Afatinib Versus Osimertinib for Non‐Small Cell Lung Cancer With Uncommon <scp>EGFR</scp> Mutations: Real‐World Outcomes

Non-small cell lung cancers (NSCLC) harboring uncommon epidermal growth factor receptor (EGFR) mutations (UMs) are clinically heterogeneous, and the optimal first-line EGFR tyrosine kinase inhibitor (EGFR-TKI), as well as the role of subsequent immune checkpoint inhibitor (ICI)-based regimens, remains uncertain. We conducted a multicenter retrospective cohort study including patients with advanced or recurrent non-squamous NSCLC harboring UMs who received first-line afatinib or osimertinib between January 2015 and January 2024 at 29 hospitals in Japan, excluding exon 20 insertions and de novo T790M mutations. Inverse probability of treatment weighting adjusted baseline imbalances, and post-EGFR-TKI treatment patterns were evaluated. Among 162 patients (afatinib, n = 95; osimertinib, n = 67), weighted analyses demonstrated no significant differences in time to treatment failure (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.61-1.77) or overall survival (HR, 1.34; 95% CI, 0.73-2.44). Afatinib was associated with higher response rates and more frequent adverse events requiring dose reduction. Subgroup analyses suggested differential treatment effects according to mutation subtype, with osimertinib favoring L861X mutations and afatinib favoring compound mutations. Among 56 patients who received subsequent systemic therapy, clinical outcomes were comparable between ICI plus platinum doublet and platinum doublet alone. These findings indicate that afatinib and osimertinib provide comparable survival outcomes as first-line therapies for NSCLC with UMs, with treatment effects varying by molecular subtype, while subsequent ICI-based regimens may confer limited additional benefit.