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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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.
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Nazartinib demonstrates potent inhibitory effects on pEGFR levels in H3255, HCC827, and H1975 cell lines, leading to effective inhibition of cell proliferation.
“The drug demonstrates potent inhibitory effects on pEGFR levels in H3255, HCC827, and H1975 cell lines, leading to effective inhibition of cell proliferation.173–176”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [174]
Several next-generation EGFR TKIs have demonstrated pre-clinical activity against EGFR exon 20 insertions and are in clinical development.
“Several next-generation EGFR TKIs (some with pan-HER activity) have demonstrated pre-clinical activity against EGFRex20ins and are in clinical development”
From Diverse EGFR Exon 20 Insertions and Co-Occurring Molecular Alterations Identified by Comprehensive Genomic Profiling of NSCLC (2018) · cites this paper as [5]
EGFR exon 20 insertions are typically unresponsive to first- and second-generation EGFR TKIs due to modified structures of their kinase domains.
“they are typically unresponsive to first and second-generation EGFR TKIs due to the modified structures of their kinase domains”
From Diverse EGFR Exon 20 Insertions and Co-Occurring Molecular Alterations Identified by Comprehensive Genomic Profiling of NSCLC (2018) · cites this paper as [5]
EGFR exon 20 insertions have previously been reported to comprise approximately 4-10% of all EGFR-mutant lung cancers.
“These alterations have previously been reported to comprise approximately 4-10% of all EGFR mutant lung cancers”
From Diverse EGFR Exon 20 Insertions and Co-Occurring Molecular Alterations Identified by Comprehensive Genomic Profiling of NSCLC (2018) · cites this paper as [5]
Nazartinib (EGF816) has promising activity in overcoming the major Ins20 subtypes V769_D770insASV and D770_N771insSVD.
“Jia et al. (2016) reveal that one of the 3G‐TKI, nazartinib (EGF816), has promising activity in overcoming the major subtypes V769_D770insASV and D770_N771insSVD.68”
From Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy (2016) · cites this paper as [68]
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- Authors
- Jia, Y., Juarez, J., Li, J., Manuia, M., Niederst, M. J., Tompkins, C., Timple, N., Vaillancourt, M.-T., Pferdekamper, A. C., Lockerman, E. L., Li, C., Anderson, J., Costa, C., Liao, D., Murphy, E., DiDonato, M., Bursulaya, B., Lelais, G., Barretina, J., McNeill, M., Epple, R., Marsilje, T. H., Pathan, N., Engelman, J. A., Michellys, P.-Y., McNamara, P., Harris, J., Bender, S., & Kasibhatla, S.
- Affiliations
- Genomics Institute of the Novartis Research Foundation (US)
- Harvard University (US)
- 3Novartis Institute for Biomedical Research, Cambridge, Massachusetts.
- Corresponding author
- Jia, Yong
- Kasibhatla, Shailaja
- ORCID
- Venue
- Cancer Research
- Published
- 2016-03-14
- Volume
- 76
- Issue
- 6
- Pages
- 1591-1602
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2292957477
- Cited by
- 121
- References
- 43
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 10 · 2023: 7 · 2022: 6 · 2021: 11 · 2020: 7 · 2019: 18 · 2018: 15 · 2017: 23 · 2016: 16 · 2014: 1
- FWCI
- 22.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- EGFR inhibitors, non-small cell lung cancer, EGFR mutation, T790M, exon 20 insertion, acquired drug resistance, irreversible binding, L858R, ex19del, c-Met, combination therapy, patient-derived xenografts, EGFR phosphorylation
- MeSH terms
- Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Female, Lung Neoplasms, Mice, Nude, Mutation, Phosphorylation, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Rats, ErbB Receptors
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