Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer

  • Nature Medicinevolume 24pages638646 (2018)
  • doi:10.1038/s41591-018-0007-9
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Although most activating mutations of epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancers (NSCLCs) are sensitive to available EGFR tyrosine kinase inhibitors (TKIs), a subset with alterations in exon 20 of EGFR and HER2 are intrinsically resistant and lack an effective therapy. We used in silico, in vitro, and in vivo testing to model structural alterations induced by exon 20 mutations and to identify effective inhibitors. 3D modeling indicated alterations restricted the size of the drug-binding pocket, limiting the binding of large, rigid inhibitors. We found that poziotinib, owing to its small size and flexibility, can circumvent these steric changes and is a potent inhibitor of the most common EGFR and HER2 exon 20 mutants. Poziotinib demonstrated greater activity than approved EGFR TKIs in vitro and in patient-derived xenograft models of EGFR or HER2 exon 20 mutant NSCLC and in genetically engineered mouse models of NSCLC. In a phase 2 trial, the first 11 patients with NSCLC with EGFR exon 20 mutations receiving poziotinib had a confirmed objective response rate of 64%. These data identify poziotinib as a potent, clinically active inhibitor of EGFR and HER2 exon 20 mutations and illuminate the molecular features of TKIs that may circumvent steric changes induced by these mutations.

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The authors wish to thank the patients and their families for participation in this study and Spectrum Pharmaceuticals for providing the drug used in the compassionate-use protocol. The authors also wish to thank J.S. (a patient) for efforts in initiating the poziotinib trial. This work was supported by the Lung SPORE grant P50 CA070907 and P50 CA196530 (J.V.H.); the Lung Cancer Research Fund (Y.Y.E.); generous philanthropic contributions to the University of Texas MD Anderson Lung Cancer Moon Shots Program (J.V.H.); NIH R01 CA190628 (J.V.H.), NIH Cancer Center Support Grant P30 CA016672 (J.V.H.), the Rexanna Foundation for Fighting Lung Cancer (J.V.H.), the Exon 20 Group (J.V.H.), the University of Texas MD Anderson Cancer Center Bruton Endowed Chair in Tumor Biology (J.V.H.), the Stading Fund for EGFR inhibitor resistance (J.V.H.), the Hallman fund (J.V.H.), and the Fox Lung EGFR Inhibitor Fund (J.V.H.). Additional support was provided from the Christine J. Burge Endowment for Lung Cancer Research at the University of Colorado Cancer Center, the Burge family, the Miramont Cares foundation (R.C.D.), a fellowship from the Italian Association for Cancer Research (A.T.), and Cancer Prevention Research Institute of Texas DP150086, National Science Foundation CHE-1411859, and National Institute of General Medical Sciences GM070737 (S.Z.). The clinical study was supported by Spectrum Pharmaceuticals.

Author information


  1. Department of Thoracic Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Jacqulyne P. Robichaux
    • , Yasir Y. Elamin
    • , Alissa Poteete
    • , Monique B. Nilsson
    • , Huiying Sun
    • , Emily Roarty
    • , Mehmet Altan
    • , Charles Lu
    • , Vassiliki Papadimitrakopoulou
    •  & John V. Heymach
  2. Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Zhi Tan
    •  & Shuxing Zhang
  3. Department of Diagnostic Radiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Brett W. Carter
  4. Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    • Shengwu Liu
    • , Shuai Li
    •  & Ting Chen
  5. University of Colorado Cancer Center, Aurora, CO, USA

    • Adriana Estrada-Bernal
    • , Anh T. Le
    •  & Robert C. Doebele
  6. Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA

    • Anna Truini
    • , Sarah B. Goldberg
    •  & Katerina Politi
  7. Department of Medicine, Yale University School of Medicine, New Haven, CT, USA

    • Sarah B. Goldberg
    •  & Katerina Politi
  8. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA

    • Julie R. Brahmer
  9. Department of Pathology, Yale University School of Medicine, New Haven, CT, USA

    • Katerina Politi
  10. Laura & Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA

    • Kwok-Kin Wong


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J.P.R., Y.Y.E., and J.V.H. coordinated the study. J.P.R., Y.Y.E., Z.T., A.P., H.S., S.Z., S. Liu. S. Li, T.C., A.E-B., A.T.L., and J.V.H. designed and/or performed experiments. J.P.R., Y.Y.E., Z.T., B.W.C., S.Z., E.R., A.T., K.P., K.-K.W, R.C.D., and J.V.H. interpreted data. A.T., S.B.G., and K.P. validated and provided the YUL0019 cell line. J.R.B. referred two patients described in the study. V.P., C.L., M.A., Y.Y.E., and J.V.H. treated patients on the clinical study. J.P.R., M.B.N, Y.Y.E., and J.V.H wrote the manuscript. All authors edited and approved the manuscript.

Competing interests

J.P.R., M.B.N., and J.V.H. have filed patent applications under the Patent Cooperation Treaty and in Taiwan.  J.V.H. has had grant or research support from AstraZeneca, Bayer, and GlaxoSmithKline and has served on advisory committees for AstraZeneca, Boehringer Ingelheim, Exelixis, Genentech, GSK, Lilly, Novartis, Spectrum, and Synta. R.C.D. has licensing fees, honorarium, and travel expenses from Ariad Pharmaceuticals, has a Sponsored Research Agreement from Threshold Pharmaceuticals, and has served as an advisory Board member for AstraZeneca.

Corresponding author

Correspondence to John V. Heymach.

Supplementary information

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    Supplementary Figures 1-10 and Supplementary Tables 1-4

  2. Reporting Summary