PD-1/ PD-l1 Inhibitors and Stereotactic Radiosurgery for Brain Metastases: a systematic review and meta-analysis.

Abstract

PurposeStereotactic radiosurgery (SRS) is the treatment of choice for limited brain metastases (BM), and its combination with PD-1/PD-L1 inhibitors is hypothesized to offer synergistic therapeutic benefits. However, there are concerns regarding augmented risk of radiation-induced brain necrosis (RIBN). This systematic review and meta-analysis evaluate the efficacy and toxicity profile of PD-1/PD-L1 inhibitors combined with SRS or fractionated stereotactic radiotherapy (FSRT).MethodsFour databases were screened, Embase, Web of Science, PubMed and Scopus from inception to November 2025. Primary outcomes were overall survival (OS), extracranial and distant intracranial progression free survival (PFS), and local control (LC). A subgroup analysis was performed based on the primary metastasis origin and radiotherapy treatment modalities. We extracted RIBN events and grade ≥ 3 neurological events. A single-arm meta-analysis was performed using the random-effects modeling. This review protocol was registered on November 2025 on PROSPERO (ID CRD420251171879).ResultsThirty-four studies were included, published between 2016 and 2025 comprising 2,587 patients with BM. The pooled one-year OS was 65% (95% CI 60-69). Patients with BM from Non-Small Cell Lung Cancer (NSCLC) had one-year OS (68%) while melanoma BM had OS (61%). LC and distant intracranial PFS at one year were 87% (95% CI 79-92) and 40.23% (95% CI 17.99-62.47), respectively. The cumulative incidence (CI) of grade 3 RIBN was 5% (95% CI 3-8), and grade ≥ 3 neurological events occurred in 7% (95% CI 4-13). No statistically significant difference in RIBN rates was found between melanoma and NSCLC primaries subgroup.ConclusionThe combination of SRS/FSRT with PD-1/PD-L1 inhibitors is associated with favorable intracranial PFS and LC and a tolerable toxicity profile, with relatively lower rates of grade 3 RIBN. These findings support the feasibility of this combined modality in the immunotherapy era. However, definitive conclusions regarding the incremental risk of RIBN require future prospective trials.