The common driver genes in non–small-cell lung cancer (NSCLC) include EGFR
. C-MET amplification coexisting with EGFR
mutation is recognized as a mechanism of primary resistance to EGFR tyrosine kinase inhibitors (TKIs).1,2
Lou and coworkers investigated the frequency of c-MET overexpression coexisting with EGFR
mutation, response to EGFR TKIs, and survival in advanced NSCLC patients with such coalterations.3
A total of 149 NSCLC patients were screened for the presence of c-MET overexpression concomitant EGFR
mutation. C-MET overexpression was detected by immunohistochemistry, in which ≥50% of tumor cells with moderate- to high-intensity staining were defined as c-MET-positive. C-MET
amplification was detected by fluorescence in situ hybridization (FISH), and FISH-positive was defined as gene focal amplification or high polysomy (at least 15% cells with ≥5 copy numbers). EGFR
mutations were tested by DNA sequencing or Scorpion amplification refractory mutation system. The frequency of concomitant c-MET overexpression and EGFR
mutation was 39% in patients with advanced NSCLC. However, the frequency of c-MET amplification was 14%. The frequency of primary resistance to EGFR TKIs was 24% in EGFR
/MET-coexisted patients and 14% in those with only EGFR
= 0.13). Response rates (RRs) to EGFR TKIs were 48% and 71% in these 2 arms, respectively (P
= 0.004). Median progression-free survival was 10.7 months versus 11.2 months (hazard ratio, 1.05; 95% confidence interval, 0.69-1.60; P
= 0.82). Primary resistance to EGFR TKIs was found in 2 cases with concomitant MET amplification and EGFR
mutations, but these patients responded to the combination of EGFR and MET inhibitors. The authors conclude that patients with advanced NSCLC and concomitant EGFR
mutation and c-MET overexpression have relatively low RR to treatment with EGFR TKIs, indicating that c-MET overexpression potentially causes primary resistance to EGFR TKIs; this resistance may be overcome by treating this patient population with a combination of EGFR and MET inhibitors.
- Sequist LV, et al. J Clin Oncol. 2008;26:2442-2449.
- Benedettini E, et al. Am J Pathol. 2010;177:415-423.
- Lou NN, et al. ASCO 2016. Abstract 9054.