The Cdk4/6 Inhibitor G1t38 Enhances Response To Targeted Therapies In Preclinical Models Of Non-Small Cell Lung Cancer

The recent FDA approvals of palbociclib, ribociclib, and abemaciclib in breast cancer validate cyclin-dependent kinases 4 and 6 (CDK4/6) as key therapeutic targets, and warrant investigations in other tumor types with frequently observed alterations in the CDK4/6 pathway. Towards this end, we assessed the preclinical antitumor efficacy of G1T38, an oral, potent, and selective small-molecule CDK4/6 inhibitor in clinical development, in models of non-small cell lung cancer (NSCLC). Importantly, preclinical studies have shown that G1T38 has a differentiated and potential best-in-class profile since it can be dosed continuously without causing severe neutropenia, which could result in better tumor efficacy. Initial efficacy screening of G1T38 in 60 patient-derived NSCLC xenografts revealed significant tumor growth inhibition (TGI), primarily in lung adenocarcinomas harboring frequently observed oncogenic alterations in KRAS, EGFR, BRAF, and ALK. In vitro analyses show that CDK4/6 inhibition enhances the antiproliferative effect of inhibitors targeting these oncogenes (or their signaling pathways), suggesting a possible role for G1T38 in augmenting response and/or delaying acquired resistance to agents currently utilized in the clinic. These results were validated in vivo in mouse NSCLC xenograft models with defined oncogenic alterations, including EGFR mutations. For example, in H1975 xenografts harboring EGFR L858R/T790M (the T790M mutation is responsible for over 50% of cases of acquired resistance to first-generation EGFR inhibitors), combination of G1T38 with erlotinib resulted in 77% TGI after 18 days–a significant improvement over either therapy alone. Moreover, in H1975 xenografts, G1T38 delayed resistance to the second-generation EGFR inhibitor afatinib, and upon development of resistance to afatinib monotherapy, addition of G1T38 to afatanib treatment resulted in stabilization of tumor growth. G1T38 also augmented the response of EGFR-mutant NSCLC xenografts to the third-generation EGFR inhibitor osimertinib, significantly enhancing TGI compared to either therapy alone. As a result, a safety, pharmacokinetics, and efficacy study of G1T38 + osimertinib (G1T38-03) is scheduled for initiation in 1Q18 in patients with EGFR-mutant, T790M-positive NSCLC. Additional efforts are ongoing to investigate the combination of G1T38 with targeted therapies in NSCLC murine models harboring alterations in KRAS, ALK, and BRAF. Together, our results suggest a compelling rationale for utilizing G1T38 as a backbone for multiple targeted therapy combination regimens in NSCLC. Citation Format: Jessica A. Sorrentino, Daniel M. Freed, John E. Bisi, Jay C. Strum, Patrick J. Roberts. The CDK4/6 inhibitor G1T38 enhances response to targeted therapies in preclinical models of non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1522.