Clinical and biological significance of erlotinib therapy after pemetrexed in non-small cell lung cancer with wild-type EGFR

Pemetrexed is a multi-targeted anti-folate agent that confers favorable benefits to patients with non-small cell lung cancer (NSCLC). However, the optimal use including treatment schedule of pemetrexed and other drugs in clinical practice remains to be determined, particularly for NSCLC with wild-type epidermal growth factor receptor (EGFR). The present study investigated a potential therapeutic strategy for NSCLC patients with wild-type EGFR who were treated with pemetrexed. To identify factors associated with a survival, medical record data from 130 patients were retrospectively reviewed, using the Kaplan-Meier method with log-rank test. Factors identified in the clinical analysis were further investigated within in vitro studies. Patients who underwent the treatment schedule of erlotinib at the time of progression after pemetrexed-based chemotherapy prolonged overall survival, compared to those treated with other schedules (p=0.010; hazard ratio, 0.418). This survival benefit was also observed in the treatment schedule of pemetrexed monotherapy and subsequent erlotinib (p=0.008; hazard ratio, 0.220). As a treatment at the time of progression after pemetrexed-based chemotherapy, erlotinib conferred a survival benefit when compared to docetaxel (p=0.024; hazard ratio, 0.377). The cell growth assay confirmed that treatment with pemetrexed followed by erlotinib significantly inhibited proliferation of NSCLC cells regardless of EGFR mutation status. In conclusion, use of erlotinib at the time of progression after pemetrexed therapy confers a survival benefit in NSCLC patients with wildtype EGFR. The result of this study provides an important clue to the optimal treatment schedule for NSCLC.