Mechanisms of Acquired Resistance to AZD9291: A Mutation-Selective, Irreversible EGFR Inhibitor

J Thorac Oncol. 2015 Dec;10(12):1736-44. doi: 10.1097/JTO.0000000000000688.


Introduction: AZD9291, a third-generation and mutation-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is active against patients with EGFR-mutant non-small-cell lung cancer (NSCLC) who failed prior treatment with EGFR TKIs. However, acquired resistance to AZD9291 is inevitable. In this study, we identified the mechanisms of acquired resistance to AZD9291 in EGFR-mutant NSCLC.

Methods: Four NSCLC patients with both an EGFR exon 19 deletion and the EGFR mutation after developing acquired resistance to first-generation EGFR TKIs received AZD9291 at doses of 20 to 80 mg/day in a phase I trial (NCT01802632). Paired tumor samples before and after treatment were obtained to evaluate EGFR modifications, alternative pathway activation, and histologic transformation. Genetic alterations were analyzed using Sanger sequencing, fluorescence in situ hybridization, real-time polymerase chain reaction, and targeted exome sequencing.

Results: All four patients achieved a partial response (median duration of response, 9 months [range, 9-11 months]) and subsequently showed resistance to AZD9291. EGFR-mutant clones depopulated AZD9291-resistant tumors to below 1% (baseline, 14%-36%) in three patients with progression: one with the loss of EGFR-double mutant clones and two accompanied by transformation to small-cell carcinoma and focal fibroblast growth factor receptor 1 (FGFR1) amplification, respectively. EGFR-mutant clones remained and the EGFR ligand was overexpressed in one patient with focal progression to AZD9291.

Conclusion: Acquired resistance mechanisms of AZD9291 in patients with EGFR-mutant NSCLC who failed treatment with first-generation EGFR TKIs include the loss of EGFR-mutant clones plus alternative pathway activation or histologic transformation and EGFR ligand-dependent activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylamides / administration & dosage*
  • Acrylamides / pharmacology
  • Aniline Compounds / administration & dosage*
  • Aniline Compounds / pharmacology
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Clinical Trials, Phase I as Topic
  • Drug Resistance, Neoplasm
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • Female
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Mutation
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / pharmacology
  • Treatment Outcome


  • Acrylamides
  • Aniline Compounds
  • Protein Kinase Inhibitors
  • osimertinib
  • EGFR protein, human
  • ErbB Receptors

Associated data