Pathophysiology, diagnosis and management of cardiac toxicity induced by immune checkpoint inhibitors and BRAF and MEK inhibitors

•Cardiotoxicity, in particular myocarditis, induced by ICI is rare (1%) but potentially lethal.•BRAFi/MEKi inhibitors may induce reduction in left ventricular ejection fraction (5–11%), hypertension (11–30%) or QT interval prolongation (0–5%)•Shared epitopes between melanoma cells and cardiac tissue might underlie ICIs induced myocarditis.•BRAFi/MEKi induced cardiotoxicity is often reversible upon treatment discontinuation or dose adaptation.•Treatment of ICI induced myocarditis mainly relies on high dose corticosteroids, steroid refractory cases are difficult to manage.•A rapid, multidisciplinary diagnostic work-up and treatment is essential to improve patient outcome. Immune checkpoint inhibitors (ICIs) and BRAF and MEK inhibitors (BRAFi/MEKi) have drastically improved the outcome of melanoma patients. ICIs can induce myocarditis, a rare immune related adverse event (irAE) with an estimated lethality of 50%. BRAFi/MEKi may induce left ventricular ejection fraction decrease, hypertension or QT interval prolongation. While the BRAFi/MEKi induced cardiotoxicity is often reversible upon treatment discontinuation or dose adaptation and symptomatic therapy is often sufficient to restore cardiac function, the treatment of ICI-induced myocarditis mainly relies on high dose corticosteroids. There is no established therapy for steroid resistant myocarditis, yet various drugs have been reported to improve outcome. Shared epitopes between melanoma cells and cardiac tissue are thought to underlie the development of ICIs induced myocarditis. The mechanism of BRAFi/MEKi induced cardiotoxicity appears to be related to the Ras-Raf-MEK-ERK pathway in cardiomyocyte repair, survival and proliferation. With the emerging application of ICI-BRAFi/MEKi combinations, so called triplet therapies, differentiating between these two types of cardiotoxicity will become important for appropriate patient management. In this article we provide a summary of the existing literature on the pathophysiology, diagnosis and management of cardiotoxicity of melanoma therapies.