Targeted Therapy for Melanoma: Dabrafenib and Trametinib
- 1. University of Georgia College of Pharmacy, USA
- 2. Department of Pharmacy, Georgia Regents Cancer Center, USA
Citation
Hood K, VanLandingham JM (2013) Targeted Therapy for Melanoma: Dabrafenib and Trametinib. J Pharmacol Clin Toxicol 1(2): 1011.
INTRODUCTION
Melanoma is a disease that has plagued mankind for years and has been documented in the medical literature since the late 1600s [1]. Despite all the experience with melanoma, the therapy options have remained very limited, consisting mainly of surgery, dacarbazine, or interleukin-2. Recent scientific advancements have provided us with two newer treatment options: immunotherapy with the anti-CTLA-4 antibody ipilimumab and targeted therapy with the BRAF kinase inhibitor vemurafenib.
BRAF mutations have been identified in approximately 50% of patients with advanced melanoma [2]. These mutations result in the hyperactivation of the RAS-RAF-MEK-ERK pathway which ultimately leads to unregulated cell growth and proliferation in melanoma cells [3]. The majority of the BRAF-mutated melanomas have a V600E mutation (80-90%) and 10-20% has a V600K mutation [2]. In 2011, vemurafenib (Zelboraf®), the first BRAF kinase inhibitor, was approved by the FDA in the United States for use in metastatic or unresectable melanoma in patients with a BRAF V600E mutation [4]. Since then, two additional agents have made it to market for use in this patient population: dabrafenib (Tafinlar®) and trametinib (Mekinist™).
Dabrafenib is the second BRAF kinase inhibitor approved by the US FDA for use in metastatic melanoma. It was approved in May 2013 after a phase III trial demonstrated significant improvement in progression-free survival (5.1 months vs. 2.7 months) when compared to dacarbazine, the only chemotherapeutic agent approved by the FDA for the treatment of malignant melanoma [2,5,6]. Confirmed objective responses were reported by the independent review committee (IRC) in 50% of patients who received dabrafenib, compared to only 6% of patients who received dacarbazine [2]. These statistics on progression-free survival and objective response rate are comparable to those found in phase III trials of vemurafenib [5]. The most common adverse events related to dabrafenib included skin-related events (hyperkeratosis, papillomas, palmar-plantar erythrodysaesthesia, and squamous cell carcinoma), pyrexia, fatigue, headache and arthralgia. Grade 3 or 4 adverse events were uncommon. It is important to note that the incidence of epithelial skin lesions observed in dabrafenib clinical trials seems to be lower when compared to phase II and phase III trials with vemurafenib. However, a direct comparison of these two agents is necessary in order to determine if this difference is significant.
Trametinib was also approved in the United States in May 2013 for use in patients with metastatic melanoma with BRAF V600E or V600K mutations [7]. It is a selective inhibitor of MEK1 and MEK2, proteins that are located downstream from BRAF kinase and are involved in the pathway that leads to proliferation of melanoma cells [3,8]. In the clinical trial that led to its FDA approval, trametinib was shown to have a statistically significant improvement in both progression-free survival (4.8 months vs. 1.5 months) and overall survival (6-month overall survival of 81% vs. 67%) compared to dacarbazine. There was also a significant difference in response rate between the two groups (22% vs. 8%). The most common adverse events associated with this agent were papulopustular rash, diarrhea, fatigue, peripheral edema, acneiform dermatitis, nausea, alopecia, hypertension, constipation and vomiting. The most common grade 3 adverse events included rash (7%), fatigue (4%) and hypertension (12%). Overall, 35% of patients experienced dose interruptions and 27% experienced dose reductions due to adverse events related to trametinib therapy. It is important to note that there were no cutaneous squamous-cell carcinomas observed in patients who received trametinib. This finding, along with other differences in the side effect profile of trametinib, suggests that MEK inhibitors have different molecular effects on wild-type BRAF [8].
Both dabrafenib and trametinib have shown promise in the treatment of metastatic or unresectable melanoma. While the improvement in progression-free survival and response rate with both of these agents compared to dacarbazine is statistically significant, it is important to determine whether this translates into clinical significance. With a median progression-free survival of only 5 months for both dabrafenib and trametinib, it is evident that melanoma cells quickly become resistant to these agents [2,8]. The mechanism of resistance is currently under investigation, and several possible mechanisms have been identified. The solution to one mechanism involves combination therapy with a BRAF and MEK inhibitor. Two different phase III clinical trials are underway to evaluate the safety and efficacy of this combination therapy [9]. The results of these clinical trials have the potential to impact the way we approach the treatment of metastatic melanoma and expand the role of BRAF and MEK inhibitors in patients with BRAF V600 mutated metastatic melanoma.
With advancements in immunotherapy and targeted therapy, combined with ongoing clinical trials, treatment options for melanoma are expanding. Further exploration of the different mechanisms that lead to treatment resistance in melanoma cells will hopefully lead to the discovery of an effective defense against the disease that has haunted humans for centuries.
Declaration
I declare that this article has not been submitted or published in any other journal.
