Clinical Outcomes of Later‐Generation EGFR ‐ TKIs for Uncommon EGFR Mutations in NSCLC : A Multicenter Real‐World Study

ABSTRACT Background Uncommon EGFR mutations, including G719X, L861Q, S768I, and compound mutations, present therapeutic challenges due to limited prospective evidence and variable drug sensitivity. Although later‐generation (i.e., second‐ and third‐) EGFR‐TKIs have shown benefit in some subtypes, real‐world data is limited. Methods We retrospectively analyzed patients with advanced or recurrent NSCLC harboring uncommon EGFR mutations diagnosed between 2014 and 2019 at Keio University Hospital and affiliated hospitals. Clinical data were updated through May 2023. EGFR mutations were detected using commercial assays. Common mutations and exon 20 insertions were excluded unless coexisting as compound mutations. Survival outcomes were estimated using the Kaplan–Meier method and compared by log‐rank test; hazard ratios were calculated using the Cox proportional hazards model. Swimmer plots depicted treatment duration by subtype and EGFR‐TKI agents. Results Among 35 patients, G719X was the most frequently detected mutation, followed by L861Q and S768I. In addition to these single mutations, various compound mutations involving combinations of G719X, L861Q, S768I, and other rare variants were also observed. While first‐generation EGFR‐TKIs were frequently used initially, 71% of patients eventually received a later‐generation EGFR‐TKI. These patients had significantly longer OS (47.7 vs. 15.5 months; p = 0.0177). Multivariate analysis identified non‐use of later‐generation EGFR‐TKIs, liver metastases, and poor performance status as independent poor prognostic factors. Afatinib showed favorable treatment duration in G719X and compound mutations. Conclusions Later‐generation EGFR‐TKIs were associated with improved outcomes in patients with uncommon EGFR mutations, with afatinib showing favorable treatment duration in G719X and compound subtypes.