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EGF816, an irreversible mutant-selective EGFR inhibitor, is effective in NSCLC with both primary activating and T790M-mediated resistant EGFR mutations

Jia, Yong and Juarez, Jose and Li, Jie and Manuia, Mari and Niederst, Matthew and Tompkins, Celin and Timple, Noelito and Vaillancourt, Mei Ting and Pferdekamper, Annemarie and Lockerman, Elizabeth and Li, Chun and Anderson, Jennifer and Costa, Carlotta and Liao, Debbie and Murphy, Eric and Didonato, Michael and Bursulaya, Badry and Lelais, Gerald and Barretina, Jordi and Mcneill, Matthew and Epple, Robert and Marsilje, Thomas and Pathan, Nuzhat and Michellys, Pierre and Mcnamara, Peter and Harris, Jennifer and Bender, Steven and Engelman, Jeffrey and Kasibhatla, Shailaja (2016) EGF816, an irreversible mutant-selective EGFR inhibitor, is effective in NSCLC with both primary activating and T790M-mediated resistant EGFR mutations. Cancer Research, 76 (6). OF1-OF12. ISSN Cancer Res; 76(6) March 15, 2016

Abstract

NSCLC patients carrying oncogenic EGFR mutations initially respond to EGFR targeted therapy. However, duration of the response is limited due to dose limiting toxicities and acquired resistance. EGF816 is a novel, irreversible mutant-selective EGFR inhibitor that specifically targets both primary activating and the T790M acquired resistant EGFR mutations, while sparing wild-type (WT) EGFR. EGF816 potently inhibits the most common EGFR mutations L858R, Ex19del and T790M in vitro which translating into strong tumor regressions in vivo in several patient-derived xenografts (PDX). Of note, EGF816 also demonstrated antitumor activity in an exon 20 insertion mutant model. At levels above efficacious doses, EGF816 showed minimal inhibition of WT EGFR receptor and was well-tolerated. In single dose studies, EGF816 showed sustained inhibition of pEGFR, consistent with its irreversible binding mechanism. In addition, EGF816 in combination with a cMET inhibitor demonstrated durable efficacy in a model that became resistant to first generation EGFR inhibitors via cMET activation. EGF816 has shown promising clinical efficacy in phase I trials.

Item Type: Article
Date Deposited: 28 Apr 2016 23:45
Last Modified: 28 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/26712

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