Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred treatment option for patients with advanced non–small-cell lung cancer (NSCLC) who have tested positive for EGFR mutations, because of better outcomes than conventional chemotherapy. However, it is unclear if EGFR TKIs are as efficacious as chemotherapy in patients without EGFR mutations (known as EGFR wild-type), which account for the majority of patients with advanced NSCLC. To determine the association between the first-generation EGFR TKI (erlotinib [Tarceva] and gefitinib [Iressa]) treatment versus chemotherapy and survival in patients with advanced NSCLC harboring wild-type EGFR, researchers conducted a systematic review and meta-analysis of randomized controlled trials (Lee JK, et al. JAMA. 2014;311:1430-1437).
Researchers identified 11 randomized controlled trials, with 1605 patients with wild-type EGFR (N = 811 in the TKI group, and N = 794 in the chemotherapy group). In all, 4 trials were performed in the first-line setting, 4 in second-line, and 3 in second-line or later settings. All 11 trials used TKIs in their standard dosing and schedule (erlotinib 150 mg daily, gefitinib 250 mg daily). The primary end point was progression-free survival (PFS), and the secondary end points were objective response rate and overall survival (OS).
The pooled analysis showed that chemotherapy was associated with longer PFS compared with EGFR TKI in patients with wild-type tumors (hazard ratio [HR], 1.41; 95% confidence interval [CI], 1.1-1.81). For a median PFS of 6.4 months in patients treated with standard chemotherapy, the corresponding reduction in PFS with the EGFR TKI would be 1.9 months. In a subgroup analysis of 4 trials using more sensitive platforms, conventional chemotherapy demonstrated a longer PFS compared with TKI (HR, 1.84; 95% CI, 1.35-2.52). The association of chemotherapy improvement in PFS was also significant in 6 second-line or later trials (HR, 1.34; 95% CI, 1.09-1.65). The higher objective response rate (including complete and partial responses) of chemotherapy also supported the longer PFS in patients with wild-type EGFR tumors compared with TKI (16.8% vs 7.2%, respectively). However, OS did not differ between the groups.
The apparent discrepancy between the PFS/objective response rate and OS can be explained by the large crossover rates of the included trials. Therefore, the findings suggest that in patients with wild-type EGFR tumors, conventional chemotherapy could be the preferred treatment option over EGFR TKI. The investigators cautioned that this recommendation cannot be conclusive, because overall comparisons were based on randomization. Toxicity outcomes were also not assessed.
