Stereotactic Radiosurgery (Srs) With Immune Checkpoint Inhibitor Therapy (Ici) For Patients With Brain Metastasis (Bm): The Impact Of Timing And Sequencing

The optimal timing and sequencing of ICI in patients with BM undergoing SRS is not adequately defined. We analyzed objective response rates in patients receiving ICI and SRS in order to determine sequencing and timing predictors for maximal intracranial control. BM patients who underwent SRS and received ICI (PD1 or PDL1 inhibitor) were divided into three cohorts based on the timing of receipt of therapy: any therapy, “concurrent” (+/- ≤5 half-lives), or “immediate” (+/- one half-life) ICI. The primary outcome was magnitude of best objective lesion-specific response (BOR) (unidimensional RECIST). Secondary outcomes included the proportion of lesions achieving RECIST-defined complete (CR) or partial responses (PR), or stable (SD) or progressive disease (PD); response durability; rate of adverse radiation effects; and overall survival. Multivariable linear regression analysis for BOR was conducted on a per-lesion basis. A total of 150 patients underwent SRS to 1003 brain metastases and received ICI during the course of their disease: 564 of the lesions (56%) were treated with SRS and "concurrent" ICI. A total of 1,073 brain MRIs were reviewed, resulting in 5,508 measurements (average of 5.5 measurements per lesion, Range: 2-26). Lesions treated with SRS and “concurrent” ICI demonstrated superior BOR, overall objective response, and durable response. These findings were most pronounced among lesions treated with "immediate" ICI (BOR: -100 vs. -57%, p<0.001; CR: 50 vs. 32%; 6-month durable response: 89 vs. 74%, p<0.001; 12-month durable response: 94 vs. 71%, p<0.001). Among lesions with 12 months of follow-up (293, 29%), those treated with "immediate" ICI had a markedly improved CR rate (85 vs. 43%, p<0.001) and significantly reduced PD rate (4 vs. 19%, p<0.001). After adjusting for confounding covariates, “concurrent” ICI was associated with a 6 % improvement in BOR (p=0.040) and “immediate” ICI with a 11% improvement in BOR (p<0.001). Pre-exposed ICI lesions treated with SRS had poorer BOR (-45%) compared to ICI naive lesions (-63%, p<0.001), with the best response rates observed in ICI naive lesions receiving SRS and "immediate" ICI (-100%, p<0.001) with no added benefit to "immediate" neoadjuvant ICI (-100%, p=0.52). Significant differences in response rates were observed across primary tumor histologies and different ICI agents. The 24-month cumulative incidence of adverse radiation effects with death as a competing risk was low among patients receiving "concurrent" (3.3%) or "immediate" ICI (3.6%). This study demonstrates that the timing of ICI and SRS in patients with brain metastasis is associated with overall response, best response, and durability of response with the most substantial effect in ICI naive patients undergoing "immediate" combined modality therapy, which is also tolerated well. Further analysis will help to individualize strategies for the optimal sequencing of systemic therapy based on tumor histology and the selected agent.