Antitumor Efficacy Of Egfr Antibody Necitumumab And Dual Pi3k/Mtor Inhibitor (Ly3023414) In Preclinical Tumor Models

Necitumumab (Nmab) in combination with chemotherapy has demonstrated overall survival benefit in patients with advanced or metastatic squamous non-small cell lung cancer (SqNSCLC). The PI3K/ mTOR pathway shows aberrant activity in multiple tumor types and is implicated in the development of intrinsic and acquired resistance to anti-EGFR therapy. LY3023414, a potent dual PI3K/mTOR inhibitor, is currently undergoing clinical evaluation. The objective of this study was to evaluate the combination effects of Nmab and LY3023414 in multiple tumor models. Nmab and/or LY3023414 were evaluated using Cancer Cell Sensitivity Profiling (CCSP) using a panel of ~500 genetically and histologically diverse human tumor cell lines. The combination treatment showed greater inhibition of tumor cell growth as compared to single-agent treatments in a large fraction of the cell lines tested. The combination effect was further assessed in 21 patient-derived xenograft (PDX) models across multiple tumor types with and without genetic alterations in the PI3K pathway. Compared to both monotherapies, the combination treatment demonstrated greater efficacy in 16 of 21 models, and reached statistical significance in 6 models. Nmab -/+ LY3023414 was also evaluated in a panel of 40 SqNSCLC PDX models using a single-mouse trial format. Combination therapy exhibited significant benefit over either monotherapy as exemplified by disease control (61% for combination vs 17.5% and 34.3% for Nmab and LY3023414, respectively) and overall response rate (22% for combination vs 10% and 5.7% for Nmab and LY3023414, respectively). Median time to tumor doubling or event-free survival (mEFS) was also in favor of the combination therapy (mEFS = 38.9 days for combination vs 14.2 and 32.4 days for Nmab and LY3023414, respectively). To gain mechanistic insights into the combinatorial effect observed, we employed a high-content gene/protein expression assay (nCounter Vantage 3D RNA:Protein Solid Tumor Signaling Pathways Panel) in a SqNSCLC PDX model harboring PIK3CA mutation that was highly sensitive to the combination therapy. nCounter Vantage 3D analysis confirmed inhibition of the PI3K/mTOR pathway in LY3023414-treated tumors. A more robust effect on signaling events downstream of mTOR was observed in the combination group. Furthermore, pathway analysis of the gene expression data suggested alterations in cell cycle/apoptosis, DNA repair, Notch, TGFb, and Wnt signaling in the combination group. Collectively, these data indicate that the Nmab/LY3023414 combination provides a benefit over both monotherapies. A more profound blockade of the PI3K/ mTOR pathway accompanied by inhibition of tumor cell cycle, survival, and DNA repair mechanisms may underlie this effect. Citation Format: Maxine A. Melchior, Xuemei Guo, Gregory P. Donoho, Philip W. Iversen, Thompson N. Doman, Manisha Brahmachary, Xueqian Gong, Gerald E. Hall, Jason R. Manro, Yung-mae M. Yao, Sean Buchanan, Tod Smeal, Michael D. Kalos, Ruslan D. Novosiadly. Antitumor efficacy of EGFR antibody necitumumab and dual PI3K/mTOR inhibitor (LY3023414) in preclinical tumor models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B108.