The impact of sequencing PD-1/PD-L1 inhibitors and stereotactic radiosurgery for patients with brain metastasis

Background. The response of brain metastases (BM) treated with stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICIs; programmed cell death 1 and its ligand) is of significant interest. Methods. Patients were divided into cohorts based on ICI sequencing around SRS. The primary outcome was best objective response (BOR) that was lesion specific. Secondary outcomes included overall objective response (OOR), response durability, radiation necrosis (RN), and overall survival (OS). Results. One hundred fifty patients underwent SRS to 1003 BM and received ICI. Five hundred sixty-four lesions (56%) treated with concurrent ICI (+/- 5 half-lives) demonstrated superior BOR, OOR, and response durability compared with 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 with 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 mo, P = 0.002). Conclusions. 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. Importance of the Study Recent reports have demonstrated modest efficacy of treatment with programmed cell death 1 (PD-1) or its ligand (PD-L1) inhibitors alone for select patients with BM. To our knowledge, this report represents the largest study to date of patients treated with SRS and ICI at varying intervals, evaluating over 1000 brain metastases with multiple objective lesion-specific and patient-specific response and toxicity outcomes. We found that responses were best in immunotherapy naive patients treated with SRS and immediate PD-1 or PD-L1 inhibitors, with extremely high response rates and sustained response durability in this cohort. Furthermore, we found that these responses directly correlated with survival. An added novel finding of this study was that steroid use lessened response rates. Therefore, given the results of this study, it is important to remain cognizant of the high response rates of optimally sequenced combined modality therapy when selecting patients for treatment with systemic therapy alone.