Comparative Efficacy and Safety of First-Line Treatment for Patients with Locally Advanced or Metastatic Epidermal Growth Factor Receptor (EGFR) Mutated Non-Small-Cell Lung Cancer (NSCLC): A Network Meta-Analysis

OBJECTIVES: The optimal first-line treatment for patients with advanced epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) remains undetermined, considering varied biologically synergistic combinations of EGFR TKIs. This Network meta-analysis aims to compare the efficacy and safety of different first-line regimens to aid clinical decision-making.

METHODS: We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov from inception until 31^st December 2022. Randomized controlled trials were included, comparing EGFR TKIs as a single agent, or in combination as first-line treatments in advanced EGFR-mutated NSCLC patients. NMA and the surface under the cumulative ranking curve (SUCRA) were used to evaluate progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and grade 3 or higher adverse events (≥3AEs).

RESULTS: 74 publications with 48 unique RCTs across 26 treatment regimens were analyzed. Erlotinib plus Pemetrexed-based chemotherapy (Erl+PbCT) provided the most favorable PFS benefit (hazard ratio, 0.48; 95% credible interval, 0.11, 2.08) versus Osimertinib plus bevacizumab (Osi+Bev). Erlotinib and Gefitinib, in combination with PbCT, showed the most favorable OS benefit. Subgroup analyses by the two most common EGFR mutation types indicated that Erlotinib plus Bevacizumab (Erl+Bev) was associated with the best PFS in patients with the Leu858Arg mutation and Osimertinib plus bevacizumab (Osi+Bev) was associated with the best PFS in patients with the exon 19 deletion. Third-generation EGFR-TKIs, particularly Aumolertinib (Aum) and Osimertinib (Osi), significantly prolonged PFS in patients with brain metastases.

CONCLUSIONS: Erl+PbCT and Gef+PbCT emerged as the most effective first-line regimens, followed by third-generation TKIs for overall patients in terms of PFS and OS, respectively. The treatments resulting in the best PFS for patients with the exon 19 deletion and Leu858Arg mutations were osimertinib plus bevacizumab and Erlotinib plus bevacizumab, respectively. The variations in efficacy and safety profiles among regimens underscore the necessity for personalized therapeutic approaches.