Noninferiority Trials in Second-Line Treatments of Nonsmall Cell Lung Cancer A Systematic Review of Literature With Meta-analysis of Phase III Randomized Clinical Trials

Background: To assess the role of the novel second-line treatments in nonsmall cell lung cancer (NSCLC). Methods: A systematic review of the literature with meta-analysis of phase III randomized clinical trials (RCTs) was independently performed by 3 authors. All the trials comparing any novel treatment with every-3-weeks docetaxel (3WD) and designed as noninferiority trial were included in the analysis. One-year survival rate (SR) was the primary end point, and quality of life and safety represented the secondary end points. Results: Four RCTs met the selection criteria. The outcomes of 3355 patients were analyzed in the pooled analysis. No heterogeneity was documented in the primary analysis either including all the trials or analyzing separately gefitinib and the chemotherapeutic alternatives to 3WD. The cumulative odds ratio was 0.927 (P = 0.313) for 1-year SR, 0.889 (P = 0.323) for the chemotherapeutic alternatives to 3WD and 0.953 (P = 0.616) for gefitinib. The experimental arms showed a significant advantage in quality of life in the cumulative analysis (odds ratio = 1.623, P = 0.01) and in the subgroup of patients treated with gefitinib (odds ratio = 1.962, P<0.001); a better safety profile for the experimental arm was observed in the cumulative analysis and in the subgroups of alternative chemotherapies or gefitinib. Conclusion: All the noninferiority trials demonstrated the noninferiority of pemetrexed, oral topotecan, or gefitinib in 1-year SR (primary end point), but the improvement in overall survival remains modest. The improvement in quality of life and safety (secondary end points) represents the main value of these treatments, whose aim is mainly palliative.