Comparing the Effectiveness and Safety of First-line Interventions in Patients With Advanced Epidermal Growth Factor Receptor-mutant Non-small Cell Lung Cancer, With Particular Focus on Brain Metastatic Status: A Systematic Review and Network Meta-analysis.

Aims: This network meta-analysis (NMA) aimed to identify the most effective first-line intervention (FLI) for advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), particularly in patients with varying brain metastasis (BM) status.

Materials And Methods: Data were collected from randomized controlled trials (RCTs) evaluating first-line EGFR-tyrosine kinase inhibitors (EGFR-TKIs), either alone or in combination, for EGFR-mutated advanced NSCLC (EMAN) patients. The sources included EMBASE, Web of Science, Cochrane Library, PubMed, and relevant conference abstracts from inception until December 2023.

Results: A total of 37 RCTs, encompassing 24 intervention options, were included in the NMA. Osimertinib combined with chemotherapy (CT) significantly improved progression-free survival (PFS) compared to aumolertinib (HR, 0.61; 95% CI, 0.40-0.93), furmonertinib (HR, 0.64; 95% CI, 0.41-0.98), lazertinib (HR, 0.64; 95% CI, 0.41-0.98), osimertinib alone (HR, 0.62; 95% CI, 0.48-0.80), osimertinib + bevacizumab (HR, 0.72; 95% CI, 0.51-1.00), befotertinib (HR, 0.57; 95% CI, 0.36-0.90), and zorifertinib (HR, 0.61; 95% CI, 0.39-0.93). Further, amivantamab + lazertinib showed slightly better PFS compared to aumolertinib, furmonertinib, zorifertinib, and osimertinib + bevacizumab (HR <1, but P >0.05). Regarding overall survival (OS), amivantamab + lazertinib demonstrated superior results relative to furmonertinib (HR, 0.54; 95% CI, 0.30-0.95) and befotertinib (HR, 0.43; 95% CI, 0.24-0.77). No significant OS differences were observed among osimertinib, osimertinib + bevacizumab, osimertinib + CT, lazertinib, and amivantamab + lazertinib. In BM patients, osimertinib + CT significantly enhanced PFS compared to osimertinib (HR, 0.47; 95% CI, 0.33-0.66), furmonertinib (HR, 0.44; 95% CI, 0.21-0.90), befotertinib (HR, 0.45; 95% CI, 0.21-1.00), and zorifertinib (HR, 0.47; 95% CI, 0.25-0.89). However, no noticeable PFS differences were observed between osimertinib + CT and amivantamab + lazertinib or aumolertinib. Lastly, osimertinib + CT and zorifertinib were associated with higher rates of all-grade adverse events (AEs) and grade ≥3 AEs, respectively.

Conclusions: In EMAN patients, osimertinib + CT and amivantamab + lazertinib were associated with optimal PFS and OS, respectively. Among BM patients, osimertinib + CT offered the best PFS benefits. These findings may assist in clinical decision-making and personalized care for EMAN and BM patients. The study is registered on PROSPERO (CRD42024506995).