Concomitant driver mutations in advanced EGFR -mutated non-small-cell lung cancer and their impact on erlotinib treatment.

Background: Patients with EGFR -mutated non-small-cell lung cancer benefit from EGFR tyrosine kinase inhibitors (TKIs) like erlotinib. However, the efficacy may be impaired by driver mutations in other genes.

Methods: Five hundred and fourteen consecutive patients with NSCLC of all stages were tested for EGFR -mutations by cobas® EGFR Mutation Test. Fluorescent in situ hybridization (FISH) for MET -amplification, immunohistochemistry (IHC) for MET- and ALK-expression, and Next Generation Sequencing (NGS) for concomitant driver mutations were performed on EGFR -mutated tumor samples from erlotinib-treated patients.

Results: Thirty-six patients (7%) had EGFR -mutations, including 2 with intrinsic resistance mutation p.T790M together with the p.L858R sensitizing mutation and 1 harboring the p.G719C/S768I double-mutation. Twenty-three patients had either locally advanced or advanced disease and received first-line erlotinib-treatment. Concomitant driver mutations were found in 15/21 (71%) of NGS-analyzed TKI-treated NSCLCs, involving in 67% of cases TP53 , in 13% CTNNB1 , and in 7% KRAS , MET , SMAD4 , PIK3CA , FGFR1 , FGFR3 , NRAS, DDR2 , and ERBB4 . No ALK-expression was found, whereas MET-overexpression and MET -amplification were observed in 5 and 4 patients, respectively. Objective responses occurred in 17/23 patients (74%), 4 did not respond (17%), and 2 harboring a SMAD4 -mutation (p.R135* (stop)) and a FGFR3 -mutation (p.D785fs* 31), respectively, displayed mixed response with simultaneously progressing and responding tumors (8.7%). Thus, EGFR -mutated tumors harboring co-mutations were not less likely to respond.

Conclusion: Co-mutations in other cancer-driver genes (oncogenes or tumor suppressor genes) were frequent in EGFR -mutated NSCLCs and few cases harbored concomitant activating and resistance EGFR -mutations before TKI-treatment. Most co-mutations did not impact the response to first-line erlotinib-treatment, but may represent potential additional therapeutic targets.