Updates in Pharmacotherapy for Melanoma

Angie Amado, PharmD Candidate 2019; Sonia Amin Thomas (Sonia Patel), PharmD, BCOP


US Pharmacist. 2018;43(6):HS2-HS9. 

In This Article

Dabrafenib/Trametinib Combination Therapy

Approximately one-half of patients with metastatic cutaneous melanoma harbor an activating mutation of BRAF, an intracellular signaling kinase in the MAP kinase pathway.[37–39] Dabrafenib and vemurafenib were developed to inhibit BRAF with mutations at V600.[40,41] Despite high initial response rates, one-half of patients with previously untreated stage IV or unresectable stage III melanoma receiving BRAF-targeted monotherapy relapse within about 6 months because of the development of drug resistance.[42–44] To bypass possible BRAF-inhibitor therapy resistance, other drugs have been developed to target the MAP kinase pathway in different ways. Trametinib and cobimetinib are oral small-molecule inhibitors of MEK1 and MEK2, signaling molecules downstream of BRAF in the MAP kinase pathway. Although MEK-inhibitor monotherapy has limited utility for treating advanced metastatic melanoma, phase III trials have demonstrated that combination therapy with a BRAF/MEK inhibitor has better efficacy than BRAF-inhibitor monotherapy for previously untreated unresectable or metastatic disease.[45,46] Compared with single-agent dabrafenib or vemurafenib, combination therapy with dabrafenib and trametinib improved response rate and duration, PFS, and OS.[45,46]

These studies have established dabrafenib/trametinib combination regimens as FDA-approved options for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations.[47–49] In phase III trials, common toxicities associated with BRAF-inhibitor monotherapy were fatigue, arthralgia or myalgia, pyrexia and chills, cutaneous events, alopecia, and cutaneous AEs.[45,46] Skin complications that occurred with notable prevalence, severity, and variety included not only rash, pruritus, and photosensitivity, but also keratoacanthomas, cutaneous squamous-cell carcinomas, papillomas, hyperkeratoses, and actinic keratosis. For patients receiving BRAF-inhibitor therapy, the panel recommends regular dermatologic evaluation with referral to a dermatologist to monitor for skin complications.[8]

As is the case with dabrafenib/trametinib, vemurafenib/cobimetinib combination regimens are approved to treat patients who have unresectable or metastatic melanoma with BRAF V600E or V600K mutations. However, further follow-up is needed to determine whether vemurafenib/cobimetinib also improves OS. Among recommended BRAF-targeted therapy options, the BRAF/MEK inhibitor combination is preferred over BRAF inhibitor monotherapy based on improved outcomes and similar risk of toxicity. In patients with documented BRAF V600 mutations, choosing between first-line checkpoint immunotherapy and BRAF-targeted therapy can be difficult given the lack of comparative phase III clinical trials.[5] Clinical trials are under way to address questions regarding the optimal sequencing and/or combination of these agents.