-null cell lines. BLU-222 and BLU-956 were well tolerated as single agents and in combination with cisplatin in immunodeficient mice. CDK2 inhibitor monotherapy achieved tumor stasis in pre-clinical SCLC CDX models, including NCI-H526. Responses were enhanced in combination with cisplatin, superior to cisplatin monotherapy, and led to tumor regression. Conclusions: CDK2 inhibition represents a novel therapeutic approach in SCLC, an aggressive cancer with high unmet medical need. In pre-clinical models of SCLC, BLU-222 and BLU-956 demonstrated substantial anti-tumor activity as single agents, with enhanced effects in combination with cisplatin. These findings provide rationale for exploring targeting CDK2 in combination with cisplatin in SCLC and suggest that specific biomarkers could be useful to predict response. Citation Format: Nealia House, Liang Yuan, Christophe Lemetre, Maxine Chen, Philip Ramsden, Scott Ribich, Lakshmi Muthuswamy, Kerrie Faia. Antitumor activity of potent and selective CDK2 inhibitors as monotherapy and in combination with chemotherapy in models of 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 5330.