title: EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor.
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.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California. yjia@gnf.org skasibhatla@gnf.org.
authors.forename: Yong
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Jose
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authors.lastname: Juarez
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Jie
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authors.lastname: Li
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Mari
authors.initials: M
authors.lastname: Manuia
authors.affiliation: Massachusetts General Hospital/Harvard Medical School Cancer Center, Charlestown, Massachusetts.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Niederst
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Celin
authors.initials: C
authors.lastname: Tompkins
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Noelito
authors.initials: N
authors.lastname: Timple
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Mei-Ting
authors.initials: MT
authors.lastname: Vaillancourt
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: AnneMarie Culazzo
authors.initials: AC
authors.lastname: Pferdekamper
authors.affiliation: Massachusetts General Hospital/Harvard Medical School Cancer Center, Charlestown, Massachusetts.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Lockerman
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Anderson
authors.affiliation: Massachusetts General Hospital/Harvard Medical School Cancer Center, Charlestown, Massachusetts.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Costa
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Debbie
authors.initials: D
authors.lastname: Liao
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Eric
authors.initials: E
authors.lastname: Murphy
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Michael
authors.initials: M
authors.lastname: DiDonato
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Badry
authors.initials: B
authors.lastname: Bursulaya
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Gerald
authors.initials: G
authors.lastname: Lelais
authors.affiliation: Novartis Institute for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Jordi
authors.initials: J
authors.lastname: Barretina
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Matthew
authors.initials: M
authors.lastname: McNeill
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Robert
authors.initials: R
authors.lastname: Epple
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Marsilje
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Nuzhat
authors.initials: N
authors.lastname: Pathan
authors.affiliation: Massachusetts General Hospital/Harvard Medical School Cancer Center, Charlestown, Massachusetts.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Michellys
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Peter
authors.initials: P
authors.lastname: McNamara
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Harris
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Steven
authors.initials: S
authors.lastname: Bender
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California. yjia@gnf.org skasibhatla@gnf.org.
authors.forename: Shailaja
authors.initials: S
authors.lastname: Kasibhatla
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors