Observational Study Assessing Survival Outcomes In Advanced Melanoma Patients With Brain Metastases Treated With Immunotherapy With Or Without Radiotherapy: Effect Of Radiotherapy Sequence And Modality.

Abstract Introduction In metastatic melanoma, brain metastases (bmets) are an important cause of death. Standard treatment of asymptomatic bmets consists of systemic therapy with checkpoint inhibitors (CPI) or targeted therapy, whereas local control with surgery or radiotherapy (RT) is typically added for symptomatic bmets. It has been reported that the addition of RT to CPI leads to better clinical outcomes. This study assessed the potential benefit of RT, RT modality, and timing in patients who also receive CPI using real-world data (RWD). Approach This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database (January 2011-April 2019). It included melanoma (MEL) patients with histologically confirmed stage III or IV disease at diagnosis, treated with CPI (ipilimumab, nivolumab, pembrolizumab, and/or a combination) and with documented metastasis to the brain prior to or during the first line of therapy with such treatment. Patients who received CPI in the adjuvant setting were excluded. Patients (N=531) were identified as: 1) CPI alone (N=70), 2) sequential RT-CPI (RT followed by CPI within 4 weeks and 3 months, N=96), and 3) Concurrent RT-CPI (N=365). Of patients receiving RT, 65.9% received SRS and 34.1% WBRT. The sequential RT-CPI group was balanced (49% SRS, 51% WBRT) whereas the concurrent RT-CPI group received mostly SRS (70.4%). The index date was defined as the latest of start date for CPI or RT after the first brain met diagnosis. Associations with survival outcomes were assessed through multivariable Cox regression analysis. Results The addition of RT to CPI, or the timing of RT relative to CPI did not significantly impact overall survival (OS) or progression free survival (PFS) in multivariable models. Focusing on the type of RT added to CPI, median OS was significantly longer among patients who received SRS compared to WBRT (19.3 and 3.4 months, respectively; log-rank p-value < 0.001). The median OS of patients receiving only CPI alone was also 3.4 months, suggesting minimal survival benefit from WBRT. SRS maintained significance vs WBRT in multivariable Cox analysis adjusting for patient and treatment covariates (adj HR=0.34, 95% CI 0.26-0.45). Similarly, median PFS was significantly longer for patients receiving SRS compared to WBRT (3.3 vs 2.3 months; log-rank p-value < 0.001) and SRS was associated with lower risk of progression or death (adj HR=0.65, 95% CI 0.52-0.83). The timing of SRS relative to CPI (sequential vs concurrent) did not show significant association with OS or PFS. Conclusions The results suggest that combined SRS-CPI therapy significantly improves the outcome of CPI; however they must be considered along with the limitations of RWD, mainly selection bias owing to physician preference and disease severity. Importantly, this study was not designed to compare CPI modalities. The potential of SRS-CPI warrants further exploration in clinical trials, including the timing of SRS around CPI. Citation Format: Nataly Manjarrez Orduno, Xiao Shao, Charlie Garnett-Benson, Jasmine Rizzo, Rebecca Moss, Trong Le, Christos Hatzis. Observational study assessing survival outcomes in advanced melanoma patients with brain metastases treated with immunotherapy with or without radiotherapy: Effect of radiotherapy sequence and modality [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-045.