Tumor heterogeneity affects the activity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR mutant non-small cell lung cancer (NSCLC) patients (pts)

Background

Recent findings suggest that a fraction of EGFR mutant NSCLC carries additional driver mutations which could potentially affect the activity of EGFR TKIs. We investigated the role of KRAS, NRAS, BRAF, PIK3CA, MET and ERBB2 mutations (other mutations) on the outcome of NSCLC pts treated with EGFR TKIs.

Methods

EGFR mutant NSCLC pts who received first line therapy with EGFR TKIs were eligible. Genomic DNA from EGFR mutant NSCLC samples as assessed with routine diagnostic methods, was retrospectively analyzed with the Ion AmpliSeq Colon and Lung Cancer Panel using Ion Torrent semiconductor sequencing. The panel assesses over 500 somatic mutations in 22 genes at a sensitivity of 2%. Mutations were detected using the Ion Reporter Software v4.6.

Results

132 pts, treated between Jun 2008 and Dec 2014 in 7 centers, were enrolled: median age 71 (range 41-92); 70% women; 61% never smokers. Analysis of EGFR mutant samples with NGS revealed the presence of hotspot mutations in genes other than the EGFR, including KRAS, NRAS, BRAF, ERBB2, PIK3CA or MET, in 29/132 cases (22%). In most cases the allelic frequency of the other mutations was different as compared with EGFR mutations, suggesting intra-tumor heterogeneity. A T790M mutation was also found in 9/132 tumor samples (6.8%). The progression free survival (PFS) of pts without other mutations was 11.3 months versus 7 months in pts with other mutations (Log-rank test univariate: p = 0.0298). In a multivariate Cox regression model including the presence of other mutations, age, performance status, smoking status and the presence of T790M mutations, the presence of other mutations was the only factor significantly associated with PFS (Hazard Ratio 1.63, 95% CI 1.04-2.58; p = 0.035). Response rate in pts with or without other mutations was 59% and 68%, respectively (p = 0.349).

Conclusions

These data suggest that a subgroup of EGFR mutant tumors have intra-tumor heterogeneity and that this phenomenon might affect the activity of first line EGFR TKIs.

Clinical trial identification

This observational study was approved by the Ethical Committee of the Pascale Institute: protocol n. 16/14 OSS

Legal entity responsible for the study

Istituto Nazionale Tumori “Fondazione G. Pascale”-IRCCS, Naples, Italy

Funding

Associazione Italiana per la Ricerca sul Cancro (AIRC)

Disclosure

All authors have declared no conflicts of interest.