Supplementary Figures 1 through 5 from EGF816 Exerts Anticancer Effects in Non–Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor

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posted on 2023-03-30, 23:47 authored by Yong Jia, Jose Juarez, Jie Li, Mari Manuia, Matthew J. Niederst, Celin Tompkins, Noelito Timple, Mei-Ting Vaillancourt, AnneMarie Culazzo Pferdekamper, Elizabeth L. Lockerman, Chun Li, Jennifer Anderson, Carlotta Costa, Debbie Liao, Eric Murphy, Michael DiDonato, Badry Bursulaya, Gerald Lelais, Jordi Barretina, Matthew McNeill, Robert Epple, Thomas H. Marsilje, Nuzhat Pathan, Jeffrey A. Engelman, Pierre-Yves Michellys, Peter McNamara, Jennifer Harris, Steven Bender, Shailaja Kasibhatla

This file shows the Supplementary figures. Figure S1 shows the chemical structure of EGF816 and its binding to EGFR T790M mutant. Figure S2 shows the tolerability of EGF816 in the in vivo xenograft models. Figure S3 shows the in vivo PK and PD after a single dose of EGF816. Figure S4 shows the selectivity profile of EGF816 in the kinome tree. Figure S5 shows the morphology of EGF816 resistance clones.

History

ARTICLE ABSTRACT

Non–small cell lung cancer patients carrying oncogenic EGFR mutations initially respond to EGFR-targeted therapy, but later elicit minimal response due to dose-limiting toxicities and acquired resistance. EGF816 is a novel, irreversible mutant-selective EGFR inhibitor that specifically targets EGFR-activating mutations arising de novo and upon resistance acquisition, while sparing wild-type (WT) EGFR. EGF816 potently inhibited the most common EGFR mutations L858R, Ex19del, and T790M in vitro, which translated into strong tumor regressions in vivo in several patient-derived xenograft models. Notably, EGF816 also demonstrated antitumor activity in an exon 20 insertion mutant model. At levels above efficacious doses, EGF816 treatment led to minimal inhibition of WT EGFR and was well tolerated. In single-dose studies, EGF816 provided sustained inhibition of EGFR phosphorylation, consistent with its ability for irreversible binding. Furthermore, combined treatment with EGF816 and INC280, a cMET inhibitor, resulted in durable antitumor efficacy in a xenograft model that initially developed resistance to first-generation EGFR inhibitors via cMET activation. Thus, we report the first preclinical characterization of EGF816 and provide the groundwork for its current evaluation in phase I/II clinical trials in patients harboring EGFR mutations, including T790M. Cancer Res; 76(6); 1591–602. ©2016 AACR.