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Review
. 2015 Mar;7(2):122-36.
doi: 10.1177/1758834014566428.

Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma

Sarah J Welsh  1 , Pippa G Corrie  2
Affiliations
Review

Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma

Sarah J Welsh et al. Ther Adv Med Oncol. 2015 Mar.

Abstract

Following the discovery that nearly half of all cutaneous melanomas harbour a mutation in the BRAF gene, molecular targeted kinase inhibitors have been developed for the treatment of metastatic melanoma and have dramatically improved outcomes for those patients with BRAF mutant disease, achieving high levels of objective response and prolonging survival. Since 2011, the specific BRAF targeted agents, vemurafenib and dabrafenib, and the MEK inhibitor, trametinib, have been licensed for the treatment of patients with unresectable or metastatic BRAF mutant melanoma. As with other biological targeted agents, these drugs are associated with predictable patterns of adverse events. Proactive toxicity management is important to ensure maximum treatment benefit and avoid unnecessary treatment discontinuation. We review the most common and serious adverse events associated with BRAF targeted agents and suggest management algorithms to guide practitioners in using these drugs effectively in the clinic.

Keywords: BRAF inhibitor; MEK inhibitor; dabrafenib; management; melanoma; toxicity; trametinib; vemurafenib.

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Conflict of interest statement

Conflict of interest statement: SJW has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. PC has received consultancy and advisory board honoraria and research funding from Roche and GSK. No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1.
Figure 1.
(a) Suggested management of skin toxicities (based on algorithms suggested in Sinha et al. [2012]). (b) Suggested management of macular/papular rash or perifollicular eruptions. KI, kinase inhibitor; SCC, squamous cell carcinoma; SPF, sun protection factor; UVA, ultraviolet A; UVB, ultraviolet B. Adapted with written permission from Sinha et al. [2012].
Figure 2.
Figure 2.
Suggested management of diarrhoea. ADL, activity of daily living; KI, kinase inhibitor.
Figure 3.
Figure 3.
Suggested management of pyrexia. BP, blood pressure; FBC, full blood count; KI, kinase inhibitor; NSAID, nonsteroidal anti-inflammatory drug.
Figure 4.
Figure 4.
Suggested management of arthralgia. ADL, activity of daily living; BRAFi, BRAF inhibitor; KI, kinase inhibitor; NSAID, nonsteroidal anti-inflammatory drug.
Figure 5.
Figure 5.
(a) Suggested management of reduced left ventricular ejection fraction (LVEF). (b) Suggested management of prolonged QTc. ADL, activity of daily living; BRAFi, BRAF inhibitor; KI, kinase inhibitor; LLN, lower limit of normal; LVEF, left ventricular ejection fraction; QTc, corrected QT interval.
Figure 6.
Figure 6.
Suggested management of pneumonitis. ADL, activity of daily living; CT, computed tomography; CXR, chest X-ray; KI, kinase inhibitor; MEKi, MEK inhibitor.
Figure 7.
Figure 7.
Suggested management of ocular complications. ADL, activity of daily living; BRAFi, BRAF inhibitor; KI, kinase inhibitor; MEKi, MEK inhibitor; RVO, retinal vein occlusion; RPED, retinal pigment epithelial detachment.
Figure 8.
Figure 8.
Suggested management of hypertension. ADL, activity of daily living; BP, blood pressure; KI, kinase inhibitor; MEKi, MEK inhibitor; ULN, upper limit of normal; WNL, within normal limits.
Figure 9.
Figure 9.
Suggested management of liver function abnormalities. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, asparate aminotransferase; BRAFi, BRAF inhibitor; CMV, cytomegalovirus; EBV, Epstein Barr virus; INR, international normalized ratio; KI, kinase inhibitor; LFTs, liver function tests; MEKi, MEK inhibitor; ULN, upper limit of normal.
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