Clinical Impact of Rare and Compound Mutations of Epidermal Growth Factor Receptor in Patients With Non-Small-Cell Lung Cancer

Clin Lung Cancer. 2019 Sep;20(5):350-362.e4. doi: 10.1016/j.cllc.2019.04.012. Epub 2019 May 11.


Background: Standard therapy of advanced non-small-cell lung cancer harboring an activating mutation in the epidermal growth factor receptor (EGFR) gene is treatment with tyrosine kinase inhibitors (TKI). However, for rare and compound mutations of the EGFR gene, the clinical evidence of TKI therapy is still unclear.

Patients and methods: A total of 2906 lung cancer samples were analyzed for EGFR mutations during routine analysis between 2010 and 2017. The samples have been investigated by Sanger sequencing and since 2014 by next-generation sequencing.

Results: We detected EGFR mutations in 408 specimens (14%). Among these, we found 41 samples with rare and 22 with compound mutations. In these 63 samples, 56 different rare EGFR mutations occurred. Information about the clinical outcome was available for 37. Among those with rare mutations, only one patient harboring the mutation p.G874D had disease that responded to first-generation TKI therapy. In contrast, the disease of all patients with compound mutations responded to first- or second-generation TKI therapy. Furthermore, we collected data on clinical relevance regarding TKI therapy from different databases and from an additional literature search, and only found data for 36 of the 56 detected rare mutations.

Conclusion: Information about the clinical outcome of patients with rare and compound EGFR mutations remains limited. At present, second- and third-generation TKIs are available, which may represent new treatment strategies for these patients. Therefore, it is becoming increasingly important to maintain databases concerning rare EGFR mutations.

Keywords: Clinical evidence; Compound EGFR mutations; NSCLC; Rare EGFR mutations; TKI therapy.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / therapy
  • Drug Resistance, Neoplasm
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / therapy
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Protein Kinase Inhibitors / therapeutic use*
  • Treatment Outcome


  • Protein Kinase Inhibitors
  • EGFR protein, human
  • ErbB Receptors