	Stage IV melanoma is an aggressive malignancy with a median survival shorter than 1 year. The identification of activating mutations in a component of the mitogen activated protein kinase (MAPK) pathway called BRAF in 40% to 60% of melanomas has allowed for the development of efficacious therapies that inhibit the activity of the pathway. Targeted inhibition of BRAF with vemurafenib or dabrafenib or direct inhibition of MEK with trametinib confers high response rates and statistically significant survival benefits relative to treatment with traditional chemotherapy. The FDA has approved these agents as monotherapies for the treatment of metastatic melanoma containing a V600 BRAF mutation. Phase II data suggest that treatment with the combination of a BRAF and a MEK inhibitor, dabrafenib plus trametinib, can further increase the rate and durability of treatment responses and lengthen the survival benefit conferred by single-agent treatment. Combined treatment with dabrafenib and trametinib was conditionally approved by the FDA in January 2014 for the treatment of unresectable and metastatic melanoma expressing a V600E or V600K BRAF mutation.

 It is estimated that in 2014 more than 76,000 people will be diagnosed with melanoma and approximately 9700 people will die from the malignancy.

 When melanoma metastasizes to distant sites, the prognosis is poor with a median survival of less than 1 year. The current American Joint Committee on Cancer (AJCC) staging system for melanoma uses histologic features to predict the outcome of patients with localized or regionally advanced disease. In distantly metastatic melanoma, the location of metastases and level of lactate dehydrogenase (LDH) in the blood are predictors of outcomes. Until 2011, there were only 2 systemic therapies FDA approved for the treatment of stage IV melanoma—the chemotherapy dacarbazine and the immunotherapy high dose interleukin-2 (HDIL2). Dacarbazine treatment confers a 5% to 20% response rate that does not translate into a survival benefit.

	HD-IL2 offers a 5% chance for durable benefit but requires in-patient management, and the toxicity profile limits the patients who are eligible for this treatment.

 Neither of these therapies target defined molecular abnormalities selected by the tumor cells. Identifying driver mutations offers the potential to define targets for more effective therapeutic interventions. The MAPK pathway (

) relays signals from activated cell surface receptors to RAS proteins leading to the dimerization and activation of A-, B-, and C-RAF.

 Active RAF activates MEK1 and MEK2, leading to ERK activation and cell proliferation. Using a genome-wide screen to systematically identify genes mutated in human cancer, researchers at the Wellcome Trust Sanger Institute identified activating mutations in BRAF in the majority of melanomas sampled.

 More than 90% of the BRAF mutations are located at position 600 with the substitution of valine by a negatively charged glutamate (V600E BRAF mutation).

	This mutation causes constitutive activation of BRAF. Other rarer activating mutations also have been identified at position 600, including V600K and V600R mutations.

 The location from which a primary melanoma arises predicts for the likelihood of a BRAF mutation.

	Vemurafenib (Zelboraf) is a potent inhibitor of BRAF activity.

 In preclinical models, an analogue of vemurafenib inhibited the proliferation of V600E BRAF-expressing melanoma cell lines.

 A phase I study evaluated the safety of oral vemurafenib in patients with advanced melanoma and established a recommended phase II dosage of 960 mg twice daily.

	Responses were detected in melanomas expressing V600E BRAF mutations but not in those expressing wild-type BRAF. Rapid treatment responses were detected as evidenced by decreases in metabolic activity of metastatic deposits seen on FDG-PET imaging performed 15 days after treatment initiation. A multicenter phase II trial (BRIM-2) enrolled patients with stage IV V600E BRAF-expressing melanoma who received at least 1 prior systemic therapy; the trial assessed the response rate to vemurafenib.

 The study enrolled 132 patients; 53% developed a response to treatment (6% complete and 47% partial responses). The median duration of response was 6.7 months and the median progression-free survival (PFS) was 6.8 months.

	A randomized phase III study (BRIM-3) was conducted to compare survival in patients with untreated stage IV V600E or V600K BRAF-expressing melanoma treated with vemurafenib versus dacarbazine chemotherapy.

 The response rate for vemurafenib was 48% as opposed to 5% for dacarbazine. Treatment with vemurafenib conferred a significant improvement in both PFS and overall survival (OS). The median PFS was 6.9 months following vemurafenib treatment as compared to 1.6 months following chemotherapy. The median OS increased from 9.7 months in the dacarbazine arm to 13.6 months in the vemurafenib arm. Following the first interim analysis, the Data and Safety Monitoring Board recommended that patients randomized to dacarbazine be crossed over to vemurafenib. This crossover confounds subsequent OS analysis.

	The survival benefit seen with vemurafenib is not drugspecific, as evidenced by activity seen in clinical trials with another oral BRAF inhibitor, dabrafenib (Tafinlar). In a phase I study, 50% of patients with V600 BRAF-mutated melanoma treated with dabrafenib developed a response.

 A phase II (BREAK-2) study treating patients with dabrafenib at the maximum tolerated dose of 150 mg twice daily demonstrated a 59% confirmed response rate in subjects with V600E-mutated melanoma and a 6.3 month median PFS.

	The phase III BREAK-3 study randomized in a 3:1 fashion 250 patients with V600 BRAF-mutated stage IV melanoma to dabrafenib (187 patients) or dacarbazine (63 patients).

 Dabrafenib conferred a significant improvement in median PFS: 2.7 months in the dacarbazine arm versus 5.1 months in the dabrafenib arm.

	Targeted inhibition of V600-mutated BRAF in patients with advanced melanoma leads to high response rates and to survival benefits. However, PFS remains limited due to selection for resistance to treatment in the tumor cells. Multiple resistance mechanisms have been identified,

 including but not limited to tumor selection for activating NRAS mutations, increase in CRAF expression, and activation of COT kinase, which activates MEK independent of BRAF.

 Certain resistance mechanisms remain MEK dependent.

	Trametinib is a selective inhibitor of MEK with a recommended oral dosage of 2 mg daily.

 Treatment with trametinib demonstrated a 33% response rate in a phase I study consisting of 30 patients with BRAF-mutated melanoma.

 A phase II study enrolled 2 cohorts of patients with BRAF-mutated melanoma and demonstrated a 25% response rate to trametinib treatment with a median PFS of 4 months in a BRAF inhibitornäive cohort. The response rate in a cohort of patients previously treated with a BRAF inhibitor was 0%.

 As such, sequential treatment with a MEK inhibitor after progressing on treatment with a BRAF inhibitor does not appear to be a promising strategy, at least with trametinib.

	The METRIC phase III study randomized BRAF inhibitornaïve patients with V600 BRAF-mutated melanoma to trametinib or chemotherapy (dacarbazine or paclitaxel).

 Trametinib significantly improved PFS (4.8 months vs 1.5 months) and OS despite a high crossover rate in the dacarbazine arm to trametinib upon progression. The hazard ratio for death was 0.54 favoring the trametinib-treated patients. The 6-month OS in the trametinib arm was 81% compared with 67% in the dacarbazine arm. Similar to that seen with BRAF inhibition, trametinib can significantly improve survival but the extent of the median PFS benefit remains limited.

	Another limitation of BRAF or MEK targeted therapy is toxicity. In the BRIM-3 study, 38% of patients treated with vemurafenib required dose interruptions or reductions.

 The most common high-grade adverse events (AEs) were cutaneous toxicities, arthralgias, photosensitivity, and fatigue. Cutaneous squamous cell carcinomas or keratoacanthomas developed in 18% of patients. A grade-2 or higher rash developed in 18% of patients. The development of cutaneous squamous cell carcinomas (SCCs) appears to be related to paradoxical activation by BRAF inhibitors of the MAPK pathway in the setting of RAS mutations present in the squamous cells.

 In the METRIC study, 27% of patients treated with trametinib required dose reductions. The most common AEs were rash, peripheral edema, diarrhea, and fatigue.25 Rash developed in 57% of treated patients, with 8% developing a grade-3 or -4 rash. No cutaneous SCCs or hyperproliferative cutaneous lesions were diagnosed.

	While single-agent inhibition of either BRAF or MEK confers survival benefits, there are several limitations to approaches that target a single component of the MAPK pathway. These include only a few months’ improvements in median PFS, the development of resistance, and the development of toxicity, including SCCs associated with BRAF targeted therapies.

	In theory more complete inhibition of the MAPK pathway using the combination of dabrafenib and trametinib could potentially lead to more durable clinical benefit, delayed time to treatment resistance, and decreased incidence of SCCs.

	A phase I/II trial assessed the safety, clinical efficacy, and pharmacokinetics of combined therapy with dabrafenib and trametinib in patients with V600-mutated BRAF melanoma.

	With a median follow-up of 14.1 months, the median PFS of patients randomized to the 150 mg/2 mg arm was 9.4 months compared with 5.8 months in the dabrafenib monotherapy arm. The response rate of 76% in the 150 mg/2 mg arm was higher than the 54% seen with dabrafenib. The median duration of response in the 150 mg/2 mg arm (10.5 months) almost doubled the 5.6 months with dabrafenib monotherapy.

	In concordance with preclinical data, the incidence of cutaneous SCCs or other hyperproliferative skin lesions was less in the combination therapy group. The most frequent AEs in the 150 mg/2 mg arm were fever and chills developing in the majority of patients. MEK-inhibitor—related peripheral edema, cardiac toxicity, hypertension, and ocular toxicity occurred more frequently in the combination arm. A total of 58% of patients in the 150 mg/2 mg arm required dose reductions, most commonly because of the development of fever.

	Randomized phase III studies directly comparing the clinical efficacy and safety of BRAF inhibition alone to the combination of BRAF and MEK inhibition have completed enrollment. The MEK115306 (COMBI-D) study randomized patients with V600E/K-mutated melanoma to dabrafenib plus placebo (D+P) versus dabrafenib plus trametinib (D+T), while the MEK 116513 study randomized patients to vemurafenib versus dabrafenib plus trametinib. Results of the COMBI-D study were recently presented.

 Patients with untreated stage IV V600E or V600K BRAF-expressing stage IV melanoma were randomized in a 1:1 fashion to receive treatment with either D+T or D+P.

	The study met its primary end point of improvement in investigator assessed PFS at 9 month median follow-up with a HR for recurrence of 0.75 (P= .035) favoring the combination therapy arm. The median PFS increased from 8.8 months in the D+P arm to 9.3 months in the D+T arm. Six-month PFS increased from 57% to 70% of patients. Response rate also improved from 51% in the D+P arm to 67% in the D+T arm. A preplanned interim analysis of OS demonstrated an improvement in 6-month OS from 85% in the D+P arm to 93% in the D+T arm. However, this difference did not cross the stopping boundary for the study and an updated OS analysis is planned following 70% of death events. The addition of trametinib to dabrafenib led to fewer cutaneous SCCs and cutaneous hyperproliferative events. The incidence of pyrexia and chills increased with combination therapy. Adverse events led to a higher frequency of dose interruptions and dose reductions in the D+T arm (33% vs 49% of patients for dose interruptions and 13% vs 25% for dose reductions). This study is the first study to demonstrate in a randomized fashion that the addition of a MEK inhibitor to a BRAF inhibitor leads to survival benefits. The OS data remains immature and longer follow-up is necessary.

 compares the efficacy demonstrated in phase II and III clinical trials following treatment with single-agent or combined BRAF and MEK inhibitory approaches.

	Single-agent vemurafenib was approved by the FDA in 2011 for the treatment of V600E BRAF—mutated metastatic melanomas. In 2013, dabrafenib and trametinib received FDA approval as monotherapy treatments of V600 BRAF–mutated melanomas. In 2014, the FDA granted accelerated conditional approval for dual therapy with the combination of dabrafenib and trametinib (

) in melanoma expressing a V600E or V600K BRAF mutation. Combined therapy may create more durable and frequent responses with longer PFS when compared with single-agent treatment. Combining BRAF and MEK inhibition appears to decrease the incidence of certain cutaneous toxicities.

			Table 1. Comparison of Efficacy in Phase II and Phase III Trials With Dabrafenib, Trametinib, and Combination Therapy in Patients With V600 BRAF-Mutated Unresectable or Stage IV Metastatic Melanoma

Articles

It is estimated that in 2014 more than 76,000 people will be diagnosed with melanoma and approximately 9700 people will die from the malignancy.

Philip Friedlander, MD, PhD

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Combination BRAF-MEK Inhibition With Dabrafenib and Trametinib for BRAF-Mutant Melanoma