Cardiotoxicity in patients with metastatic melanoma treated with BRAF/MEK inhibitors: a real-world analysis of incidence, risk factors, and reversibility

Background: BRAF/MEK inhibitors (BRAFi/MEKi) improve outcome in patients with BRAF-mutated metastatic melanoma but are associated with cardiotoxicity, leading to a decline in left ventricular ejection fraction (LVEF). This study aimed to evaluate the incidence, timeline, risk factors, and reversibility of BRAFi/ MEKi-induced cardiotoxicity in a real-world setting. Patients/materials and methods: Patients with metastatic melanoma (n = 170) treated with Encorafenib/ Binimetinib, Vemurafenib/Cobimetinib, or Dabrafenib/Trametinib at Aarhus and Odense University Hospital, Denmark, from 2015 to 2023 were included. Cardiac function was assessed at baseline and every 3 months during treatment with either echocardiograms or multigated acquisition scans. Cardiotoxicity was defined as a reduction of LVEF by >= 10 percentage points (pp) to an LVEF < 50% (Major cardiotoxicity) ora reduction of LVEF by >= 15 pp but remaining > 50%(Minorcardiotoxicity). Results: Cardiotoxicity occurred in 21% of patients, with 14% experiencing major cardiotoxicity. The mean time to LVEF decline was 187 days, with 92% of major cardiotoxicity cases occurring within the first year. Cardiotoxicity was reversible in 79% of patients following dose reduction, treatment pauses, heart failure therapy, or continued treatment with monitoring. Baseline atrial fibrillation (odds ratio 13.67, p = 0.008) was identified as a risk factor for major cardiotoxicity. Interpretation: BRAFi/MEKi-induced cardiotoxicity is a significant but manageable complication, often reversible with timely interventions. Routine LVEF monitoring is recommended. The majority (92%) of major cardiac events were diagnosed within the first year of treatment, which might warrant a discontinuation of routine LVEF monitoring after 1 year of BRAFi/MEKi treatment.