Concomitant administration of cobimetinib with strong or moderate CYP3A inducers should be avoided, as should strong inhibitors and strong inducers of CYP3A4 or CYP2C8 with dabrafenib and vemurafenib. 1,2,4 When administered with dabrafenib, loss of efficacy may result in agents that are sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6.2 Vemurafenib can increase concentrations of CYP1A2 substrates; those with a narrow therapeutic window should be avoided or, if coadministered, patients should be monitored closely for toxicities and the dose of the CYP1A2 substrate reduced.4

All 4 agents can cause fetal harm; therefore, women of childbearing potential should be advised of the risk to a fetus and to use effective contraception.1-4 Dabrafenib can render hormonal contraceptive ineffective, both during treatment and for 2 weeks after the last dose, requiring a nonhormonal method of contraception.2 Patients taking cobimetinib should continue contraception for 2 weeks following their last dose; for patients taking trametinib, contraception should be continued for 4 months after treatment has stopped.3

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Breastfeeding is not recommended while undergoing treatment with any of these agents.1-4 Both male and female patients taking dabrafenib and trametinib may experience impaired fertility.2,3

Increased cell proliferation can occur with BRAF inhibitors; specifically, dabrafenib and vemurafenib may cause tumor promotion in BRAF wild-type melanoma.2.4 Cobimetinib and trametinib have been linked to new primary malignancies, both cutaneous and noncutaneous; therefore, patients should be monitored for new malignancies before, during, and after treatment, including for up to 6 months after their last dose of cobimetinib.1,3

Patients taking vemurafenib should undergo dermatologic evaluation prior to treatment initiation, every 2 months while on therapy, and for up to 6 months following discontinuation. New primary cutaneous malignancies should be excised without adjusting vemurafenib dose. In addition, patients should be evaluated for symptoms or clinical signs of new noncutaneous squamous cell carcinoma, both before and during treatment with vemurafenib, with close monitoring for other malignancies also advised.4

Adverse Effects and Management

Prescribing information for the 4 kinase inhibitors include warnings and cautions for adverse effects. In this review, we discuss the management recommendations for effects involving these organ systems: cardiovascular, dermatologic, endocrine and metabolic, hematologic, hepatic, ocular, pulmonary, renal.

Cardiovascular Cardiomyopathy can occur with cobimetinib, dabrafenib, and trametinib. Risk is increased in those patients treated with cobimetinib and vemurafenib vs vemurafenib alone.1-3

Recommendations suggest evaluating patients for left ventricular ejection fraction (LVEF) before initiating cobimetinib; repeat the evaluation 1 month after treatment has started and every 3 months thereafter until treatment discontinuation. When restarting cobimetinib after a dose reduction or interruption, evaluate for LVEF at approximately 2, 4, 10, and 16 weeks, and as clinically indicated thereafter.1

Similarly, in patients receiving dabrafenib or trametinib as a single agent or with dabrafenib, assess LVEF via echocardiography or multigated acquisition (MUGA) scan prior to initiating treatment, at 1 month, and every 2 to 3 months thereafter.2,3

Dabrafenib should be withheld in cases of symptomatic cardiomyopathy or asymptomatic left ventricular dysfunction of more than 20% from baseline that is below the institutional lower limit of normal (LLN). Treatment may be resumed at the same dose level if the patient’s cardiac function recovers to at least the institutional LLN for LVEF and absolute decrease 10% or less compared to baseline.2

Trametinib should be withheld if absolute LVEF deceases by 10% from pretreatment values and is less than the institutional LLN.3 The agent should be discontinued in patients with symptomatic cardiomyopathy or persistent, asymptomatic left ventricular dysfunction greater than 20% from baseline below LNN that does not resolve within 4 weeks.3

Vemurafenib should not be initiated in patients who have uncorrectable electrolyte abnormalities, QTc greater than 500 ms, or long QT syndrome, or in those taking medicinal products known to prolong the QT interval. ECG and electrolytes (potassium, magnesium, and calcium) should be evaluated for 15 days, monthly during the first 3 months, and then every 3 months thereafter prior to and following treatment initiation or after dose modification for QTc prolongation. If a patient develops grade 3 QTc greater than 500 ms, withhold vemurafenib and permanently discontinue the agent if the QTc interval remains greater than 500 ms and increased more than 60 ms from pretreatment values after controlling for cardiac risk factors for QT prolongation. If a patient recovers to QTc 500 ms or lower at grade 2 or lower, vemurafenib can be restarted at a reduced dose.4