Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — Although the incidence of malignant melanoma is increasing, most cases are diagnosed at an early stage. In that setting, surgical excision is curative in most cases, and patients at high risk of developing metastatic disease may benefit from adjuvant immunotherapy with interferon alpha or ipilimumab (algorithm 1) . (See "Initial surgical management of melanoma of the skin and unusual sites" and "Adjuvant immunotherapy for melanoma".)
The management of patients with disseminated disease is a difficult problem (algorithm 2). Approaches that have been shown to provide clinically important benefit for appropriately selected patients with disseminated melanoma include immunotherapy with high-dose interleukin-2 (IL-2), immunotherapy with antibodies targeting programmed cell death protein 1 (PD-1) and/or with ipilimumab (a monoclonal antibody targeting cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]), and inhibition of the mitogen-activated protein (MAP) kinase pathway in patients whose tumors contain a V600 mutation in the BRAF gene using either a BRAF inhibitor or an MEK inhibitor. There are no randomized trials that compare targeted therapy with immunotherapy, and there are no prospective data on the appropriate sequencing of these therapies for patients with a BRAFV600 mutation.
The use of targeted therapies in the treatment of advanced melanoma will be reviewed here.
APPROACH TO TREATMENT — An understanding of the role of activation of the mitogen-activated protein (MAP) kinase pathway has led to the identification of several drug targets (figure 1). This is resulting in the development of important therapeutic approaches for the treatment of advanced melanoma in various patient subsets. These include inhibition of BRAF, MEK, NRAS, and KIT.
The general approach to the treatment of advanced melanoma and the integration of targeted therapy with other treatment modalities is presented separately (algorithm 2). (See "Overview of the management of advanced cutaneous melanoma" and "The molecular biology of melanoma".)
Mutation status of tumor — All patients with advanced cutaneous melanoma should have their tumors assayed for the presence or absence of a driver mutation at the V600 site in BRAF. Testing for NRAS in patients with wild-type BRAF should also be considered. Patients with an acral or mucosal primary tumor and those with melanoma in an area of chronically sun-exposed skin that does not contain a BRAF mutation should have their tumor assessed for the presence of a driver mutation in KIT. Next-generation sequencing platforms can provide information on NRAS and KIT mutational status as well as identify alternative mutations in BRAF and NF1 that could potentially be targetable. This approach should be considered in patients with wild-type BRAF melanoma whose disease has progressed on immunotherapy and/or in those patients who are not candidates for immunotherapy.
BRAF INHIBITION — BRAF inhibitors represent an important advance in the treatment of metastatic melanoma for patients whose tumors contain the characteristic activating BRAF mutation. Although the impact of these agents was originally demonstrated using single-agent therapy, combinations with MEK inhibitors have largely replaced single-agent BRAF inhibition. (See 'Combined MEK plus BRAF inhibition' below.)
Activating mutations in BRAF are present in approximately 40 to 60 percent of advanced melanomas [2-4]. In 80 to 90 percent of cases, this activating mutation consists of the substitution of glutamic acid for valine at amino acid 600 (V600E mutation), with most of the remainder consisting of an alternate substitution (lysine for valine) at the V600 locus (V to K).
In one study, advanced melanomas with a mutation in BRAF appear to have some clinical differences that are associated with a more aggressive clinical course . In a consecutive series of 197 patients at a single institution, the presence of mutant BRAF was significantly more frequent in patients with a truncal primary, an earlier age of onset, and a lack of chronic skin damage. Furthermore, for patients not treated with a BRAF inhibitor, survival was shorter overall.
Vemurafenib and dabrafenib, inhibitors of BRAF, have demonstrated dramatic antitumor activity in phase III trials in patients with advanced disease whose tumors have characteristic mutations in BRAF. However, virtually every patient treated with an inhibitor of BRAF eventually has disease progression . Additional data will be required to determine whether different agents have a differential effect depending upon the specific mutation present.
In an analysis from the large, phase II, single-arm BRIM-2 trial of vemurafenib, tumor samples were centrally collected and analyzed for mechanisms of resistance through use of sequenom mutation analysis, Sanger DNA sequencing of MEK1 exons 2, 3, and 6, and immunohistochemistry for activation of the mitogen-activated protein (MAP) kinase pathway . Nearly all tumors demonstrated reactivation of the MAP kinase pathway with elevation of pERK at the time of resistance. In some patients, progression was associated with an additional NRASQ61 mutation. In a small subset of patients, several MEK1 mutations were found in association with resistance, which was the first time these mutations were found in patient tumor samples. These included MEK1Q56 and MEK1E203 mutations. On the other hand MEK1P124L was not associated with resistance and was seen de novo. All relapse tumor specimens continued to demonstrate the BRAFV600 mutation.
Vemurafenib — Vemurafenib is a potent inhibitor of the kinase domain in mutant BRAF. Vemurafenib prolonged both progression-free and overall survival as a single agent in melanoma patients whose tumors contain a V600 mutation. Vemurafenib is now used primarily in combination with an MEK inhibitor. (See 'Combined MEK plus BRAF inhibition' below.)
In the phase III BRIM-3 trial, 675 patients were randomly assigned to either vemurafenib (960 mg twice a day) or dacarbazine (1000 mg/m2 intravenously every three weeks) . Treatment was to be continued until disease progression. All patients had either metastatic disease or unresectable stage IIIC disease (95 and 5 percent, respectively). The co-primary endpoints of the trial were overall survival and progression-free survival. Crossover from dacarbazine to vemurafenib was allowed based upon the results of a planned interim analysis.
With a median follow-up of 12.5 months for patients treated with vemurafenib and 9.5 months for those initially receiving dacarbazine, overall survival was significantly prolonged with vemurafenib compared with dacarbazine (13.6 versus 9.7 months, hazard ratio [HR] 0.70, 95% CI 0.57-0.87) . Progression-free survival was also significantly prolonged (6.9 versus 1.6 months, HR 0.38, 95% CI 0.32-0.46)
Dabrafenib — Dabrafenib is a BRAF kinase inhibitor that has demonstrated significant activity as a single agent in patients with advanced melanoma compared with dacarbazine chemotherapy. Dabrafenib is now used primarily in combination with an MEK inhibitor. (See 'Combined MEK plus BRAF inhibition' below.)
In the pivotal phase III trial, 250 patients with unresectable stage III or stage IV melanoma were randomly assigned in a 3:1 ratio to either dabrafenib (150 mg orally twice a day) or dacarbazine (1000 mg/m2 intravenously every three weeks) [8,9]. All patients had the V600E mutation in BRAF. Patients were allowed to cross over to the alternative treatment upon the development of progressive disease.
●Overall survival was presented at the 2013 American Society of Clinical Oncology meeting . With a median follow-up of 15 and 13 months for the two groups, overall survival favored patients treated with dabrafenib (HR 0.76, 95% CI 0.48-1.21) but was not statistically significant. However, 36 of 63 patients (57 percent) originally treated with dacarbazine crossed over to dabrafenib, potentially obscuring an overall survival benefit from initial dabrafenib therapy.
Brain metastases — Both vemurafenib and dabrafenib have activity in patients with brain metastases. The results of clinical studies in this setting and the role of these agents in the management of brain metastases in patients with melanoma are discussed separately. (See "Management of brain metastases in melanoma".)
Toxicity from BRAF inhibition — The most common toxicities associated with BRAF inhibition include dermatologic complications (rash, photosensitivity reactions, hyperkeratosis), arthralgia, fatigue, alopecia, nausea, and diarrhea. These have all been reported in 15 percent or more of patients in extended postmarketing experience .
Toxicities of particular concern and those associated with particular agents are discussed in this section.
Cutaneous toxicity and secondary tumors — Clinically significant cutaneous side effects are common with both vemurafenib and dabrafenib [12,13]. These include squamous cell carcinomas, including keratoacanthomas, in 19 to 26 percent of cases . These skin tumors occur within weeks of initiation of treatment with these BRAF inhibitors and are generally treated with excision. The development of such lesions did not require discontinuation of therapy. (See "Keratoacanthoma: Management and prognosis".)
In addition, in the BRIM-3 trial comparing vemurafenib with dacarbazine, 8 of 337 (2.4 percent) patients assigned to vemurafenib developed a second primary melanoma [5,15]. Similarly, 3 of 187 patients in the phase III dabrafenib trial developed new melanomas . Patients with advanced melanoma are at risk for development of further primary melanomas; whether the incidence rates in patients treated with BRAF inhibitors is higher than in those not receiving these agents is not clear .
Molecular studies indicate that these squamous cell carcinomas and keratoacanthomas are due to a paradoxical activation of the MAP kinase pathway that bypasses the inhibition of BRAF . Furthermore, the short latency period until the development of these skin lesions is consistent with the presence of preexisting RAS mutations in the skin that enhance their activation of downstream proteins in the MAP kinase pathway when subjected to BRAF inhibition.
Data from studies of the combination of a BRAF inhibitor and an MEK inhibitor indicate that there is a reduced incidence of skin toxicity, including the development of skin cancers, presumably by the MEK inhibitor blocking this paradoxical activation of the MAP kinase pathway . (See 'Combined MEK plus BRAF inhibition' below.)
At least one case report has observed rapid progression of a chronic myelomonocytic leukemia that was associated with a RAS mutation concurrent with the initiation of vemurafenib therapy . As experience with BRAF inhibitors increases, it is possible that progression of other malignancies associated with RAS mutation may also be observed. It is hypothesized that the combination of a BRAF inhibitor and an MEK inhibitor could reduce the incidence of such cancers, similar to that seen with skin cancers, although this remains to be determined.
A spectrum of other cutaneous toxicities (rash, photosensitivity reactions, alopecia, etc) are common with both vemurafenib and dabrafenib, and may be somewhat more common with vemurafenib [8,14]. (See "Cutaneous complications of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'Vemurafenib and dabrafenib'.)
Other toxicities — Other toxicities frequently reported with both BRAF inhibitors include arthralgias, headache, and weakness or fatigue [5,8,9]. Ocular toxicity (including uveitis, conjunctivitis, dry eyes) has been reported with both vemurafenib and dabrafenib [8,20].
Radiation sensitization and recall, in some cases severe, involving cutaneous and visceral organs have been reported in patients treated with radiation prior to, during, or subsequent to treatment with vemurafenib and dabrafenib . Holding treatment with a BRAF inhibitor for at least three days before and after fractionated radiation therapy, and at least one day before and after stereotactic radiation appears to minimize the risk of significant toxicity.
There are other clinically significant toxicities that appear to be specific to each agent rather than being a class effect. A full understanding of the frequency and mechanism of less common toxicities will require additional clinical experience.
Vemurafenib — Areas of specific concern associated with vemurafenib include:
●Prolongation of the QT interval can occur with vemurafenib administration. Vemurafenib is a cytochrome P450 3A4 (CYP3A4) substrate, and it should be used with caution in patients with congenital long QT syndrome and those who are receiving other drugs that prolong the QT interval (table 1) or inhibit CYP3A4 (table 2). The US Food and Drug Association (FDA)-approved manufacturers' labeling recommends that electrocardiogram (ECG) and electrolytes be monitored before treatment and after dose modification. (See "Cardiotoxicity of nonanthracycline cancer chemotherapy agents", section on 'Vemurafenib'.)
●Peripheral facial palsy has been reported and may be bilateral .
Dabrafenib — Areas of specific concern associated with dabrafenib include:
●Febrile reactions are relatively common and were reported in 28 percent of patients in the phase III trial. In approximately 4 percent of cases, these were severe and required drug discontinuation or dose modification.
●Hyperglycemia severe enough to require treatment was observed in 6 percent of cases.
MEK INHIBITION — The MEK inhibitor trametinib has significant clinical activity in melanoma patients whose tumor contains a BRAFV600 mutation; several other BRAF inhibitors are under development. Although MEK inhibitors are now largely used in combination with BRAF inhibitors, the MEK inhibitors may have a role for single-agent use in BRAF wild-type patients with RAS mutant tumors, as well as in those with variant BRAF mutations. In addition, these agents may ultimately have a role in combination with checkpoint inhibitors.
Trametinib — Trametinib is a potent, highly specific inhibitor of MEK1/MEK2.
●Trametinib was originally approved for the treatment of patients who had previously been treated with a BRAF inhibitor for advanced melanoma that contained a BRAFV600E or BRAFV600K mutation . This approval was based upon prolongation of overall survival using trametinib as a single agent in patients who had not received prior treatment with a BRAF inhibitor.
●Subsequently, trametinib was approved for use in combination with dabrafenib as the initial targeted therapy for patients whose melanoma contained a BRAFV600E or BRAFV600K mutation . (See 'Combined MEK plus BRAF inhibition' below.)
Efficacy as a single agent — The efficacy of trametinib as a single agent was demonstrated in the phase III METRIC trial, in which 322 patients with advanced melanoma were randomly assigned in a 2:1 ratio to either trametinib (2 mg/day orally) or chemotherapy (dacarbazine or paclitaxel) [26,28]. All patients had either the V600E or V600K mutation in their melanoma (87 and 13 percent, respectively). One third of patients had received prior chemotherapy, and 30 percent had received prior immunotherapy, but prior BRAF inhibitor therapy was not allowed. Crossover to trametinib was permitted in patients who progressed on chemotherapy.
Key results included the following:
●Progression-free survival (PFS), the primary endpoint of the trial, was significantly increased with trametinib compared with chemotherapy (median 4.8 versus 1.5 months, hazard ratio [HR] 0.47, 95% CI 0.34-0.65).
●Overall survival was significantly improved with trametinib (six-month survival rate 81 versus 67 percent, HR for death 0.54, 95% CI 0.32-0.92), even though 47 percent of patients who progressed on chemotherapy received secondary treatment with trametinib.
●The improvements in PFS and overall survival were present in all patient subsets, including those with brain metastases or other visceral metastases (M1c).
Toxicity — Cutaneous toxicity was reported by 87 percent of patients in the phase III trial. This was severe in 12 percent of cases and required hospitalization in 6 percent of patients. Other common side effects included diarrhea and edema in 43 and 26 percent of cases, respectively.
●A decreased cardiac ejection fraction was seen in 7 percent of patients treated with trametinib in the phase III trial, and this led to discontinuation of trametinib in four cases (2 percent) and dose reduction in seven cases (3 percent).
●Interstitial lung disease was reported in approximately 2 percent of cases.
●Visual problems, due to retinal detachment and retinal vein occlusion (0.5 and 0.2 percent of cases).
Trametinib has been combined with dabrafenib, a BRAF inhibitor, in an effort to delay the development of resistance to treatment and to minimize the toxicity associated with BRAF inhibition. (See 'Dabrafenib plus trametinib' below.)
Other MEK inhibitors
Binimetinib — Binimetinib is a specific inhibitor of MEK that has demonstrated activity in patients with advanced melanoma and a mutation of NRAS.
Binimetinib was studied in a phase II study in 71 patients with advanced melanoma and either a BRAFV600 mutation or an NRAS mutation (41 and 30 cases, respectively) . At a median follow-up of three months, partial responses were observed in 8 of 41 cases with BRAF mutation (20 percent) and 6 of 30 patients with NRAS mutation (20 percent). The rates of objective response plus stable disease were 52 and 63 percent, respectively, for those with BRAF and NRAS mutations .
The combination of binimetinib plus a BRAF inhibitor is being compared in a phase III trial with BRAF inhibition alone. (See 'Encorafenib plus binimetinib' below.)
Results of a phase III trial comparing binimetinib with dacarbazine in patients with advanced NRAS mutation-positive melanoma were presented at the 2016 American Society of Clinical Oncology meeting . In this trial, 402 patients with a Q61 mutation in NRAS were randomly assigned in a 2:1 ratio to binimetinib or dacarbazine. The median PFS was significantly increased with binimetinib (2.8 versus 1.5 months, HR 0.62, 95% CI 0.47-0.80). However, there was no significant difference in overall survival (11 versus 10 months) in a prespecified interim analysis, although the survival data were immature.
Binimetinib is also being studied in combination with a cyclin-dependent kinase (CDK) 4/6 inhibitor as a way to enhance its activity in patients with NRAS-mutant melanoma . Significant antitumor responses were noted in one-third of patients, stimulating further interest in this combination.
COMBINED MEK PLUS BRAF INHIBITION — Two different combinations of BRAF inhibitors plus MEK inhibitors have been shown to yield a higher response rate, longer progression-free survival (PFS), and longer overall survival compared with BRAF inhibition alone.
Dabrafenib plus trametinib — Trametinib has been combined with dabrafenib, a BRAF inhibitor, in an effort to delay the development of resistance to treatment and to reduce some toxicities directly associated with BRAF inhibition.
Based upon phase I and phase II results [33,34], two phase III trials have been conducted:
●In the phase III COMBI-d trial, 423 patients were randomly assigned to either dabrafenib (150 mg twice per day) plus trametinib (2 mg once per day) or to dabrafenib plus placebo [35-37]. All patients had advanced melanoma with a V600E or V600K mutation, and all were previously untreated. Final results of the trial (median follow-up 20 months with the combination and 16 months with dabrafenib alone) were published , and they were subsequently updated at the 2016 American Society of Clinical Oncology meeting :
•PFS, the primary endpoint of the trial, was significantly prolonged with the combination compared with dabrafenib alone (median 11.0 versus 8.8 months, hazard ratio [HR] 0.67, 95% CI 0.53-0.84). With an additional 13 months of follow-up, the three-year PFS rate remained prolonged with the combination regimen (22 versus 12 percent) . The improvement in PFS rate with the combination was seen in all subsets analyzed.
•Overall survival was improved with the combination (median 25.1 versus 18.7 months, HR 0.71, 95% CI 0.55-0.92). With additional follow-up, the overall survival rate at three years was prolonged in those treated with the combination (44 versus 32 percent), and 58 percent of patients alive and treated with the combination continued on dabrafenib plus trametinib . The improvement in overall survival was seen despite the fact that more patients assigned to dabrafenib alone subsequently received additional systemic therapy.
•The objective response rate (complete plus partial) was significantly improved (69 versus 53 percent) with the combination compared with dabrafenib alone; the complete response rates were 16 versus 13 percent, respectively.
•There were substantial differences in toxicity.
-Cutaneous toxicities were significantly more common in patients treated with dabrafenib plus placebo compared with dabrafenib plus trametinib; they included dry skin, pruritus, hyperkeratosis, hand-foot syndrome, alopecia, and skin papilloma. Squamous cell carcinoma was observed in 9 percent with dabrafenib plus placebo versus 3 percent with the combination.
-Toxicities more frequently associated with the combination included diarrhea (18 versus 9 percent), pyrexia (52 versus 25 percent), and chills (28 versus 14 percent).
-Treatment discontinuation was more common with the combination (11 versus 7 percent), primarily due to pyrexia and chills.
●In the other phase III trial, 704 patients with previously untreated metastatic melanoma were randomly assigned to either dabrafenib plus trametinib or vemurafenib . All patients had melanoma containing a BRAFV600 mutation. The trial was stopped based upon positive results after a planned interim analysis. Results were updated at the 2016 European Society for Medical Oncology meeting :
•Overall survival, the primary endpoint of the trial, was significantly increased with the dabrafenib plus trametinib combination (one-year survival rate 72 versus 65 percent, HR for death 0.69, 95% CI 0.53-0.89). Three-year overall survival remained higher with the combination of dabrafenib plus trametinib (25 versus 11 percent); 58 percent of the patients assigned to dabrafenib plus trametinib who were alive at three years remain on their original regimen.
•Median PFS was also significantly increased (11.4 versus 7.3 months, 95% CI 0.46-0.69) as was the objective response rate (67 versus 53 percent).
•The incidence of cutaneous squamous cell carcinoma and keratoacanthoma was significantly decreased with the combination of dabrafenib plus trametinib compared with vemurafenib alone (1 versus 18 percent).
Responses to this combination are relatively durable. The duration of disease control was analyzed in 78 patients who took part in the phase I study and in the randomized phase II trial with the longest follow-up . All patients in this analysis received the combination of dabrafenib and trametinib at the same doses and schedules used in the phase III trial (150 mg once a day and 2 mg once a day, respectively). Median follow-ups for the two cohorts were 46 and 47 months, respectively. PFS rates at one, two, and three years were 41 to 44 percent, 22 to 25 percent, and 18 to 21 percent, respectively. Median overall survival was 25 and 27 months in the two cohorts, and the one-, two-, and three-year overall survival rates were 72 to 80 percent, 51 to 60 percent, and 38 to 47 percent, respectively.
Factors associated with a favorable outcome from treatment with the combination of dabrafenib and trametinib were assessed in a retrospective individual patient analysis of 617 cases from three randomized trials with more than 24 months' follow-up after data cutoff . For the entire cohort, the median PFS and the median overall survival were 11.1 and 25.6 months, respectively, and were consistent across three trials. Patients with a normal lactate dehydrogenase (LDH) and less than three organs containing metastases had significantly longer PFS and overall survival compared with those with an LDH at least twice the upper limit of normal and three or more sites of organ metastasis.
Vemurafenib plus cobimetinib — Based upon the results of a phase I trial , the combination of vemurafenib plus cobimetinib was evaluated in a phase III trial in which 495 patients with previously untreated advanced melanoma were randomly assigned to vemurafenib plus cobimetinib or vemurafenib plus placebo [43,44]. All patients' tumors contained a V600 mutation.
With a median follow-up of 14.2 months, results included the following :
●PFS, the primary endpoint of the trial, was significantly increased with vemurafenib (980 mg twice per day on days 1 to 28 of each 28-day cycle) plus cobimetinib (60 mg once per day on days 1 to 21 of each 28-day cycle) compared with vemurafenib plus placebo (median 12.3 versus 7.2 months, HR 0.58, 95% CI 0.46-0.72).
●The final analysis for overall survival occurred when there were 255 deaths. Median survival was significantly longer with cobimetinib plus vemurafenib compared with placebo plus vemurafenib (22.3 versus 17.4 months, HR 0.70, 95% CI 0.55-0.90)
Encorafenib plus binimetinib — Phase I results with the combination of the novel BRAF inhibitor encorafenib (LGX818) plus binimetinib have led to the initiation of a phase III trial  in which this combination is being compared with vemurafenib alone and encorafenib alone (NCT01909453). Neither encorafenib nor binimetinib is approved for use outside a clinical trial setting.
KIT INHIBITION — Mutations in c-kit are seen in approximately 15 to 20 percent of patients with acral or mucosal melanomas and in a smaller percentage of melanomas arising in areas of chronic skin damage. Phase II studies using imatinib in unselected groups of patients with advanced melanoma demonstrated only minimal evidence of activity [48-50].
However, KIT inhibitors have useful clinically activity in some patients with activating mutations of the c-kit gene. Additional studies using targeted inhibitors are in progress in selected patient populations with mutations of c-kit; results are pending. The data supporting the use of KIT inhibitors are discussed in conjunction with their use for patients with mucosal melanomas. (See "Mucosal melanoma", section on 'Targeted therapy'.)
ANGIOGENESIS — Numerous angiogenesis-promoting molecules are overexpressed in melanoma, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and interleukin-8 (IL-8). The expression of these factors has been associated with a poorer prognosis in patients with melanoma. Inhibition of small-molecule tyrosine kinases and the monoclonal antibody bevacizumab, which binds to VEGF, have been most extensively studied. Clinical trials using these approaches have demonstrated only limited activity [51-60], and none of the agents currently has a role in the treatment of patients with metastatic melanoma.
SUMMARY AND RECOMMENDATIONS
●The mitogen-activated protein (MAP) kinase pathway is made up of several important targets for therapy of melanoma. Specific mutations in BRAF, which are present in approximately 40 to 60 percent of advanced cutaneous melanomas, can stimulate this pathway. Patients with metastatic melanoma should have their tissue assessed for the presence or absence of the V600 mutation in the BRAF gene. (See 'Approach to treatment' above.)
●The presence of a V600E or V600K mutation predicts responsiveness to BRAF inhibitors or MEK inhibition. Three agents have demonstrated significant clinical benefit and have been approved for use in patients with BRAF mutations: the BRAF inhibitors vemurafenib and dabrafenib and the MEK inhibitor trametinib. There are no clinical trials comparing these three agents with each other; however, data suggest that the BRAF inhibitors vemurafenib and dabrafenib are more active than the MEK inhibitor trametinib. Dabrafenib and vemurafenib appear to have similar clinical activity, so the choice between those two agents will likely be based on other factors, including their distinct toxicity profiles. (See 'Vemurafenib' above and 'Dabrafenib' above and 'Trametinib' above.)
●In patients with a BRAFV600E or BRAFV600K mutation, the combination of a BRAF inhibitor and an MEK inhibitor (dabrafenib plus trametinib or vemurafenib plus cobimetinib) has a longer progression-free survival, higher objective response rate, and longer overall survival compared with a BRAF inhibitor alone. The combination is also associated with significantly less skin toxicity, but greater pyrexia and chills (for dabrafenib/trametinib) and other side effects, including creatine kinase elevations, visual problems, and bleeding risk (for vemurafenib/cobimetinib). For patients who are candidates for targeted therapy, we recommend starting with a combination of a BRAF inhibitor and an MEK inhibitor rather than a single agent (Grade 1A). (See 'Combined MEK plus BRAF inhibition' above.)
●Whether patients with V600 BRAF-mutant melanoma should receive immunotherapy or molecularly targeted therapy as initial systemic therapy is unclear. For patients with a BRAFV600 mutation and an Eastern Cooperative Oncology Group performance status of 0 or 1, we suggest enrollment in the EA6134 protocol (NCT02224781) or a similar study to formally address the question of whether initial treatment with immunotherapy or targeted therapy is preferred. (See "Overview of the management of advanced cutaneous melanoma", section on 'Choice and sequence of therapy'.)
•For patients with a BRAFV600 mutation who were initially treated with immunotherapy and whose disease can no longer be controlled with immunotherapy, we recommend targeted therapy rather than chemotherapy (Grade 1A).
●Targeted therapy with BRAF inhibitors is not indicated in patients without a characteristic BRAFV600 mutation. (See 'BRAF inhibition' above.)
●For patients without a BRAFV600 mutation but with a KIT mutation, use of a KIT inhibitor (eg, imatinib) may provide an important treatment option, preferably in the context of a formal clinical trial. (See "Mucosal melanoma", section on 'Targeted therapy'.)
- Cole BF, Gelber RD, Kirkwood JM, et al. Quality-of-life-adjusted survival analysis of interferon alfa-2b adjuvant treatment of high-risk resected cutaneous melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol 1996; 14:2666.
- Wellbrock C, Hurlstone A. BRAF as therapeutic target in melanoma. Biochem Pharmacol 2010; 80:561.
- Smalley KS, Sondak VK. Melanoma--an unlikely poster child for personalized cancer therapy. N Engl J Med 2010; 363:876.
- Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 2011; 29:1239.
- Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364:2507.
- Sosman JA, Pavlick AC, Schuchter LM, et al. Analysis of molecular mechanisms of response and resistance to vemurafenib (vem) in BRAFV600E melanoma (abstract #8503). J Clin Oncol 2012. 30s.
- McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 2014; 15:323.
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202806s000lbl.pdf (Accessed on May 30, 2013).
- Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012; 380:358.
- Hauschild A, Grob JJ, Demidov LV, et al. An update on BREAK-3, a phase III, randomized trial: Dabrafenib versus dacarbazine in patients with BRAF V600E-positive mutation metastatic melanoma (Abstract 9013). American Society of Clinical Oncology 2013 meeting.
- Larkin J, Del Vecchio M, Ascierto PA, et al. Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet Oncol 2014; 15:436.
- Anforth R, Fernandez-Peñas P, Long GV. Cutaneous toxicities of RAF inhibitors. Lancet Oncol 2013; 14:e11.
- Boyd KP, Vincent B, Andea A, et al. Nonmalignant cutaneous findings associated with vemurafenib use in patients with metastatic melanoma. J Am Acad Dermatol 2012; 67:1375.
- Lacouture ME, Duvic M, Hauschild A, et al. Analysis of dermatologic events in vemurafenib-treated patients with melanoma. Oncologist 2013; 18:314.
- Chapman PB, et al. Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma. J Clin Oncol 2012.
- Zimmer L, Haydu LE, Menzies AM, et al. Incidence of new primary melanomas after diagnosis of stage III and IV melanoma. J Clin Oncol 2014; 32:816.
- Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 2012; 366:207.
- Carlos G, Anforth R, Clements A, et al. Cutaneous Toxic Effects of BRAF Inhibitors Alone and in Combination With MEK Inhibitors for Metastatic Melanoma. JAMA Dermatol 2015; 151:1103.
- Callahan MK, Rampal R, Harding JJ, et al. Progression of RAS-mutant leukemia during RAF inhibitor treatment. N Engl J Med 2012; 367:2316.
- Choe CH, McArthur GA, Caro I, et al. Ocular toxicity in BRAF mutant cutaneous melanoma patients treated with vemurafenib. Am J Ophthalmol 2014; 158:831.
- Anker CJ, Grossmann KF, Atkins MB, et al. Avoiding Severe Toxicity From Combined BRAF Inhibitor and Radiation Treatment: Consensus Guidelines from the Eastern Cooperative Oncology Group (ECOG). Int J Radiat Oncol Biol Phys 2016; 95:632.
- Klein O, Ribas A, Chmielowski B, et al. Facial palsy as a side effect of vemurafenib treatment in patients with metastatic melanoma. J Clin Oncol 2013; 31:e215.
- Launay-Vacher V, Zimner-Rapuch S, Poulalhon N, et al. Acute renal failure associated with the new BRAF inhibitor vemurafenib: a case series of 8 patients. Cancer 2014; 120:2158.
- Regnier-Rosencher E, Lazareth H, Gressier L, et al. Acute kidney injury in patients with severe rash on vemurafenib treatment for metastatic melanomas. Br J Dermatol 2013; 169:934.
- Uthurriague C, Thellier S, Ribes D, et al. Vemurafenib significantly decreases glomerular filtration rate. J Eur Acad Dermatol Venereol 2014; 28:978.
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204114s000lbl.pdf (Accessed on May 30, 2013).
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204114s001lbl.pdf (Accessed on January 09, 2014).
- Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012; 367:107.
- Ascierto PA, Schadendorf D, Berking C, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol 2013; 14:249.
- Ascierto PA, et al. Efficacy and safety of oral MEK162 in patients with locally advanced and unresectable or metastatic cutaneous melanoma harboring BRAFV600 or NRAS mutations (abstract #8511). J Clin Oncol 2012.
- Dummer R,Schadendorf D, Ascierto PA, et al. Results of NEMO: A phase III trial of binimetinib (BINI) vs dacarbazine (DTIC) in NRAS-mutant cutaneous melanoma. Abstract 9500, 2016 American Society of Clinical Oncology meeting.
- Sosman JA, Kittaneh M, Lolkema MP, et al. A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRAS-mutant melanoma: Early encouraging clinical activity (abstract 9009). 2014 American Society of Clinical Oncology meeting.
- Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012; 367:1694.
- Flaherty K, Daud A, Weber JS, et al. Updated overall survival (OS) for BRF113220, a phase 1-2 study of dabrafenib (D) alone versus combined dabrafenib and trametinib (D+T) in pts with BRAF V600 mutation-positive (+) metastatic melanoma (MM) (abstract 9010). 2014 American Society of Clinical Oncology (ASCO) meeting.
- Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 2014; 371:1877.
- Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 2015; 386:444.
- Flatherty K, Davies MA, Grob JJ, et al. Genomic analysis and 3-y efficacy and safety update of COMBI-d: A phase 3 study of dabrafenib (D) + trametinib (T) vs D monotherapy in patients (pts) with unresectable or metastatic BRAF V600E/K-mutant cutaneous melanoma. Abstract 9502 American Society of Clinical Oncology meeting.
- Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2015; 372:30.
- Robert C, Karaszewska B, Schacter J, ert al. Three-year estimate of overall survival in COMBI-v, a randomized phase 3 study evaluating first-line dabrafenib + trametinib in patients with unresectable or metastatic BRAF V600E/K-mutant cutaneous melanoma (abstract LBA40). Presented at the 2016 European Society for Medical Oncology meeting.
- Long GV, Weber JS, Infante JR, et al. Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib. J Clin Oncol 2016; 34:871.
- Long GV, Grob JJ, Nathan P, et al. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol 2016.
- Ribas A, Gonzalez R, Pavlick A, et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. Lancet Oncol 2014; 15:954.
- Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 2014; 371:1867.
- Larkin JM, Yan Y, McArthur GA, et al. Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: Phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma. J Clin Oncol 33, 2015 (suppl; abstr 9006)
- Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol 2016; 17:1248.
- Sullivan RY, Weber JS, Patel SP, et al. A phase Ib/II study of BRAF inhibitor (BRAFi) encorafenib (ENCO) plus MEK inhibitor (MEKi) binimetinib (BINI) in cutaneous melanoma patients naive to BRAFi treatment. J Clin Oncol 33, 2015 (suppl; abstr 9007)
- Penel N, Delcambre C, Durando X, et al. O-Mel-Inib: a Cancéro-pôle Nord-Ouest multicenter phase II trial of high-dose imatinib mesylate in metastatic uveal melanoma. Invest New Drugs 2008; 26:561.
- Wyman K, Atkins MB, Prieto V, et al. Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer 2006; 106:2005.
- Ugurel S, Hildenbrand R, Zimpfer A, et al. Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer 2005; 92:1398.
- Flaherty KT, Brose M, Schuchter L. Phase I/II trial of BAY 43-9006, carboplatin and paclitaxel demonstrates preliminary amtotumor activity in the expansion cohort of patients with metastatic melanoma. Proc Am Soc Clin Oncol 2004; 23:708a.
- Amaravadi RK, Schuchter LM, McDermott DF, et al. Phase II Trial of Temozolomide and Sorafenib in Advanced Melanoma Patients with or without Brain Metastases. Clin Cancer Res 2009; 15:7711.
- Eisen T, Marais R, Affolter A, et al. Sorafenib and dacarbazine as first-line therapy for advanced melanoma: phase I and open-label phase II studies. Br J Cancer 2011; 105:353.
- Hauschild A, Agarwala SS, Trefzer U, et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol 2009; 27:2823.
- Flaherty KT, Lee SJ, Zhao F, et al. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol 2013; 31:373.
- Fruehauf J, Lutzky J, McDermott D, et al. Multicenter, phase II study of axitinib, a selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, in patients with metastatic melanoma. Clin Cancer Res 2011; 17:7462.
- Varker KA, Biber JE, Kefauver C, et al. A randomized phase 2 trial of bevacizumab with or without daily low-dose interferon alfa-2b in metastatic malignant melanoma. Ann Surg Oncol 2007; 14:2367.
- González-Cao M, Viteri S, Díaz-Lagares A, et al. Preliminary results of the combination of bevacizumab and weekly Paclitaxel in advanced melanoma. Oncology 2008; 74:12.
- Perez DG, Suman VJ, Fitch TR, et al. Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N047A. Cancer 2009; 115:119.
- Kim KB, Sosman JA, Fruehauf JP, et al. BEAM: a randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced melanoma. J Clin Oncol 2012; 30:34.