A group of researchers led by John V. Heymach of the Department of Thoracic Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA reported in Nature Medicine the results from the study that identifies poziotinib as a potent, clinically active inhibitor of EGFR and HER2 exon 20 mutations in metastatic non-small cell lung cancer (NSCLC). The findings illuminate the molecular features of tyrosine kinase inhibitors (TKIs) that may circumvent the steric changes induced by these mutations.

The authors wrote in the study background that although most activating mutations of epidermal growth factor receptor (EGFR)-mutant NSCLCs are sensitive to available EGFR TKIs, a subset with alterations in exon 20 of EGFR and HER2 are intrinsically resistant and lack an effective therapy.

The study team included the researchers from the University of Texas MD Anderson Cancer Center, Dana-Farber Cancer Institute, University of Colorado Cancer Center, Yale University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, and New York University Langone Medical Center.

The investigators used in silico, in vitro, and in vivo testing to model structural alterations induced by exon 20 mutations and to identify effective inhibitors. 3-D modeling indicated alterations restricted the size of the drug-binding pocket, limiting the binding of large, rigid inhibitors. Owing to its small size and flexibility, poziotinib can circumvent these steric changes and is a potent inhibitor of the most common EGFR and HER2 exon 20 mutants.

Furthermore, 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%.