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

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.

• Authors: Yasir Y Elamin, Jacqulyne P Robichaux, Brett W Carter, Mehmet Altan, Hai Tran, Don L Gibbons, Simon Heeke, Frank V Fossella, Vincent K Lam, Xiuning Le, Marcelo V Negrao, Monique B Nilsson, Anisha Patel, R S K Vijayan, Jason B Cross, Jianjun Zhang, Lauren A Byers, Charles Lu, Tina Cascone, Lei Feng, Rajyalakshmi Luthra, Francis A San Lucas, Geeta Mantha, Mark Routbort, George Blumenschein Jr, Anne S Tsao, John V Heymach
• Journal: Cancer cell (Cancer Cell) Vol. 40 Issue 7 Pg. 754-767.e6 (07 11 2022) ISSN: 1878-3686 [Electronic] United States
• PMID: 35820397 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• HM781-36B
• Protein Kinase Inhibitors
• Quinazolines
• EGFR protein, human
• ErbB Receptors

Topics

• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (genetics)
• Exons (genetics)
• Humans
• Lung Neoplasms (drug therapy, genetics)
• Mutation
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Quinazolines
• Treatment Outcome