EGFR activating mutations have been recognized as the most important predictor of response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, 20-30% of patients harboring EGFR activating mutations show a poor response requiring investigation for underlying mechanisms.

Characteristics of 541 patients with lung cancer harboring EGFR activating mutations were analyzed to determine contributing factors that could differentiate responders and non-responders. In addition, previously suggested moleculo-pathologic factors of resistance such as IκB, IGF1R, PTEN, MET, AXL and BIM were evaluated in patients exhibiting primary resistance who had sufficient biopsied tissues available for analyses.

Responders to EGFR-TKIs had a higher incidence of deletion mutations and more frequent presence of EGFR amplifications than non-responders. The median OS was 21 months (95% CI 26.1-30.4) in responders compared to 8 months (95% CI 8.7-15.8) in non-responders (p<0.001). In analyses of patients with primary resistance, we found that 27.3% (6/22) of them exhibited decreased expression of IκB, and 9.1% (2/22) of patients showed increased expression of IGF1R. Loss of PTEN was noted in 54.5%, and BIM polymorphism was found in 19% of patients. No patients had MET amplification, while expression of AXL was detected in 5 patients. Two patients had simultaneous T790M EGFR or PIK3CA mutation alongside EGFR activating mutation. Most of patients exhibited multiple abnormalities of these factors. The overall survival was worse in the group with multiple resistant factors.

Our study suggests that mechanisms of primary resistance may be more complex than those underlying acquired resistance, with several factors concomitantly contributing to primary resistance.