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Melanoma Treatment (Professional) (cont.)

Stage IV and Recurrent Melanoma

Stage IV melanoma is defined by the American Joint Committee on Cancer's TNM classification system:[1]

  • Any T, any N, M1

Treatment Options for Patients With Stage IV and Recurrent Melanoma

  1. Immunotherapy.
    • Ipilimumab.
    • Interleukin-2 (IL-2).
  2. Signal transduction inhibitors.
    • BRAF (V-raf murine sarcoma viral oncogene homolog B1) inhibitors (for patients who test positive for the BRAF V600 mutation).
  3. Chemotherapy.
  4. Palliative local therapy.
  5. Clinical trials should be strongly considered because of the rapid advances in the development of novel agents and combinations of agents designed to reverse or interrupt aberrant molecular pathways that support tumor growth.

Treatment option overview for patients with stage IV and recurrent melanoma

Although melanoma that has spread to distant sites is rarely curable, both ipilimumab and vemurafenib have demonstrated an improvement in progression-free survival (PFS) and overall survival (OS) in international, multicenter, randomized trials in patients with unresectable or advanced disease, resulting in U.S. Food and Drug Administration (FDA) approval in 2011. Ipilimumab is an antibody against the cytotoxic T-lymphocyte antigen (anti-CTLA-4). Vemurafenib is a selective BRAF V600E kinase inhibitor, and its indication is limited to patients with unresectable or metastatic melanoma with a demonstrated BRAF V600E mutation.

IL-2 was approved by the FDA in 1998 on the basis of durable complete response (CR) rates in a minority of patients (0%–8%) with previously treated metastatic melanoma in eight phase I and II studies. No improvement in OS has been demonstrated in randomized trials.

Dacarbazine (DTIC) was approved in 1970 based on overall response rates. Phase III trials indicate an overall response rate of 10% to 20% with rare CRs observed. An impact on OS has not been demonstrated in randomized trials.[2,3,4,5,6] Temozolomide, an oral alkylating agent, appeared to be similar to DTIC (intravenous administration) in a randomized phase with a primary endpoint of OS; however, the trial was designed for superiority, and the sample size was inadequate to prove equivalency.[3]

Attempts over the past two decades to develop combination regimens, for example, multiagent chemotherapy;[7,8] combinations of chemotherapy and tamoxifen;[9,10,11] and combinations of chemotherapy and immunotherapy;[7,12,13,14,15,16,17] have not demonstrated an improvement of the combination on OS. However, advances in understanding of key molecular pathways are enabling rational development of combination therapy.

In smaller subsets of melanoma, activating mutations may occur in NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog] (15%–20%), c-KIT (28%–39% of melanomas arising in chronically sun-damaged skin, or acral and mucosal melanomas), and CDK4 (cyclin-dependent kinase 4) (<5%), whereas GNAQ is frequently mutated in uveal melanomas. Drugs developed to target these mutations are currently in clinical trials.

Malignant melanoma has been reported to spontaneously regress; however, the incidence of spontaneous complete regressions is less than 1%.[18]



Ipilimumab is a human monoclonal antibody that blocks the activity of CTLA-4, blocking the function of CTLA-4 as a down regulator of T-cell activation. It is approved for the treatment of unresectable or metastatic melanoma and supported by two prospective, randomized, international trials, one each in previously untreated and treated patients.[6,19]

Previously treated patients. A total of 676 patients with previously treated, unresectable stage III or stage IV disease, who were HLA-A*0201-positive patients, were entered into a three-arm, multinational, randomized, double-blind trial comparing ipilimumab with or without glycoprotein 100 (gp100) peptide vaccine to the gp100 vaccine plus placebo.[19] Patients were stratified by baseline metastases and prior receipt or nonreceipt of IL-2 therapy. Of the patients, 82 had metastases to the brain at baseline. The median OS was 10 months and 10.1 months among patients receiving ipilimumab alone or with the gp100 vaccine, respectively, versus 6.4 months for patients receiving the vaccine alone (hazard ratio [HR], 0.68; P < .001; HR, 0.66; P < .003).

An analysis at 1 year showed that among those patients treated with ipilimumab, 44% and 45% of them were alive compared with 25% of the patients who received vaccine only. Grade 3 to grade 4 immune-related adverse events (AEs) occurred in 10% to 15% of patients treated with ipilimumab. These immune-related AEs most often included diarrhea or colitis, and endocrine-related events (i.e., inflammation of the pituitary) that required cessation of therapy and institution of anti-inflammatory agents, such as corticosteroids or in four cases, infliximab (i.e., an anti-tumor necrosis factor-alpha antibody). There were 14 deaths related to study drugs (2.1%), and seven were associated with immune-related AEs.[19][Level of evidence: 1iA]

Previously untreated patients. A multicenter, international trial randomly assigned 502 patients untreated for metastatic disease (adjuvant treatment was allowed) in a 1:1 ratio to ipilimumab (10 mg/kg) plus dacarbazine (850 mg/m2) or placebo plus dacarbazine (850 mg/m2) at weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22.[6] Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary endpoint was survival.

Patients were stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (PS) and metastatic stage. Approximately 70% of the patients had an ECOG PS of 0, and the remainder of the patients had an ECOG PS of 1. Approximately 55% of the patients had stage M1c disease. The median OS was 11.2 months (95% confidence interval [CI], 9.4–13.6) versus 9.1 months (95% CI, 7.8–10.5). Estimated survival rates in the two groups respectively were 47.3% and 36.3% at 1 year; 28.5% and 17.9% at 2 years; and 20.9% and 12.2% at 3 years (HR for death with ipilimumab-dacarbazine, 0.72; P < .001). The most common study-drug–related AEs were those classified as immune related. Grade 3 to 4, immune-related AEs were seen in 38.1% of patients treated with ipilimumab plus dacarbazine versus 4.4% in patients treated with placebo plus dacarbazine, the most common being hepatitis and enterocolitis. No drug-related deaths occurred.[6][Level of evidence: 1iA]

Clinicians and patients should be aware that immune-mediated adverse reactions may be severe and fatal. Early identification and treatment, including potential administration of systemic glucocorticoids or other immunosuppressants according to the immune-mediated–adverse reaction management guide provided by the manufacturer, is necessary.[20]


Response to high-dose IL-2 regimens generally ranges from 10% to 20%.[12,13,21] Approximately 4% to 6% of patients may obtain a durable complete remission and be long-term survivors; these results were the basis for approval by the FDA in 1998. Phase III confirmatory trials have not been conducted, and there are currently no predictive biomarkers to select who is likely to respond to treatment.

Attempts to improve on this therapy have included the addition of lymphokine-activated killer cells (i.e., autologous lymphocytes activated by IL-2 ex vivo) and tumor-infiltrating lymphocytes (TIL) (i.e., lymphocytes derived from tumor isolates cultured in the presence of IL-2). A single-institution trial reports that adoptive cell therapy (ACT) with lymphodepletion (using cyclophosphamide plus fludarabine with or without total-body irradiation) followed by autologous TIL transfer and high-dose IL-2 may improve durable response.[22][Level of evidence: 3iiiDiv] A multicenter, randomized trial of high-dose IL-2 with and without a peptide vaccine [gp100:209–217(210M)] in patients with locally advanced stage III or stage IV melanoma who were HLA*A0201-positive reported an increase in response rate with the combination.[23][Level of evidence:1iiDiv] Multicenter, phase III trials powered for an assessment on OS are needed for validation, because response rates are not known to be a surrogate for OS in melanoma.

Signal transduction inhibitors

Studies to date indicate that both BRAF and MEK (mitogen-activated ERK-[extracellular signal-regulated kinase] activating kinase) inhibitors can significantly impact the natural history of melanoma, although as single agents, they do not appear to provide a cure.

BRAF inhibitors


Vemurafenib is an orally available, small molecule, selective BRAF inhibitor that is approved by the FDA for patients with unresectable or metastatic melanoma that tests positive for the BRAF V600E mutation. Treatment with vemurafenib is discouraged in wild-type BRAF melanoma because data from preclinical models has demonstrated that BRAF inhibitors can enhance rather than downregulate the MAPK (mitogen-activated protein kinase) pathway in tumor cells with wild-type BRAF and upstream RAS mutations.[24,25,26,27]

Previously untreated patients. The approval of vemurafenib was supported by an international, multicenter trial (BRIM-3 [NCT01006980]) that screened 2,107 patients with previously untreated, stage IIIC or IV melanoma for the BRAF V600 mutation and identified 675 patients by the cobas® 4800 BRAF V600 Mutation Test.[5] Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m2 intravenously [ IV] every 3 weeks). Coprimary endpoints were rates of OS and PFS.[5][Levels of evidence: 1iiA and 1iiDiii]

At the planned interim analysis, the Data and Safety Monitoring Board determined that both the OS and PFS endpoints had met the prespecified criteria for statistical significance in favor of vemurafenib and recommended that patients in the dacarbazine group be allowed to cross over to receive vemurafenib. A total of 675 patients were evaluated for OS; although the median survival had not yet been reached for vemurafenib and the data were immature for reliable Kaplan-Meier estimates of survival curves, the OS in the vemurafenib arm was clearly superior to that in the dacarbazine arm. The HR for death in the vemurafenib group was 0.37 (95% CI, 0.26–0.55; P < .001). The survival benefit in the vemurafenib group was observed in each prespecified subgroup, for example, age, sex, ECOG PS, tumor-stage lactic dehydrogenase, and geographic region. The HR for tumor progression in the vemurafenib arm was 0.26 (95% CI, 0.20–0.33; P < .001). The estimated median PFS was 5.3 months versus 1.6 months in the vemurafenib and dacarbazine arms, respectively.

Twenty patients had non-V600E mutations: 19 with V600K and 1 with V600D. Four patients with a BRAF V600K mutation had a response to vemurafenib.

AEs required dose modification or interruption in 38% of patients receiving vemurafenib and 16% of those receiving dacarbazine. The most common AEs with vemurafenib were cutaneous events, arthralgia, and fatigue. Cutaneous squamous cell carcinoma (SCC), keratoacanthoma, or both, developed in 18% of patients and were treated by simple excision. The most common AEs with dacarbazine were fatigue, nausea, vomiting, and neutropenia.

Previously treated patients. A total of 132 patients with a BRAF V600E or BRAF V600K mutation were enrolled in a multicenter phase II trial of vemurafenib, which was administered as 960 mg orally twice daily.[28] Of the enrolled patients, 61% percent had stage M1c disease, and 49% had an elevated lactate dehydrogenase level. All patients had received one or more prior therapies for advanced disease. Median follow-up was 12.9 months. An Independent Review Committee (IRC) reported a 53% response rate (95% CI, 44–62) with eight patients (6%) achieving CR. Median duration of response per IRC assessment was 6.7 months (95% CI, 5.6–8.6). Most responses were evident at the first radiologic assessment at 6 weeks; however, some patients did not respond until they received therapy for more than 6 months.[28][Level of evidence: 3iiiDiv]


Dabrafenib is an orally available, small molecule, selective BRAF inhibitor that has been compared with DTIC in an international, multicenter trial (BREAK-3 [NCT01227889]). A total of 250 patients with unresectable stage III or IV melanoma and BRAF V600E mutations were randomly assigned in a 3:1 ratio (dabrafenib 150 mg orally twice a day or DTIC 1000 mg/m2 IV every 3 weeks). IL-2 was allowed as prior treatment for advanced disease. The primary endpoint was PFS; patients could cross over at the time of progressive disease after confirmation by a blinded IRC.[29]

With 126 events, the HR for PFS was 0.30 (95% CI, 0.18–0.51; P < .0001). The estimated median PFS was 5.1 months versus 2.7 months for dabrafenib and DTIC, respectively. OS data are limited by the median duration of follow up and crossover. Partial response was 47% versus 5%, and CR was 3% versus 2% in patients receiving dabrafenib versus DTIC, respectively.[29][Level of Evidence: 1iiDiii]

The most frequent AEs in patients treated with dabrafenib were cutaneous (i.e., hyperkeratosis, papillomas, palmar-plantar erythrodysesthesia), pyrexia, fatigue, headache, and arthralgia. Cutaneous SCC or keratoacanthoma occurred in twelve patients, basal cell carcinoma occurred in four patients, mycosis fungoides occurred in one patient, and new melanoma occurred in two patients.[29]

MEK inhibitors


Trametinib is an orally available, small molecule, selective inhibitor of MEK1 and MEK2. Preclinical data suggest that MEK inhibitors can restrain growth and induce cell death of some BRAF-mutated human melanoma tumors. BRAF activates MEK1 and MEK2 proteins, which, in turn, activate MAP kinases.

A total of 1,022 patients were screened for BRAF mutations, resulting in 322 eligible patients (281 with V600E, 40 with V600K and 1 with both mutations).[30] Patients were randomly assigned in a 2:1 ratio to receive trametinib (2 mg once daily) or IV chemotherapy (either DTIC 1000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 every 3 weeks). Crossover was allowed, and the primary endpoint was PFS. The investigator-assessed PFS was 4.8 months in patients receiving trametinib versus 1.5 months in the chemotherapy group (HR for PFS or death, 0.45; 95% CI, 0.33–0.63; P < .001). Median OS has not yet been reached.

AEs leading to dose interruptions occurred in 35% of patients in the trametinib group and 22% of those in the chemotherapy group. AEs leading to dose reductions occurred in 27% of patients receiving trametinib and 10% of those receiving chemotherapy. The most common AEs included rash, diarrhea, nausea, vomiting, fatigue, peripheral edema, alopecia, hypertension, and constipation. Central serous retinopathy and retinal-vein occlusion are uncommon, but serious, AEs associated with trametinib. On-study cutaneous SCCs were not observed.

Combinatorial therapy with signal transduction inhibitors

Resistance to BRAF inhibitors, in patients with BRAF V600 mutations, may be associated with reactivation of the MAP kinase pathway. Early phase II data with combinations of BRAF and MEK inhibitors have supported testing this combination in phase III trials, such as NCT01584648, NCT01597908, and NCT01689519.[31]

Multikinase inhibitors


The multikinase inhibitor sorafenib has activity against both the vascular endothelial growth-factor signaling and the Raf/MEK/ERK pathway at the level of RAF kinase. This agent had minimal activity as a single agent in melanoma and two large, multicenter, placebo-controlled, randomized trials of carboplatin and taxol plus or minus sorafenib showed no improvement over chemotherapy alone as either first-line treatment or second-line treatment.[32,33]

KIT inhibitors

Early data suggest that mucosal or acral melanomas with activating mutations or amplifications in c-KIT may be sensitive to a variety of c-KIT inhibitors.[34,35,36] Phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-KIT mutation.


The objective response rate to DTIC and the nitrosoureas, carmustine and lomustine, is approximately 10% to 20%.[2,37,38,39] Responses are usually short-lived, ranging from 3 to 6 months, though long-term remissions can occur in a limited number of patients who attain a CR.[37,39] A randomized trial compared IV DTIC with temozolomide (TMZ), an oral agent that hydrolyzes to the same active moiety as DTIC; OS was 6.4 months versus 7.7 months, respectively (HR, 1.18; 95% CI, 0.92–1.52). While these data suggested similarity between DTIC and TMZ, no benefit in survival has been demonstrated for either DTIC or TMZ and therefore, demonstration of similarity did not result in approval from the FDA.[3][Level of evidence: 1iiA] An extended schedule and escalated dose of TMZ was compared with DTIC in a multicenter trial randomly assigning 859 patients ( EORTC-18032 [NCT00101218]). No improvement was seen in OS or PFS for the TMZ group, and this dose and schedule resulted in more toxicity than standard dose, single-agent DTIC.[40][Level of evidence: 1iiA]

The design of two recent randomized, phase III trials in previously untreated patients with metastatic melanoma included DTIC as the standard therapy arm. Vemurafenib (in BRAF V600 mutant melanoma) and ipilimumab showed superior OS compared with DTIC in the two separate trials.

Other agents with modest, single-agent activity include vinca alkaloids, platinum compounds, and taxanes.[37,38]

Palliative local therapy

Melanoma metastatic to distant, lymph node-bearing areas may be palliated by regional lymphadenectomy. Isolated metastases to the lung, gastrointestinal tract, bone, or sometimes the brain, may be palliated by resection with occasional long-term survival.[15,16,17]

Although melanoma is a relatively radiation-resistant tumor, palliative radiation therapy may alleviate symptoms. Retrospective studies have shown that patients with multiple brain metastases, bone metastases, and spinal cord compression may achieve symptom relief and some shrinkage of the tumor with radiation therapy.[41,42] (Refer to the PDQ summary on Pain for more information.) The most effective dose-fractionation schedule for palliation of melanoma metastatic to the bone or spinal cord is unclear, but high-dose-per-fraction schedules are sometimes used to overcome tumor resistance. A phase I and II clinical trial (MCC-11543 [NCT00005615]) evaluated adjuvant radiation therapy plus interferon in patients with recurrent melanoma and results are pending.


A published data meta-analysis of 18 randomized trials (15 of which had survival information) that compared chemotherapy with biochemotherapy (i.e., the same chemotherapy plus interferon alone or with IL-2) demonstrated no impact on OS.[43][Level of evidence:1iiA]

Other Treatment Options Under Clinical Evaluation for Patients With Stage IV and Recurrent Melanoma

  1. Immunotherapy, including anti-PD-1 and vaccines.
  2. Signal transduction inhibitors, including P13K (phosphoinositide-3 kinase) and Akt (protein kinase B inhibitors).
  3. Antiangiogenesis agents. Preclinical data suggest that increased vascular endothelial growth factor production may be implicated in resistance to BRAF inhibitors.[44]
  4. Intralesional injections; for example, oncologic viruses.
  5. Complete surgical resection of all known disease versus best medical therapy.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV melanoma and recurrent melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.


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