Meta-Analysis of EGFR Tyrosine Kinase Inhibitors Compared with Chemotherapy as Second-Line Treatment in Pretreated Advanced Non-Small Cell Lung Cancer

Background: Since efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) versus chemotherapy in the treatment of patients with pretreated advanced non-small cell lung cancer (NSCLC) remain controversial, we performed a meta-analysis to compare them. Methods: An internet search of several databases was performed, including PubMed, Embase, and the Cochrane database. Randomized trials that compared an EGFR-TKI with chemotherapy in the second-line setting were included. The outcomes were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and grade 3-4 toxicities. The PFS, OS for the EGFR mutation-positive (EGFR M+) and EGFR mutation-negative (EGFR M-) subgroups were pooled. The pooled hazard ratios (HRs) and odds ratios (ORs) with their corresponding confidence intervals (CIs) were calculated on the STATA software. Results: Our meta-analysis combined 3,825 patients from 10 randomized trials. Overall, EGFR-TKIs and second-line chemotherapy have equivalent efficacy in terms of PFS (HR, 1.03; 95% CI, 0.87-1.21; P = 0.73; I-2 = 78.7%, P-heterogeneity<0.001), OS (HR, 1.00; 95% CI, 0.92-1.08; P = 0.90; I-2 = 0.0%, P-heterogeneity = 0.88), and ORR (OR, 1.34; 95% CI, 0.86-2.08; P = 0.20; I-2 = 73.1%, P-heterogeneity<0.001). However, subgroup analysis based on EGFR mutation status showed that second-line chemotherapy significantly improved PFS (HR, 1.35; 95% CI, 1.09-1.66; P = 0.01; I-2 = 55.7%, P-heterogeneity = 0.046) for EGFR M- patients, whereas OS was equal (HR, 0.96; 95% CI, 0.77-1.19; P = 0.69; I-2 = 0.0%, P-heterogeneity = 0.43); EGFR-TKIs significantly improved PFS (HR, 0.28; 95% CI, 0.15-0.53; P<0.001; I-2 = 4.1%, P-heterogeneity = 0.35) for EGFR M+ patients, whereas OS was equal (HR, 0.86; 95% CI, 0.44-1.68; P = 0.65; I-2 = 0.0%, P-heterogeneity = 0.77). Compared with chemotherapy, EGFR-TKIs led to more grade 3-4 rash, but less fatigue/asthenia disorder, leukopenia and thrombocytopenia. Conclusions: Our analysis suggests that chemotherapy in the second-line setting can prolong PFS in EGFR M- patients, whereas it has no impact on OS. EGFR-TKIs seem superior over chemotherapy as second-line therapy for EGFR M+ patients. Our findings support obtaining information on EGFR mutational status before initiation of second-line treatment.