ABSTRACT 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/mm 2 ), 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.
Srour et al. (Fri,) studied this question.