Clinical and molecular prognostic factors associated with outcomes of first-line osimertinib in EGFR-Mutated advanced NSCLC: a systematic review and meta-analysis

Osimertinib is the standard first-line therapy for epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC), but outcomes remain heterogeneous. This meta-analysis evaluated baseline clinical and molecular prognostic factors associated with poorer outcomes in this setting. PubMed, Embase, Web of Science, Scopus, and the Cochrane Library were searched through 20 May 2026. Eligible studies included patients with EGFR-mutated advanced, recurrent, or metastatic NSCLC receiving first-line osimertinib with extractable prognostic data. The primary outcome was progression-free survival or real-world progression-free survival (PFS/rwPFS); overall survival or real-world overall survival (OS/rwOS) was secondary. Hazard ratios (HRs) were pooled using random-effects models. Eighteen studies involving 4,070 first-line osimertinib-treated patients were included. TP53 mutation was associated with shorter PFS/rwPFS (HR 1.65, 95% confidence interval [CI] 1.15–2.37) and worse OS/rwOS (HR 1.55, 95% CI 1.14–2.12). EGFR L858R, versus exon 19 deletion, was associated with shorter PFS/rwPFS (HR 1.62, 95% CI 1.39–1.90) and worse OS/rwOS (HR 1.63, 95% CI 1.40–1.88), with consistent estimates across sensitivity analyses. Eastern Cooperative Oncology Group performance status ≥ 2, central nervous system/brain metastasis, and liver metastasis were associated with poorer outcomes. The OS/rwOS association for liver metastasis was sensitive to alternative estimate selection. Evidence for bone metastasis and programmed death-ligand 1 expression was less robust. Evidence-tier assessment identified EGFR L858R, ECOG PS ≥ 2, and CNS/brain metastasis as high-certainty adverse prognostic factors. Liver metastasis was supported by moderate certainty for PFS/rwPFS but lower certainty for OS/rwOS. TP53 mutation, PD-L1 expression, and bone metastasis were lower-certainty or exploratory findings. These findings support future integrated prognostic models, but do not establish criteria for selecting intensified first-line therapy over osimertinib monotherapy.