OBJECTIVES: A biological and genetical variation of lung cancer is non-small cell lung cancer (NSCLC) bearing activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR m+). In this population the EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib have shown significant increase in progression-free survival (PFS) compared to chemotherapy. Erlotinib is not yet licensed for this indication; however, an EMA marketing authorization submission is currently ongoing. Therefore both therapies will be competing to be primary choice in treatment naïve patients with EGFR m+ NSCLC; hence, in the absence of direct head-to-head comparison, there is a need for indirect treatment comparison (ITC) assessment. METHODS: Published phase-III evidence was used as the basis for the ITC. The Bucher et al. ITC methodology was applied to the PFS hazard ratios (HRs) obtained by comparing the TKIs versus chemotherapy. Erlotinib obtained a HR of 0.16 (95%CI: 0.10-0.26, p<0.0001) based on the OPTIMAL trial; gefitinib obtained the following PFS HRs vs. chemotherapy: IPASS trial: 0.48 (95%CI: 0.36-0.64, p<0.001); WJTOG trial: 0.33 (95%CI: 0.20-0.54, p<0.0001) and NEJGSG trial: 0.30 (95%CI: 0.22-0.41, p<0.001). Besides comparing the erlotinib PFS HR with each single gefitinib trial, erlotinib was compared to the pooled gefitinib evidence. RESULTS: Comparing the PFS HRs of erlotinib versus gefitinib based on the OPTIMAL trial and the IPASS trial resulted in a statistically significant PFS difference (ITC HR: 0.33; 95%CI: 0.19-0.58; p=0.0001). This statistically significant PFS difference was also observed when comparing OPTIMAL versus WJTOG (ITC HR: 0.48; 95%CI: 0.24-0.97, p=0.0395) and versus NEJGSG (ITC HR: 0.53; 95%CI: 0.30-0.9, p=0.0307). Comparing erlotinib vs. the pooled gefitinib phase-III evidence confirmed these findings. CONCLUSIONS: According to the underlying indirect comparison of published phase-III evidence, erlotinib is the most efficacious EGFR TKI in first-line EGFR m+ NSCLC.