Venous thromboembolism and bleeding in advanced melanoma: a propensity-matched cohort analysis comparing first-line immunotherapy and targeted therapy.

BACKGROUND: Venous thromboembolism (VTE) is a leading cause of morbidity in cancer. Immune checkpoint inhibitors and BRAF/MEK-targeted therapy (BRAF/MEKi) are competing first-line options for advanced melanoma, but their comparative thrombotic and bleeding risks remain poorly characterized. OBJECTIVES: To compare VTE and bleeding outcomes between first-line ipilimumab/nivolumab (Ipi/Nivo) and BRAF/MEKi in advanced melanoma. METHODS: We conducted a retrospective cohort study using the TriNetX federated electronic health record network. Adults with advanced melanoma initiating Ipi/Nivo or BRAF/MEKi were matched 1:1 by propensity score matching. The primary outcome was composite VTE (pulmonary embolism or deep vein thrombosis) at 6 months; secondary outcomes included bleeding events and all-cause mortality. Hazard ratios (HRs) with 95% CIs were estimated using Cox proportional hazards models. RESULTS: After 1:1 matching, 1043 patients per group were included, with well-balanced covariates. Ipi/Nivo was associated with significantly higher 6-month composite VTE (7.0% vs 4.1%; HR, 1.76; 95% CI, 1.19-2.61; P = .004), pulmonary embolism (5.0% vs 2.8%; HR, 1.89; 95% CI, 1.17-3.04; P = .008), and deep vein thrombosis (3.2% vs 1.7%; HR, 1.91; 95% CI, 1.04-3.50; P = .03). No significant differences were observed in composite bleeding (HR, 1.07; 95% CI, 0.79-1.45; P = .65), intracranial hemorrhage, or gastrointestinal bleeding. Six-month all-cause mortality was numerically higher with Ipi/Nivo but did not reach statistical significance (18.9% vs 16.1%; HR, 1.22; 95% CI, 0.99-1.51; P = .06). CONCLUSION: First-line Ipi/Nivo appears to be associated with a higher VTE risk compared with BRAF/MEKi in advanced melanoma, without a concomitant increase in bleeding. These hypothesis-generating findings support prospective evaluation of thromboprophylaxis strategies in Ipi/Nivo-treated patients.