Intracranial outcomes of dual immune-checkpoint inhibition and srs combination in patients with melanoma and nsclc brain metastases

Abstract INTRODUCTION The intracranial benefit of offering dual immune checkpoint inhibition (D-ICPI) with ipilimumab and nivolumab to melanoma and non-small cell lung cancer (NSCLC) patients receiving SRS for brain metastases is unknown. We hypothesized that D-ICPI improves local control compared to SRS alone. METHODS Melanoma and NSCLC patients treated with SRS between 2016-2022 were evaluated. Patients were stratified by treatment with D-ICPI, single ICPI (S-ICPI), or SRS alone. Local recurrence (LR), intracranial progression (IP), and overall survival (OS) were estimated using competing risk and Kaplan-Meier analyses. IP included both local and distant intracranial recurrence. RESULTS 288 patients (44% melanoma, 56% NSCLC) with 1,704 brain metastases were included. 53% of patients had symptomatic metastases. Median follow up was 58.8 months. Patients were treated with D-ICPI (28%), S-ICPI (45%), or SRS alone (27%). 12-month local control rates with D-ICPI, S-ICPI, and SRS alone were 94.73% (95%CI:91.11-96.90%), 91.72% (89.29-93.64%), and 88.22% (84.06-91.41%). Only D-ICPI was significantly associated with reduced LR (p = 0.0032). 173 patients (60%) developed IP. The 12-month cumulative incidence of IP was 41.27% (95%CI:30.27-51.92%), 51.86% (42.78-60.19%), and 57.15% (44.98-67.59%) following D-ICPI, S-ICPI, and SRS alone. On competing risk analysis, only D-ICPI was significantly associated with reduced IP (p = 0.0408). On multivariate Cox regression, D-ICPI (HR:0.595,95%CI:0.373-0.951,p = 0.0300) and presentation with >10 BMs (2.492,1.68-3.725,p < .0001) remained significantly correlated with IP. Median OS following D-ICPI, S-ICPI, and SRS alone was 26.1 (95%CI:15.5-40.7), 21.5 (16.5-29.6) and 17.5 (11.3-23.8) months. Only D-ICPI trended toward improved OS (p = 0.0772). S-ICPI, fractionation, and timing of immunotherapy were not predictive of clinical outcomes. CONCLUSIONS The addition of D-ICPI for melanoma and NSCLC patients undergoing SRS is associated with improved local and intracranial control. This appears to be an effective strategy, including for symptomatic brain metastasis patients, regardless of fractionation or immunotherapy timing. Toxicity with this combination should be evaluated and balanced against clinical benefits.