Mechanistic and Clinical Overview Cardiovascular Toxicity of BRAF and MEK Inhibitors

Rapidly accelerated fibrosarcoma B-type (BRAF) and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors have revolutionized melanoma treatment. Approximately half of patients with melanoma harbor a BRAF gene mutation with subsequent dysregulation of the RAF-MEK-ERK signaling pathway. Targeting this pathway with BRAF and MEK blockade results in control of cell proliferation and, in most cases, disease control. These pathways also have cardioprotective effects and are necessary for normal vascular and cardiac physiology. BRAF and MEK inhibitors are associated with adverse cardiovascular effects including hypertension, left ventricular dysfunction, venous thromboembolism, atrial arrhythmia, and electrocardiographic QT interval prolongation. These effects may be underestimated in clinical trials. Baseline cardiovascular assessment and follow-up, including serial imaging and blood pressure assessment, are essential to balance optimal anti-cancer therapy while minimizing cardiovascular side effects. In this review, an overview of BRAF/MEK inhibitor–induced cardiovascular toxicity, the mechanisms underlying these, and strategies for surveillance, prevention, and treatment of these effects are provided.

The prognosis for patients with metastatic cutaneous melanoma has, historically, been very poor.
Immunotherapy and targeted therapies have transformed the outlook for many of these patients. 2 These options are now available for the palliative treatment of patients with unresectable stage III or stage IV (metastatic) disease and as adjuvant therapy, with curative intent, after complete resection of stage III disease. 2,3 Activating mutations of the rapidly accelerated fibrosarcoma B-type (BRAF) gene are found in approximately 60% of cutaneous melanomas, 4 and the therapeutic potential of BRAF inhibition has been harnessed. Vemurafenib, the first BRAF inhibitor approved for the treatment of melanoma, was associated with a 63% reduction in the risk of death compared with dacarbazine chemotherapy. 5 However, inhibition of BRAF alone was asso- resistance, limiting the benefits of this intervention, even in patients whose disease was initially sensitive to the drugs. 12 13 delays the emergence of resistance, and is associated with prolonged progression-free and overall survival when compared with BRAF inhibitor monotherapy ( Table 2). [14][15][16] While immunotherapy with T cell checkpoint in- treatment responses tend to be more rapid than those achieved using immunotherapy. 17 Patients may ultimately receive both treatments. 17  Hypertension and LVSD are most common, and incidence is higher with combination therapy.
Understanding the incidence and mechanisms of BRAF/MEK inhibitor-associated cardiovascular toxicity will aid the refinement of strategies for cardiotoxicity prevention and treatment. ing artery than wild-type mice. 45 Although the role of ERK pathway activation in cardioprotection has been studied extensively, the precise mechanism by which it evokes this effect is less well understood and is likely to involve multiple processes. This may include interleukin-10 activation of ERK1/2 to inhibit tumor necrosis factor-a-induced apoptosis, 46   The Ras-RAF-MEK-ERK pathway interacts with VEGF, fibroblast growth factor, and platelet- in trials has been defined using the Common Terminology Criteria for Adverse Events (CTCAE) definitions. 53 To meet CTCAE definitions of ejection fraction decreased, the LVEF must be below 50% and with at least a 10% decline from baseline assessment. However, the CTCAE also includes separate (and frequently overlapping) criteria for symptomatic heart failure as well as another category for LVSD.  57 For all of these reasons, the reported incidence of LVSD or heart failure is likely to be an underestimate of the "real-world" population. Long-term follow-up is absent, and patients with asymptomatic cardiovascular toxicity may be underrecognized. This is an increasing concern as patients with cancer now survive longer and receive treatment over longer periods, especially as these medications are increasingly used with curative intent in the adjuvant setting, in which many patients will have near normal life expectancy.
An asymptomatic decline in LVEF of $10% to an absolute value of <50% is considered to be evidence of cardiotoxicity. A decline in LVEF by <10% from baseline and to 40% to 49% may also reflect cardiotoxicity but the diagnostic certainty of this is less clear, unless accompanied by an associated worsening in LV global longitudinal strain by >15% from baseline. We recognize that this echocardiographic measurement is not routinely performed in all centers but strongly encourage its use. Any new reduction in LVEF to <40% or the development of symptoms or signs of heart failure is considered to be "severe" cardiotoxicity. These definitions are in keeping with a recent consensus statement from the International Cardio-Oncology Society. 70 The safety of BRAF inhibitor and MEK inhibitor use in patients with a baseline LVEF that is either below 50% or the institutional lower limit of normal has not been established and therefore these drugs should be used with caution for this patient group. [63][64][65][66][67][68] We propose a pathway for the management of BRAF inhibitor-and MEK inhibitor-associated LVSD ( Figure 2). Importantly, these suggestions are made in the absence of international guidelines, evolved from previous management algorithms, 10           The combination of BRAF inhibitor/MEK inhibitor with immunotherapy may be a therapeutic option to reduce immune-mediated resistance in BRAFmutated melanoma.
Ongoing phase 3 trials are essential to inform treatment strategy and characterize the adverse effects of combination treatment.