The response of brain metastases (BM) treated with stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI; PD(L)-1) is of significant interest.

Patients were divided into cohorts based on ICI sequencing around SRS. The primary outcome was best objective lesion-specific response (BOR). Secondary outcomes included overall objective response (OOR), response durability, radiation necrosis (RN), and overall survival (OS).

150 patients underwent SRS to 1003 BM and received ICI. 564 lesions (56%) treated with concurrent ICI (±5 half-lives) demonstrated superior BOR, OOR, and response durability compared to lesions treated with SRS and delayed ICI. Responses were best in those treated with immediate (±1 half-life) ICI (BOR: -100 vs. -57%, p<0.001; complete response: 50 vs. 32%; 12-month durable response: 94 vs. 71%, p<0.001). Lesions pre-exposed to ICI and treated with SRS had poorer BOR (-45%) compared to ICI naive lesions (-63%, p<0.001); best response was observed in ICI naive lesions receiving SRS and immediate ICI (-100%, p<0.001). The 12-month cumulative incidence of RN with immediate ICI was 3.2% (95% CI: 1.3-5.0%). First radiographic follow-up and best intracranial response were significantly associated with longer OS; steroids were associated with inferior response rates and poorer OS (median 10 vs. 25 months, p=0.002).

Sequencing of ICI around SRS is associated with overall response, best response, and response durability, with the most substantial effect in ICI naive BM undergoing immediate combined modality therapy. First intracranial response for patients treated with immediate ICI and SRS may be prognostic for OS, whereas steroids are detrimental.