Deciphering the Role of Combination Therapy of Cobimetinib, Vemurafenib, and Antidepressant Drugs in QTc Prolongation and Torsade De Pointes (TDP) in Malignant Melanoma

Abstract

combination of MEK inhibitors (cobimetinib and trametinib), and BRAF inhibitors (vemurafenib and dabrafenib) is now considered as the first-line treatment of patients with BRAF V600-mutated metastatic melanoma. The common side-effects of BRAF inhibitors are cutaneous toxicity, nephrotoxicity, and cardiotoxicity.1 In a previous clinical study, the combined administration of vemurafenib and cobimetinib has been associated with cardiotoxicity (heart failure) and QTc prolongation, that persisted after the discontinuation of therapy but returned to normal after six months. The patient was discharged with an implantable intracardiac defibrillator (ICD) for safety.2 Most TKIs significantly increase the QT interval, while the incidence of arrhythmias was noted highest in vemurafenib.3 Additionally, vemurafenib might induce severe acute renal failure, including persistent renal injury.4 Though, the result from the previous clinical study which was based on 38 patients, showed that the adjunction of MEK inhibitor to vemurafenib in the treatment of metastatic melanoma reduces the incidence and severity of nephrotoxicity compared to monotherapy in a study of 38 patients, while a phase IB dose-escalation study of the cobimetinib and duligotuzumab showed that the 26% of the patients experienced hypokalemia, further indicating cobimetinib which might have some adverse effects on the renal tubular system.5,6 J Oncol Sci.2020;6(2):123-6