First-line therapeutic strategy for patients with advanced non–small cell lung cancer with Leu858Arg epidermal growth factor receptor mutations: a Bayesian network meta-analysis

Aim: The objective of this network meta-analysis was to determine the most useful first-line therapeutic strategy for patients with advanced (IIIB/IV or relapsed) non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) Leu858Arg or EGFR 19del mutations. Methods: PubMed, the Web of Science, Medline, and reports of the top three world cancer conferences (WCLC, ESMO, and ASCO) were searched for appropriated randomized controlled studies (RCTs) discussing the use of various generations of tyrosine kinase inhibitors (TKIs; gefitinib, erlotinib, icotinib, afatinib, dacomitinib, osimertinib, aumolertinib), chemotherapy [pemetrexed-based chemotherapy (PC), non-pemetrexed-based chemotherapy (NPC)], and different combined therapies (osimertinib plus bevacizumab, afatinib plus cetuximab, erlotinib plus bevacizumab, erlotinib plus ramucirumab, gefitinib plus apatinib, gefitinib plus PC, and gefitinib plus pemetrexed) to treat patients with advanced NSCLC with EGFR Leu858Arg or 19del mutations. OpenBugs and Stata software were used to analyze the data. Results: We included 21 studies with 16 arms (including 2479 cases with EGFR Leu858Arg mutations and 3325 cases with EGFR 19del mutations). Among patients with NSCLC with EGFR Leu858Arg mutations, compared with the first-generation TKIs (such as gefitinib), the second- or third-generation TKIs [dacomitinib: hazard ratio (HR) = 0.63; 95% confidence index (CI) = (0.45, 0.89); osimertinib: HR = 0.63; 95% CI = (0.42, 0.97)] showed significant benefits in improving progression-free survival (PFS), as did afatinib plus cetuximab [HR = 1.98; 95% CI = (1.01, 3.95)], erlotinib plus bevacizumab [HR = 1.79; 95% CI = (1.22, 2.62)], and erlotinib plus ramucirumab [HR = 1.62; 95% CI = (1.07, 2.48)]. In terms of overall survival (OS), these 16 arms showed no significant differences between each other ( p > 0.05). Among patients with NSCLC with EGFR 19del mutations, compared with the first- or second-generation TKIs (such as gefitinib and afatinib), aumolertinib [ versus gefitinib: HR = 0.39; 95% CI = (0.28, 0.55) versus afatinib: HR = 0.53; 95% CI = (0.35, 0.84)] and osimertinib [ versus gefitinib: HR = 0.40; 95% CI = (0.32, 0.51) versus afatinib: HR = 0.53, 95% CI = (0.38, 0.79)] showed significantly beneficial effects. Among these first-line therapeutic strategies for patients with EGFR Leu858Arg mutations, the combination of afatinib and cetuximab ranked as the best to prolong PFS (33.0%). For NSCLC patients with 19del mutations, however, osimertinib plus bevacizumab was the best at prolonging PFS (84.3%). Conclusion: For NSCLC patients with EGFR Leu858Arg mutations, the second-generation TKIs, the third-generation TKIs, and the combined treatments showed better efficacy than the first-generation TKIs for PFS. There were, however, no significant differences between each group for OS.