INTRODUCTION — The incidence of malignant melanoma is increasing at a rate greater than any other human cancer [1]. The optimal therapy varies with the stage of the disease. Surgical excision is the treatment of choice for early disease, while some patients who are at high risk for developing metastatic disease (particularly those with stage II and III cancers (table 1)) may benefit from adjuvant therapy with interferon alfa (IFNa) [2,3]. (See "Adjuvant interferon alfa for intermediate- and high-risk melanoma".)
The management of patients with disseminated disease is a difficult problem. The use of targeted therapies in the treatment of advanced melanoma will be reviewed here. Other treatments for systemic disease (immunotherapy, chemotherapy) are presented separately.
CHOICE OF THERAPY FOR DISSEMINATED DISEASE — Approaches that have been shown to provide clinically important benefit for patients with disseminated melanoma in appropriately selected patients include immunotherapy with high-dose interleukin-2 (IL-2), immunotherapy with ipilimumab, a monoclonal antibody targeting CTLA-4, and inhibition of the MAP kinase pathway with vemurafenib in patients whose tumors contain a V600 mutation in the BRAF gene.
There are no randomized trials that compare these different approaches and there are no data on the appropriate sequencing of these therapies. Until such data are available, the choice of treatment needs to be individualized. Treatment decisions depend upon multiple factors including the overall condition of the patient (eg, age and comorbidity), a molecular analysis for the presence of a V600 mutation in the BRAF gene, and the extent of metastatic disease.
- Immunotherapy with high-dose interleukin-2 (IL-2) is associated with long-term disease-free survival in a small minority of carefully selected patients and may actually result in cure. Because of the severe multiorgan toxicity associated with this therapy, treatment with high-dose IL-2 is limited to patients with excellent organ function who are treated by experienced clinicians in specialized programs capable of providing the necessary intensive care. There currently are no data on the activity of high-dose IL-2 in patients who have previously been treated with either ipilimumab or vemurafenib. (See "Immunotherapy for advanced melanoma", section on 'Interleukin-2'.)
- Ipilimumab is a monoclonal antibody that targets CTLA-4. Treatment with ipilimumab significantly increases median overall survival in both previously untreated and previously treated patients with metastatic or unresectable melanoma. Responses in patients treated with ipilimumab may develop slowly and patients may have a transient worsening of disease before disease stabilizes or tumor regresses.
Similar to IL-2, a small subset of patients treated with ipilimumab experience long-term disease-free survival. However, in contrast to IL-2, ipilimumab appears to show activity in patients with central nervous system metastases and to be tolerable in older patients and those with comorbidities. Further, ipilimumab has shown activity in patients whose disease has progressed after IL-2 therapy. Due to its toxicity profile, ipilimumab is not considered safe in patients with a history of symptomatic autoimmune disease.
Thus, patients with BRAF wild-type tumors who are not considered candidates for or do not have access to IL-2 therapy, and have no history of autoimmunity, should receive ipilimumab. For patients with BRAF V600 mutant tumors who are not candidates for, do not have access to, or have progressed after IL-2 therapy, treatment with ipilimumab rather than vemurafenib may be preferred, especially in those with a limited metastatic disease burden and/or minor disease related symptoms. (See "Anti-CTLA-4 immunotherapy in advanced melanoma".) - Vemurafenib is a specific inhibitor of activated BRAF and has been shown to significantly increase survival in patients whose tumor contains a V600 mutation in the BRAF gene. The use of vemurafenib should be limited to patients whose tumor contains this mutation. Vemurafenib produces rapid tumor regressions in the vast majority of patients with V600 mutant melanoma including those with extensive tumor burden and significant disease-related symptoms. Median progression-free survival is typically around six months; however, tumor regressions last for more than a year in many patients. Continued treatment appears necessary to maintain efficacy. Side effects are typically modest and do not generally restrict or limit treatment.
Thus, vemurafenib may be preferred over ipilimumab or high-dose IL-2 in those patients whose tumors contain a V600 mutation where a prompt response to treatment is desirable due to symptoms or the presence of bulky disease, or when there is a contraindication to ipilimumab or IL-2 therapy. Vemurafenib has shown anti-tumor activity in patients whose disease has progressed after IL-2 or ipilimumab. (See 'BRAF inhibition' below.) - Although cytotoxic chemotherapy has been widely used in patients with metastatic disease, neither single agent chemotherapy nor combination chemotherapy has been shown to consistently improve overall survival. Single agent chemotherapy (dacarbazine, temozolomide, fotemustine) should be reserved for patients who are not candidates for treatment with high-dose IL-2, ipilimumab, or vemurafenib. (See "Cytotoxic chemotherapy for metastatic melanoma".)
- In carefully selected patients, excision of one or a limited number of distant metastases can delay the need for systemic treatment or occasionally produce durable benefit. (See "Surgical management of metastatic melanoma".)
MOLECULAR PATHOGENESIS — An understanding of the molecular pathogenesis of melanoma has provided important insights that are leading to the development of targeted therapies for specific subsets of patients with metastatic melanoma. The molecular pathogenesis of melanoma is discussed separately. (See "The molecular biology of melanoma".)
BRAF INHIBITION — Activating mutations in BRAF are present in approximately 40 to 60 percent of advanced melanomas [4-6]. 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 the remainder consisting of an alternate substitution 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 [6]. 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 lack of chronic skin damage. Furthermore, for patients not treated with a BRAF inhibitor, survival was shorter overall.
Inhibitors of BRAF have demonstrated dramatic antitumor activity in early clinical studies in patients with advanced disease whose tumors have the V600E and V600K mutations. Additional data will be required to determine whether different agents have a differential effect depending upon the specific mutation present.
Virtually every patient treated with an inhibitor of BRAF eventually has disease progression [7]. Mechanisms of resistance are discussed separately. (See "The molecular biology of melanoma", section on 'Mechanisms of resistance'.)
Vemurafenib — Vemurafenib is a potent inhibitor of the kinase domain in mutant BRAF. Phase I and II studies showed that vemurafenib had a high level of activity against advanced melanomas containing characteristic mutations of the BRAF gene [8,9].
These findings were confirmed in a phase III trial that compared vemurafenib with dacarbazine in previously untreated patients whose tumors contained the V600 mutation in BRAF [7]. In the 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. Following a planned interim analysis based upon predetermined criteria, patients assigned to dacarbazine were allowed to crossover to vemurafenib. Median follow-ups at the interim analysis for the vemurafenib and dacarbazine treatment arms were 3.8 and 2.3 months, respectively. Results of the trial, based upon that interim analysis, include the following:
- Overall survival was significantly increased in patients assigned to vemurafenib compared with dacarbazine (estimated six-month survival rates 84 versus 64 percent, hazard ratio [HR] for death 0.37, 95%CI 0.26-0.55).
- Progression-free survival was significantly longer in those initially treated with vemurafenib (median 5.3 versus 1.6 months, HR 0.26, 95% CI 0.20-0.33).
- The objective response rate was significantly higher with vemurafenib (48 versus 4 percent). The trial included 10 patients with V600K mutations who were treated with vemurafenib: four of these (40 percent) had a partial response to treatment.
- Planned subset analyses found that the improvement in overall survival and progression-free survival with vemurafenib therapy appeared to be independent of age, sex, disease stage (IIIC, M1a, M1b, or M1c (table 1)), or lactate dehydrogenase level (normal or elevated).
- The most common significant side effects with vemurafenib were cutaneous, and included squamous cell carcinomas and keratoacanthomas in 12 and 8 percent, respectively, and photosensitivity reactions in 12 percent. These skin tumors occur within weeks of initiation of treatment with these BRAF inhibitors and were treated with excision. The development of such lesions did not require discontinuation of vemurafenib therapy.
Molecular studies indicate that these lesions are due to a paradoxical activation of the mitogen activated protein kinase MAPK pathway that bypasses the inhibition of BRAF [10]. 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 become oncogenic when subjected to BRAF inhibition.
Other grade 2 or 3 side effects seen in 10 percent or more of patients included arthralgia and fatigue (21 and 13 percent, respectively). Overall, 38 percent of patients required vemurafenib dose modification or interruption.
Vemurafenib has been associated with prolongation of the QT interval. The FDA-approved manufacturers’ labeling recommends that ECG and electrolytes be monitored before treatment and after dose modification. Vemurafenib is a 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 2) or inhibit CYP3A4 (table 3). (See "Cardiotoxicity of nonanthracycline cancer chemotherapy agents", section on 'Vemurafenib'.)
Additional data supporting the efficacy of vemurafenib from the BRIM-2 phase II study, which was conducted in 132 patients who had previously received at least one prior to systemic therapy [9]. With a median follow-up of 12.9 months, the objective response rate was 53 percent, including 6 percent with complete responses. The median progression-free survival was 6.8 months and the median overall survival was 15.9 months, with a one-year survival rate of 58 percent.
Vemurafenib was approved by the US Food and Drug administration in August 2011 for use in patients whose tumors contain the V600E mutation in BRAF [11]. The role of vemurafenib versus high-dose IL-2 or ipilimumab is discussed above. (See 'Choice of therapy for disseminated disease' above.)
Dabrafenib — Another specific BRAF inhibitor, dabrafenib (GSK2118436), has also shown significant activity in patients with metastatic melanoma [12]. Preliminary results of a phase I-II study with this agent were presented at the 2010 American Society of Clinical Oncology (ASCO) meeting. Among the 57 melanoma patients with an activating mutation of BRAF, 27 objective responses were observed, including 10 of 16 at the planned phase II dose. A phase III trial comparing dabrafenib with dacarbazine is currently in progress (NCT01227889) [13].
Dabrafenib appears to have activity against previously untreated brain metastases. In a preliminary analysis presented at the 2010 ESMO meeting, brain metastases decreased in size in all seven evaluable patients, and three patients had a complete response of their brain lesions [14].
Sorafenib — Sorafenib blocks BRAF, as well as tyrosine kinases associated with vascular endothelial growth factor and platelet derived growth factor. However, sorafenib does not block the V600E mutated oncogenic BRAF. There is no rationale at present for sorafenib either as a single agent or in combination with chemotherapy in melanoma patients, regardless of their V600 mutation status.
Although sorafenib had little or no activity as a single agent in a phase II trial in patients with advanced melanoma [15], substantial antitumor activity was observed when sorafenib was combined with carboplatin plus paclitaxel, dacarbazine, or temozolomide [16-18]. Despite these phase II observations, two randomized phase III trials failed to confirm any benefit from combining sorafenib with cytotoxic chemotherapy [19,20]. In the larger of these, 823 patients were randomly assigned to carboplatin plus paclitaxel with or without sorafenib [20]. Results of this trial were presented at the American Society of Clinical Oncology (ASCO) meeting in 2010. The median overall survival was 11 months on both treatment arms (hazard ratio 1.0), and the objective response rate was not significantly higher in those receiving chemotherapy plus sorafenib compared to chemotherapy alone (18 versus 16 percent).
OTHER MAP KINASE TARGETED THERAPIES
MEK inhibitors — Several MEK inhibitors are under development for treating metastatic melanoma and other malignancies. Although initial clinical studies suggested that these agents had only limited activity in patients with melanoma, more recent work indicates that these agents may have clinically useful activity in patients with activating mutations in BRAF [21,22]. (See 'BRAF inhibition' above.)
At least some evidence of activity as single agents has been observed with two inhibitors of MEK:
- Selumetinib – Selumetinib was compared with temozolomide in a randomized, phase II trial that included 200 patients with previously untreated, unresectable stage III or IV melanoma. There was no significant difference in progression-free survival, the primary endpoint. In a retrospective analysis, Among patients with a BRAF mutation, 5 of 45 (11 percent) patients with a BRAF mutation had an objective tumor response.
- GSK1120212 – In a phase II study, 97 patients with stage IV, BRAF-mutated melanoma were treated with GSK1120212 [22]. A preliminary report of results found that there was one complete response (2 percent) and 10 patients (25 percent) with stable disease in the 40 patients previously treated with a BRAF inhibitor. Among the 57 patients who had only received prior chemotherapy or immunotherapy but had not been treated with a BRAF inhibitor, there were 2 complete and 17 partial responses, plus 27 patients with stable disease (4, 30, and 47 percent, respectively).
Kit inhibitors — 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 [23-25].
However, kit inhibitors may have useful clinically activity in patients with activating mutations of the c-kit gene. The efficacy of imatinib was analyzed in two phase II studies in patients whose tumors contained either c-kit mutation or amplification [26,27]. Together these studies included 68 evaluable patients, and the objective partial response rate for these studies was 21 percent with some of the responses long-term and on-going.
Additional studies using other kit inhibitors are in progress in selected patient populations with mutations of c-kit, including an international randomized trial comparing nilotinib to DTIC (NCT01028222) [28].
ANGIOGENESIS — Numerous angiogenesis-promoting molecules are overexpressed in melanoma, including VEGF, PDGF, fibroblast growth factor, and interleukin-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.
Axitinib — Axitinib, a potent inhibitor of multiple vascular endothelial growth factor receptors, was evaluated in a phase II study that included 32 patients with metastatic melanoma, 25 of whom had received one prior systemic treatment modality [29]. The objective response rate was 19 percent, and the median progression-free and overall survival durations were 2.9 and 6.6 months. Additional clinical trials will be required to determine whether axitinib has a role in patients with metastatic melanoma, either alone or in a combination regimen.
Bevacizumab — Several small phase II studies evaluating bevacizumab, either alone or in combination with interferon-alfa or chemotherapy (paclitaxel, carboplatin), showed evidence of activity in patients with advanced melanoma [30-32].
Based upon these results, the randomized Bevacizumab in Advanced Melanoma (BEAM) phase II trial was conducted, in which 214 patients were treated with carboplatin plus paclitaxel, with or without bevacizumab [33]. In the planned analysis with a median follow-up of 13-months, progression-free survival and overall survival were better with the bevacizumab (5.6 versus 4.2 months, p=0.14 and 12.3 versus 8.6 months, p=0.04). The combination with bevacizumab resulted in a higher response rate (25.5 versus 16.4 percent, p=0.16). Although the overall data only showed a trend toward benefit, in the subset of patients with M1c disease, particularly those with high LDH, there was significant OS benefit. A randomized phase III trial is being considered in this subset of patients to prospectively validate this observation.
APOPTOSIS PATHWAY
Oblimersen — Oblimersen is an antisense oligonucleotide that suppresses expression of Bcl-2, a key anti-apoptotic protein in malignant cells.
In a multinational trial comparing dacarbazine with and without oblimersen in 771 patients with previously untreated melanoma, combined therapy was associated with a significantly higher objective response rate (14 versus 8 percent) and longer time to progression (2.6 versus 1.6 months), as well as a trend towards longer overall survival (9.0 versus 7.8 months, p = 0.08) [34]. Overall survival was significantly prolonged in patients with a normal serum lactic dehydrogenase (LDH). Eleven patients who received oblimersen achieved a complete response (CR). Six of these were alive and free of disease, including four who were followed for at least 36 months. Only three patients receiving dacarbazine alone achieved CR, two of whom were alive and disease-free, at 28 and 29 months, respectively.
An additional phase III clinical trial is underway to define the role of oblimersen in combination with dacarbazine in patients with normal LDH. Oblimersen has not been approved by the FDA.
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. Vemurafenib is a specific inhibitor of activated BRAF, and thus provides a means for individualized therapy in selected patients with advanced disease. (See "The molecular biology of melanoma", section on 'MAPK pathway'.)
- Patients with metastatic melanoma should have tissue assessed for the presence or absence of the V600 mutation in the BRAF gene. The presence of a V600E or K mutation predicts responsiveness to BRAF inhibition with vemurafenib. (See 'BRAF inhibition' above.)
- The treatment of metastatic melanoma depends upon multiple factors including the overall condition of the patient (eg, age and comorbidity), a molecular analysis for the presence of a V600 mutation in the BRAF gene, and the extent of metastatic disease. There are no randomized trials that compare these different approaches and there are no data on the appropriate sequencing of these therapies. (See 'Choice of therapy for disseminated disease' above.)
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