Overall Survival Benefits of First-Line Treatments for Asian Patients With Advanced EGFR-Mutated NSCLC Harboring L858R Mutation: A Systematic Review and Network Meta-Analysis

Abstract

Introduction: Randomized controlled trials have investigated different first-line treatments for patients with advanced EGFR-mutated NSCLC. Nevertheless, their efficacy, in particular, the long-term overall survival (OS) benefit in Asian patients with L858R mutation, remains unclear.

Methods: We performed a systematic review and frequentist network meta-analysis by retrieving relevant literature from PubMed/MEDLINE, Ovid, EMBASE, Cochrane Library, trial registries, and other sources. We included randomized controlled trials comparing two or more treatments in the first-line setting for Asian patients with L858R mutation. This study was registered in the Prospective Register of Systematic Reviews (CRD 42022295897).

Results: There were a total of 18 trials that involved 1852 Asian patients and 12 treatments, including the following: EGFR tyrosine kinase inhibitors (TKIs) (osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib), pemetrexed-based chemotherapy, pemetrexed-free chemotherapy, and combination treatments (gefitinib plus apatinib, erlotinib plus ramucirumab, erlotinib plus bevacizumab and gefitinib plus pemetrexed-based chemotherapy). Asian patients with L858R mutation had no significant OS benefits from all these treatments. Gefitinib plus pemetrexed-based chemotherapy, dacomitinib, osimertinib, and erlotinib plus bevacizumab were found to be consistent in yielding the best progression-free survival benefit (p scores = 93%, 79%, 77%, and 70%). Combination treatments caused more toxicity, especially erlotinib plus bevacizumab and gefitinib plus pemetrexed-based chemotherapy, resulting in the greatest incidence of grade greater than or equal to 3 adverse events.

Conclusions: In Asian patients harboring L858R mutation, EGFR TKIs and combination treatments had no OS benefit when compared with conventional chemotherapies. Further studies are warranted to investigate the resistance mechanism with TKIs and potential combination strategies in patients with this common but less favorable mutation.

Keywords: Asian; Epidermal growth factor receptor; L858R mutation; Non–small-cell lung cancer; Tyrosine kinase inhibitors.

Figure 1

Study flowchart illustrating the results of systematic review identified from PubMed/MEDLINE, Ovid, Embase, Cochrane Library, CINAHL Databases, trial registries, and other sources.

Figure 2

Network diagrams of comparisons on different outcomes of treatments in Asian patients with advanced EGFR-mutated NSCLC harboring L858R mutation. (A) Comparisons on overall survival. (B) Comparisons on progression-free survival. (C) Comparisons on adverse events of grade 3 or higher. Each circular node represents a type of treatment. The node size is proportional to the total number of patients receiving a treatment (in brackets). Each line represents a type of head-to-head comparison. The width of lines is proportional to the number of trials comparing the connected treatments. PbCT, pemetrexed-based chemotherapy; PfCT, pemetrexed-free chemotherapy.

Figure 3

Pooled estimates of the network meta-analysis. (A) Pooled hazard ratios (95% confidence intervals) for overall survival (upper triangle) and progression-free survival (lower triangle). p scores for overall survival (left) and progression-free survival (right) are indicated under each treatment. (B) Pooled ORs (95% confidence intervals) for adverse events of grade 3 or higher. p scores are indicated under each treatment. Data in each cell are hazard or ORs (95% confidence intervals) for the comparison of row-defining treatment versus column-defining treatment. Hazard ratios or OR less than one favor row-defining treatment. Significant results are in bold. NA, not available; PbCT, pemetrexed-based chemotherapy; PfCT, pemetrexed-free chemotherapy.