Opportunities and challenges for non-small cell lung cancer brain metastases in the immunotherapy era.

Brain radiotherapy (BRT) has traditionally been the mainstay of treatment for non-small cell lung cancer brain metastases (NSCLC-BM), given the low intracranial efficacy of conventional systemic therapies. In recent years, immune checkpoint inhibitors (ICIs) have emerged as a standard treatment for advanced NSCLC without actionable driver mutations and have shown promising benefits in patients with BM. However, their intracranial efficacy remains modest, as the highest reported intracranial objective response rate and median intracranial progression-free survival in first-line populations reaching only 56.3 % and 12.7 months, respectively, which is likely explained by restricted blood-brain barrier permeability, the immunosuppressive tumor microenvironment within BM, and both primary and acquired resistance to ICIs. Preclinical evidence suggests that BRT can synergize with ICIs by enhancing antitumor immunity and overcoming immune resistance, primarily through blood-brain barrier disruption and tumor microenvironment remodeling. Consistently, encouraging clinical outcomes have been reported with the combination of BRT and ICI (BRT-ICI) in NSCLC-BM, while prospective data remain scarce. A recent phase II trial reported some of the most favorable outcomes to date with BRT-ICI plus chemotherapy, showing an intracranial objective response rate of 82.5 %, a median intracranial progression-free survival of 16.1 months, and a median overall survival of 20.9 months in treatment-naive patients with NSCLC-BM. Despite these advances, the optimal schedule of BRT-ICI remains controversial, with ongoing debates on treatment sequencing, timing, and radiation dose-fractionation. Additionally, critical challenges persist, including the risk of neurological toxicity, particularly radiation necrosis, and the absence of predictive biomarkers for patient selection. This review summarizes the current advances in ICI-based systemic therapies for NSCLC-BM, discusses the existing opportunities and progress of BRT-ICI, and reflects on challenges in optimizing this strategy in the immunotherapy era.