Abstract
INTRODUCTION: Patients with NSCLC and brain metastases have a poor prognosis. Combining brain-directed radiation therapy (RT) with immune checkpoint inhibitors (ICIs) may be synergistic. Nevertheless, predictors of response and toxicity are lacking. METHODS: This retrospective study conducted at Dana-Farber Brigham Cancer Center from 2015 to 2023 included patients with non-EGFR and non-ALK-altered NSCLC and newly diagnosed brain metastases starting ICI within 90 days of brain-directed RT. We assessed all-cause mortality, systemic and neurologic death, systemic and intracranial progression at the patient level, and local recurrence and radiation necrosis at the metastasis level. RESULTS: Among the 178 patients with 536 brain metastases, the median age was 64 years, and 53% were female individuals. The median number of brain metastases detected at diagnosis was three. Most patients received pembrolizumab (93%) and were treated with stereotactic radiation (81%). Higher programmed death-ligand 1 (PD-L1) expression was associated with improved all-cause mortality (median survival: PD-L1 less than 1%: 10.7 mo, 1%-49%: 14.3 mo, more or equal to 50%: 29.5 mo), driven by longer time to systemic death. Higher PD-L1 was also associated with improved systemic progression-free survival (p (≥50% versus <1%) = 0.02) and distant intracranial disease-free survival (p (≥50% versus <1%) = 0.02). The rate of local recurrence was low across all groups (1%-4% at 2 y). Patients with higher PD-L1 had numerically higher radiographic radiation necrosis rates (2.3%, 5.5%, 9.3% at 2 y for PD-L1 <1%, 1%-49%, and ≥50%, respectively, p (≥50% versus <1%) = 0.08) and significantly higher symptomatic radiation necrosis rates (p (≥50% versus <1%) = 0.04). CONCLUSIONS: The combination of brain-directed RT and ICI is effective in treating patients with NSCLC and brain metastases. Although high PD-L1 levels are associated with longer survival and improved intracranial control, radiation necrosis occurs more frequently in patients with high PD-L1 expression. Clinicians should be aware of long-term treatment-related toxicities in this population.