Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity

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37 Scopus citations

Abstract

We report a phase II study of 50 advanced non-small cell lung cancer (NSCLC) patients with point mutations or insertions in EGFR exon 20 treated with poziotinib (NCT03066206). The study achieved its primary endpoint, with confirmed objective response rates (ORRs) of 32% and 31% by investigator and blinded independent review, respectively, with a median progression-free survival of 5.5 months. Using preclinical studies, in silico modeling, and molecular dynamics simulations, we found that poziotinib sensitivity was highly dependent on the insertion location, with near-loop insertions (amino acids A767 to P772) being more sensitive than far-loop insertions, an observation confirmed clinically with ORRs of 46% and 0% observed in near versus far-loop, respectively (p = 0.0015). Putative mechanisms of acquired resistance included EGFR T790M, MET amplifications, and epithelial-to-mesenchymal transition (EMT). Our data demonstrate that poziotinib is active in EGFR exon 20-mutant NSCLC, although this activity is influenced by insertion location.

Original languageEnglish (US)
Pages (from-to)754-767.e6
JournalCancer cell
Volume40
Issue number7
DOIs
StatePublished - Jul 11 2022

Keywords

  • epidermal growth factor receptor
  • exon 20 insertion
  • non-small cell lung carcinoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

MD Anderson CCSG core facilities

  • Advanced Technology Genomics Core
  • Tissue Biospecimen and Pathology Resource
  • Biostatistics Resource Group
  • Functional Proteomics Reverse Phase Protein Array Core
  • Bioinformatics Shared Resource

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