Melanoma Brain Metastasis, Prognostic Factors, and Survival Outcomes After First Metastatic Line Therapy: A...

Brain metastases (BMs) are a major cause of mortality in patients with melanoma. We conducted a retrospective observational study to identify prognostic factors for BM development and to evaluate the impact of first-line systemic therapy on BM occurrence and survival outcomes in patients with advanced melanoma. A total of 258 patients with unresectable Stage III or IV melanoma without BM at diagnosis were included and followed for BM occurrence. During a median follow-up of 8.7 years (95% CI, 7.0-10.6), 100 patients (38.8%) developed BM. Patients who developed BM were younger (median age 60.5 vs. 66 years; p = 0.008) and more frequently harbored a BRAF V600E/K mutation (51.4% vs. 48.6%; p < 0.001) compared with patients without BM, whereas ulceration status was similar between groups (p = 0.525). A mitotic rate ≥ 1 was more frequently observed in patients with BM (67.7% vs. 31.3%; p = 0.044). In multivariable logistic regression analyses, a high mitotic rate (≥ 6/mm²), BRAF V600 mutation, and AJCC stage IV M1b disease were independently associated with an increased risk of BM. The effect of first-line systemic therapy on BM was further assessed using Fine-Gray competing-risk models and cause-specific Cox models with a 12-week landmark analysis. Compared with combination immune checkpoint inhibitors (ICIs), first-line chemotherapy was independently associated with a markedly higher risk of BM, whereas targeted therapy showed a strong but non-significant association. Tumor-related factors, including AJCC stage IV M1b disease, high mitotic rate, and BRAF V600 mutation, remained independently associated with BM across competing-risk and cause-specific analyses. In cause-specific Cox models, chemotherapy, advanced disease stage, high mitotic rate, and BRAF V600 mutation were associated with poorer BM-free survival. In our study, the BRAF V600 mutation appears to be an independent and strong prognostic factor for BM, regardless of systemic treatment received in the metastatic setting. First-line combination ICIs significantly reduce the risk of BM and improve survival outcomes.