Background <p>This network meta-analysis (NMA) aimed to indicate the most effective first-line therapeutic options for advanced EGFR-mutated NSCLC, particularly considering their specific clinicopathological characteristics.</p> Methods <p>Articles in the EMBASE, Cochrane Library, PubMed, and Web of Science databases and conference abstracts published as of December 2023, were searched to obtain data from randomized controlled trials (RCTs) of the first-line treatment of advanced EGFR-mutated NSCLC cases with EGFR-TKIs alone or together with other agents.</p> Results <p>37 RCTs including 24 treatment regimens were incorporated into this NMA. With respect to the overall patient cohort, osimertinib + chemotherapy (CT) was associated with the greatest benefit to progression-free survival (PFS), whereas amivantamab + lazertinib yielded the greatest benefit to overall survival (OS). Osimertinib + CT yielded the best PFS outcomes irrespective of patient gender or EGFR mutation subtype. The combinations of amivantamab + lazertinib and icotinib + CT provided the best respective PFS outcomes in Asian and elderly patient cohorts. With respect to OS outcomes, afatinib + cetuximab provided the best outcomes for 19del and male cases, whereas dacomitinib provided the best OS for females and cases with L858R mutations. The respective gefitinib + CT and erlotinib + bevacizumab regimens were also associated with the greatest improvements in the OS of Asian and elderly cases.</p> Conclusions <p>This NMA revealed that cases with EGFR-mutated NSCLC may benefit from different first-line treatment regimens according to their clinicopathological characteristics. On the whole, osimertinib plus CT and amivantamab plus lazertinib emerged as the most noticeable treatment modalities for such cases. (PROSPERO ID: CRD42024506995)</p>