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Uncommon single and compound EGFR mutations: clinical outcomes of a heterogeneous subgroup of NSCLC

Sabrina Rossi1, Paola Damiano2, Luca Toschi1

  • 1IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy.

Current Problems in Cancer
|September 7, 2021
PubMed

Insights

Patients with rare epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) showed varied responses to treatments. Compound mutations may indicate better outcomes and predict response to EGFR tyrosine kinase inhibitors (TKIs).

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Molecular characterization of non-small-cell lung cancer (NSCLC) is crucial for effective treatment strategies in metastatic cases.
  • Epidermal growth factor receptor (EGFR) mutations are key targets, with most mutations (90%) predicting sensitivity to EGFR tyrosine kinase inhibitors (TKIs).
  • A small subset (10%) of EGFR mutations are uncommon, heterogeneous, and have variable responses to targeted therapies.

Purpose of the Study:

  • To investigate the clinical outcomes of metastatic NSCLC patients with uncommon EGFR mutations treated with first-line EGFR TKIs or chemotherapy.
  • To evaluate the prognostic and predictive value of single versus compound uncommon EGFR mutations.
  • To compare the efficacy of EGFR TKIs versus platinum-based chemotherapy in this patient subgroup.

Main Methods:

  • Retrospective observational study of 47 patients with metastatic NSCLC and uncommon EGFR mutations.
  • Patients received either EGFR-targeting TKIs or platinum-based chemotherapy as first-line treatment.
  • Analysis of overall survival (OS), progression-free survival (PFS), and objective response rate (ORR).

Main Results:

  • Median OS was longer in the compound mutation group (33.6 months) compared to the single rare mutation group (12 months), though not statistically significant (P=0.473).
  • Median PFS was also longer in the compound mutation group (16 months) versus the single mutation group (7.6 months), without statistical significance (P=0.281).
  • No significant differences in ORR, PFS, or OS were observed between patients treated with first-line EGFR TKIs and those treated with chemotherapy, or among different TKIs administered.

Conclusions:

  • Compound uncommon EGFR mutations may serve as a favorable prognostic indicator for OS and predict response to 1st and 2nd generation EGFR TKIs, particularly for exon 19 insertions and codon 719 mutations.
  • For mutations in exon 18 (excluding codon 719) and exon 20 insertions, chemotherapy appears to be the most effective first-line option.
  • Future research incorporating immunotherapy with chemotherapy may alter current treatment paradigms for these specific mutations.
Keywords:
AfatinibCompound mutationsGefitinibOsimertinibTKIsUncommon mutations

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