Efficacy and safety of adjuvant EGFR-TKIs for non-small cell lung cancer with EGFR mutations after surgery: an updated meta-analysis

Abstract Objectives: This study aims to investigate the efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) as adjuvant therapy for resected non-small cell lung cancer (NSCLC) patients harboring EGFR mutations compared with adjuvant chemotherapy or placebo, including the latest updated data.Methods: A comprehensively systematic search for relevant randomized controlled trials (RCTs) was performed. Hazard ratios (HRs) and 95% confidence intervals (CI) were used to analyse disease-free survival (DFS) and overall survival (OS). For dichotomous data, risk ratio (RR) of severe adverse events and relapse patterns was calculated as effect measures. Results: Nine RCTs involving 1,835 completely resected patients with NSCLC with EGFR mutations were included in the meta-analysis. The use of EGFR-TKIs resulted in a significant improvement in DFS when compared to non-EGFR-TKIs based treatment (HR:0.45; 95% CI=0.29–0.71, P < 0.0005), but no OS benefit was shown (HR:0.79; 95%CI=0.54–1.16, P =0.23). In subgroup analyses, adjuvant EGFR-TKIs elevated DFS significantly compared to single-agent chemotherapy (HR: 0.50; 95%CI = 0.30–0.82, P = 0.006). Adjuvant EGFR-TKIs following chemotherapy also improved DFS significantly compared with single-agent chemotherapy (HR:0.34; 95%CI=0.16–0.69, P=0.003). No differences were found in DFS between adjuvant EGFR-TKIs versus placebo (HR:0.51; 95% CI=0.18 –1.47, P=0.21). Patients with a median treatment time over 12 months (HR:0.42; 95% CI=0.20–0.86; P =0.02) or diagnosed with stage III non-small cell lung cancer NSCLC (HR:0.42;95% CI = 0.20–0.86; P =0.02) induced better DFS. Elevated DFS from adjuvant EGFR-TKIs was still observed regardless of EGFR Mutation Status. Nevertheless, in subgroup analysis, neither subgroup analysis of therapeutic strategies nor median treatment duration observed any benefit from adjuvant EGFR-TKIs in OS. Moreover, adjuvant EGFR-TKIs decreased the risk of lung recurrence (RR: 0.63 ;95%CI=0.44 –0.89). Rash (RR:15.28; 95% CI = 4.71–49.55), Diarrhea (RR:3.08; 95% CI = 1.26–7.52) and ALT or AST increase (RR:8.85; 95% CI = 4.14–18.90) were several common grades 3 or higher adverse events (AEs) of EGFR-TKIs treatment.Conclusions: EGFR-TKIs treatment exhibited significant improvement in DFS with fewer manageable toxicities for NSCLC patients with EGFR mutations completely resection compared with non-EGFR-TKIs treatment. However, prolonged DFS did not produce any benefits for the OS.