Simple SummaryUp to 50% of patients diagnosed with advanced melanoma develop brain metastases during the course of their disease. The prognosis of melanoma patients is heavily affected by the presence of brain metastases. Unfortunately, there is a lack of data on prognostic factors for these patients. Many of these patients are treated with immune checkpoint inhibitors. Therefore, the aim of our study was to identify prognostic factors in melanoma patients with brain metastases treated with immune checkpoint inhibitors. In a population of 1278 advanced melanoma patients, we found that serum lactate dehydrogenase levels were the strongest clinical parameter associated with survival. This information is useful for both doctors and patients to provide more insight into patients’ prognoses.AbstractThe efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced melanoma that develop brain metastases (BM) remains unpredictable. In this study, we aimed to identify prognostic factors in patients with melanoma BM who are treated with ICIs. Data from advanced melanoma patients with BM treated with ICIs in any line between 2013 and 2020 were obtained from the Dutch Melanoma Treatment Registry. Patients were included from the time of the treatment of BM with ICIs. Survival tree analysis was performed with clinicopathological parameters as potential classifiers and overall survival (OS) as the response variable. In total, 1278 patients were included. Most patients were treated with ipilimumab–nivolumab combination therapy (45%). The survival tree analysis resulted in 31 subgroups. The median OS ranged from 2.7 months to 35.7 months. The strongest clinical parameter associated with survival in advanced melanoma patients with BM was the serum lactate dehydrogenase (LDH) level. Patients with elevated LDH levels and symptomatic BM had the worst prognosis. The clinicopathological classifiers identified in this study can contribute to optimizing clinical studies and can aid doctors in giving an indication of the patients’ survival based on their baseline and disease characteristics.