Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity

Cancer Cell. 2019 Oct 14;36(4):444-457.e7. doi: 10.1016/j.ccell.2019.09.001. Epub 2019 Oct 3.

Abstract

We characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants yielded differential sensitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs) in vitro, and molecular dynamics simulations revealed that mutants with a reduced drug-binding pocket volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in ERBB2 exon 20-mutant non-small cell lung cancer resulted in a confirmed objective response rate of 42% in the first 12 evaluable patients. In pre-clinical models, poziotinib upregulated HER2 cell-surface expression and potentiated the activity of T-DM1, resulting in complete tumor regression with combination treatment.

Keywords: ERBB2 mutant; HER2 mutant; NSCLC; T-DM1; TKI; exon 20; pan-cancer; poziotinib.

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural

MeSH terms

  • Ado-Trastuzumab Emtansine / pharmacology*
  • Ado-Trastuzumab Emtansine / therapeutic use
  • Adult
  • Animals
  • Antineoplastic Agents, Immunological / pharmacology
  • Antineoplastic Agents, Immunological / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • DNA Mutational Analysis
  • Datasets as Topic
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Drug Synergism
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Mutation
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / mortality
  • Neoplasms / pathology
  • Progression-Free Survival
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Quinazolines / pharmacology*
  • Quinazolines / therapeutic use
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / genetics

Substances

  • Antineoplastic Agents, Immunological
  • HM781-36B
  • Protein Kinase Inhibitors
  • Quinazolines
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Ado-Trastuzumab Emtansine