This retrospective cohort study included 90 patients diagnosed with NSCLC and L-BM between 2017–2022 at a single institution, all of whom received immunotherapy. Patients with a non-NSCLC primary tumor or without brain metastases were excluded. Kaplan-Meier analysis was used to assess median overall survival (mOS), and t-tests compared mOS across demographic, molecular, and disease characteristics.

Median overall survival was 362.15 days among uncensored patients. Female patients survived significantly longer than males (605.30 vs. 291.64 days, p=0.026). White patients trended toward longer survival than Black patients (432.24 vs. 381.94 days, p=0.22). PD-L1 positivity (>1%) was associated with longer but non-significant survival versus PD-L1–negative tumors (527.18 vs. 326.87 days, p=0.11). Patients with a single brain metastasis survived significantly longer than those with multiple lesions (p<0.001). Those with targetable mutations (EGFR or ALK) demonstrated longer survival than PD-L1–only or wildtype patients, suggesting an advantage from prior targeted therapy or multi-line treatment exposure. However, survival did not differ between targetable mutation and PD-L1–only groups, reflecting limited intracranial efficacy of immune checkpoint blockade post–targeted therapy.

In NSCLC patients with brain metastases treated with immunotherapy, targetable mutations conferred a modest survival benefit overall but not among those previously exposed to targeted therapies. These findings highlight the need to clarify the role and optimal sequencing of immunotherapy in patients with targetable mutations and L-BM, and suggest lesion burden and sex remain important prognostic factors.