Efficacy and safety of first-line treatments for patients with advanced epidermal growth factor receptor mutated non-small cell lung cancer: a network meta- analysis

Abstract IMPORTANCE: Lung cancer, specifically non-small-cell lung cancer (NSCLC), remains a leading cause of cancer-related mortality globally. The discovery of epidermal growth factor receptor (EGFR) mutations and the subsequent development of EGFR tyrosine kinase inhibitors (TKIs) have significantly transformed the therapeutic landscape. However, identifying the most effective and safe first-line treatment for patients with advanced EGFR-mutated NSCLC remains challenging. OBJECTIVE: To assess and compare the effectiveness and safety of various first-line treatments for patients with advanced NSCLC harboring EGFR mutations, with a focus on overall outcomes and subgroup analyses based on specific EGFR mutations and clinicopathological characteristics. DATA SOURCES: PubMed, Embase, the Cochrane Central Register of Controlled Trials, and abstracts from major oncology conferences (ASCO, ESMO, WCLC) were searched from inception to Dec 2023. STUDY SELECTION: Phase II/III randomized controlled trials assessing first-line treatments in patients with advanced EGFR-mutated NSCLC were included. Trials reporting on progression-free survival, overall survival, objective response rate, or toxicity were selected. DATA EXTRACTION AND SYNTHESIS: Data were independently extracted by two authors and included study details, patient characteristics, treatments, and outcomes. Hazard ratios were used for survival outcomes, and risk ratios for binary outcomes, each with 95% credible intervals. MAIN OUTCOMES AND MEASURES: The primary outcome was progression-free survival. Secondary outcomes included overall survival, objective response rate, and incidence of severe adverse events (grade ≥ 3). RESULTS: The analysis encompassed 41 studies involving 11,302 patients across 26 treatment groups, osimertinib combined with pemetrexed plus platinum emerged as the most effective treatment, significantly extending progression-free survival (HR, 0.62; 95% CI, 0.41–0.94) in comparison to osimertinib alone. Lazertinib plus amivantamab also showed enhanced efficacy, marginally improving progression-free survival (HR, 0.70; 95% CI, 0.48–1.02) relative to osimertinib monotherapy. New Asian third-generation EGFR-TKIs demonstrated comparable efficacy to Osimertinib. Subgroup analyses, factoring in EGFR mutation types and clinicopathological features, consistently identified osimertinib combined with pemetrexed plus platinum, as well as lazertinib plus amivantamab, as among the most efficacious treatments for the majority of subgroups. Notably, furmonertinib was distinguished for its superior safety profile, whereas combination treatments generally exhibited a higher occurrence of grade 3 or more severe adverse events. CONCLUSIONS AND RELEVANCE: The combination of osimertinib and pemetrexed plus platinum, along with lazertinib combined with amivantamab, emerged as superior first-line treatment options for patients with advanced EGFR-mutated NSCLC, demonstrating efficacy across diverse mutation types and clinicopathological characteristics. However, promising combination treatments were associated with higher incidences of adverse events, emphasizing the need for cautious application and vigilant monitoring in clinical practice.