miércoles, 8 de mayo de 2019

Melanoma Treatment (PDQ®) 3/3 —Health Professional Version - National Cancer Institute

Melanoma Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute



Melanoma Treatment (PDQ®)–Health Professional Version

Unresectable Stage III, Stage IV, and Recurrent Melanoma Treatment

Treatment Options for Unresectable Stage III, Stage IV, and Recurrent Melanoma

Treatment options for unresectable stage III, stage IV, and recurrent melanoma include the following:
  1. Intralesional therapy.
    1. Talimogene laherparepvec (T-VEC).
  2. Immunotherapy.
    1. Checkpoint inhibitors.
    2. High-dose interleukin-2 (IL-2).
    3. Dual immunomodulation.
    4. Dual checkpoint inhibition.
  3. Signal-transduction inhibitors.
    1. BRAF (V-raf murine sarcoma viral oncogene homolog B1) inhibitors (for patients who test positive for the BRAF V600 mutation).
    2. Mitogen-activated protein kinase (MEK) inhibitors.
    3. KIT inhibitors.
    4. Combination therapy with signal-transduction inhibitors.
  4. Chemotherapy.
  5. Palliative local therapy.
Two approaches—checkpoint inhibition and targeting the mitogen-activated protein kinase (MAPK) pathway—demonstrated improvement in progression-free survival (PFS) and overall survival (OS) in randomized trials. Anti–PD-1 monotherapy (pembrolizumab or nivolumab) demonstrated improved efficacy outcomes with better safety profiles when compared with treatment using single-agent anti–CTLA-4 (ipilimumab) or investigator choice of chemotherapy. The combination of anti–PD-1 and anti–CTLA-4 immunotherapies (nivolumab and ipilimumab) also prolongs PFS and OS compared with ipilimumab, but the combination is associated with significant toxicity.
Because of the rapid development of new agents, combinations, and remaining questions, patients and their physicians are encouraged to consider a clinical trial for initial treatment and at the time of progression. Clinical trials are addressing the following issues:
  • Optimal doses for combination immunotherapy to decrease toxicity and preserve efficacy.
  • How to select the patients who will benefit from combination immunotherapy versus monotherapy.
  • The role of PD-L1 expression as a biomarker for efficacy.
  • The role of maintenance therapy.
  • The value of sequencing therapies, such as immunotherapy and targeted therapy.

Intralesional therapy

Talimogene laherparepvec (T-VEC)
T-VEC is a genetically modified, herpes simplex virus type 1 (HSV1) oncolytic therapy approved for local intralesional injection into unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma that recurs after initial surgery. T-VEC is designed to replicate within tumors, causing lysis, and to produce granulocyte-macrophage colony-stimulating factor (GM-CSF). Release of antigens together with virally derived GM-CSF may promote an antitumor immune response; however, the exact mechanism of action is unknown.
The approval of T-VEC by the U.S. Food and Drug Administration (FDA) is based on data that demonstrated shrinkage of lesions; however, improvement of OS or an effect on visceral metastases or improvement in quality of life has not been shown.
Evidence (T-VEC):
  1. In a multinational, randomized, open-label trial (NCT00769704), 436 patients were randomly assigned 2:1 to intralesional T-VEC or subcutaneous GM-CSF for at least 6 months or until there were no more injectable lesions.[1][Level of evidence: 1iiDiv] Eligible patients had stage IIIB, IIIC, and IV melanoma with unresectable, bidimensionally measurable lesions. The primary endpoint was durable response rate (DRR) (complete response [CR] or partial response [PR] lasting for >6 months) as assessed by independent review. The study was stratified by site of first recurrence, presence of liver metastases, disease stage, and previous nonadjuvant systemic treatment.
    • The median patient age was 63 years (range 22–94 years), 70% of patients had a baseline Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0, 30% had stage III disease, and 70% had stage IV disease (27% M1a; 21% M1b; and 22% M1c). Previous therapy for melanoma had been received by 53% of the patients.
    • The first dose only was administered at 106 plaque-forming units (pfu)/mL to a maximum of 4 mL for all lesions combined. Subsequent doses were administered at 8 pfu/mL up to 4.0 mL for all injected lesions combined with the injected volume based on the size of the lesion. Injection into visceral lesions was not allowed.
    • In patients treated with T-VEC, 16% (95% confidence interval [CI], 12.0–20.5) had a DRR versus 2% (95% CI, 0–4.5) in patients receiving GM-CSF. Subgroup analysis suggests that the differences in DRRs between T-VEC versus GM-CSF may be greater in earlier-stage disease and treatment-naïve disease. Patients with stage IIIB and IIIC had a 33% DRR with T-VEC versus 0% with GM-CSF; 16% versus 2%, respectively in patients with stage IV M1a disease; 3% versus 4%, respectively in patients with stage IV M1b disease; and, 8% versus 3%, respectively in patients with stage IV M1c disease. Patients treated with T-VEC or GM-CSF as first-line therapy had a DRR of 24% versus 0%; however, patients who received treatment as second-line therapy or greater had a DRR of 10% versus 4%.
    • The median duration of exposure to T-VEC was 23 weeks (5.3 months) with 26 patients exposed for more than 1 year. The most common adverse events (AEs) in the T-VEC group were fatigue (50%), chills (49%), pyrexia (43%), nausea (36%), influenza-like illness (30%), and injection site pain. The rate of discontinuation resulting from toxicity to T-VEC was 4% versus 2% in the GM-CSF group. Of the ten deaths in patients treated with T-VEC, eight deaths were considered the result of PD-1, salmonella infection, and one myocardial infarction; none were considered related to therapy, based on findings of the investigator.
Precautions: T-VEC is a live, attenuated HSV and may cause life-threatening, disseminated herpetic infection. It is contraindicated in immunocompromised or pregnant patients. Healthcare providers and close contacts should avoid direct contact with injected lesions. Biohazard precautions for preparation, administration, and handling are provided in the label.
Detailed prescribing information by treatment cycle and lesion size are provided in the FDA label.

Immunotherapy

Checkpoint inhibitors
Anti–PD-1 and PD-L1
The PD-1 pathway is a key immunoinhibitory mediator of T-cell exhaustion. Blockade of this pathway can lead to T-cell activation, expansion, and enhanced effector functions. PD-1 has two ligands, PD-L1 and PD-L2. Two anti–PD-1 antibodies, pembrolizumab and nivolumab, were approved by the FDA on the basis of improved OS in randomized trials.
Pembrolizumab
Evidence (pembrolizumab):
  1. Previously treated patients. A total of 173 patients with unresectable or metastatic melanoma with disease progression within 24 weeks of the last dose of ipilimumab and, if BRAF V600 mutation positive, previous treatment with a BRAF inhibitor, were randomly assigned to one of two doses of pembrolizumab—2 mg/kg or 10 mg/kg—every 3 weeks. The trial excluded patients with an autoimmune disease, a condition requiring immunosuppression, or a history of severe immune-related adverse events (irAEs) from treatment with ipilimumab.
    • The median age was 61 years; 60% were male; 67% had an ECOG PS of 0, and 33% had an ECOG PS of 1. Eighteen percent of patients had tumors that were BRAF V600 mutation positive, 39% had an elevated lactate dehydrogenase (LDH), 64% had M1c disease, 9% had brain metastases, and 72% had undergone two or more therapies for advanced disease. The primary outcome measure was overall response rate (ORR) according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) criteria as assessed by blinded independent central review.[2][Level of evidence: 1iiDiv]
    • The ORR determined by independent central review was 26% (95% CI, -14–13; P= .96) in the 2 mg/kg arm, consisting of one CR and 20 PRs in 81 patients. Median follow-up was 8 months, and all patients had a minimum of 6 months of follow-up. Among the 21 patients with an objective response, 18 had ongoing responses, ranging from 1.4+ months to 8.5+ months.
    • Response rate in the 10 mg/kg arm was similar at 26%, consisting of 20 responses in 76 patients. Responses were seen in patients with and without BRAF V600 mutations.
    • The approved dose was 2 mg/kg administered as an intravenous (IV) infusion for 30 minutes every 3 weeks.
    Pembrolizumab was discontinued because of AEs in 7% of the patients treated with 2 mg/kg, with 3% considered drug-related AEs by the investigators. The most common AEs in the 2 mg/kg versus 10 mg/kg arms were:
    • Fatigue (33% vs. 37%).
    • Pruritus (23% vs. 19%).
    • Rash (18% vs. 18%).
    Other common AEs included cough, nausea, decreased appetite, constipation, arthralgia, and diarrhea. The most frequent and serious AEs that occurred in more than 2% of a total of 411 patients treated with pembrolizumab included renal failure, dyspnea, pneumonia, and cellulitis. Additional clinically significant irAEs included pneumonitis, colitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and hepatitis.
    The FDA label provides recommendations for suspected irAEs, including withholding the drug and administering corticosteroids.
  2. Previously untreated and treated patients. A multicenter, international trial (KEYNOTE 006 [NCT01866319]) randomly assigned 834 patients with metastatic melanoma in a 1:1:1 ratio to receive pembrolizumab (10 mg/kg IV q 2 weeks or q 3 weeks) or four cycles of ipilimumab (3 mg/kg q 3 weeks).[3] Patients were stratified by ECOG PS (0 vs. 1), line of therapy (first-line vs. second-line), and PD-L1 expression (positive vs. negative). The primary endpoints were PFS and OS.[3][Level of evidence: 1iiA]
    Approximately 66% of patients had received no previous systemic therapy for advanced melanoma. BRAF V600 mutations were present in 36% of patients and of these, approximately 50% had received previous BRAF inhibitor treatments. The study did not enroll patients with BRAF V600 mutations with high LDH levels and symptomatic or rapidly progressive disease who had not received anti-BRAF therapy, which could provide rapid clinical benefit. Approximately 80% of patients had PD-L1–positive tissue samples.
    • At the time of the second interim analysis, the OS results crossed the prespecified efficacy boundary: the two pembrolizumab groups were superior to the OS in the ipilimumab group at the prespecified, one-sided, alpha level of 0.005. The Data and Monitoring Safety Board (DMSB) recommended that the study results be unblinded and pembrolizumab be made available to patients with disease progression in the ipilimumab group. The median duration of follow-up at time of second interim analysis was 12 months for all patients, with 289 deaths. Median OS had not been reached in any treatment group.
    • The 1-year estimates of survival were 74% for patients receiving pembrolizumab every 2 weeks (hazard ratio [HR]death as compared with the ipilimumab group, 0.63; 95% CI, 0.47–0.83; P < .0005); 68% for patients receiving pembrolizumab every 3 weeks (HRdeath compared with ipilimumab, 0.69; 95% CI, 0.52–0.90; P = .0036); and 58% for patients treated with ipilimumab.
    • Benefit was seen across all subgroups except for patients with PD-L1–negative tumors. However, since this subset was small (18% of patients) and the CI was wide, no definitive conclusions could be drawn from this study.
    • Grade 3 to 5 AEs considered to be related to a study drug were 13% for pembrolizumab every 2 weeks, 10% for pembrolizumab every 3 weeks, and 20% for ipilimumab. Rates of study-drug discontinuation from toxicity were 4% for pembrolizumab every 2 weeks, 7% for pembrolizumab every 3 weeks, and 9% for ipilimumab. The one death, resulting from cardiac arrest, occurred in the ipilimumab group in a patient with type 2 diabetes mellitus caused by metabolic imbalances associated with ipilimumab-induced diarrhea.
Nivolumab
Evidence (nivolumab):
  1. Previously treated patients. Accelerated approval was based on a planned noncomparative interim analysis of the first 120 patients who received nivolumab with at least 6 months' follow-up from a multicenter, open-label trial (CheckMate 037[NCT01721746]) that randomly assigned patients (2:1) to nivolumab (3 mg/kg q 2 weeks) or the investigator’s choice of chemotherapy (either dacarbazine [DTIC] 1,000 mg/m2 IV q 3 weeks or the combination of carboplatin [area under the curve 6] q 3 weeks plus paclitaxel 175 mg/m2 q 3 weeks).[FDA label][Level of evidence: 3iiiDiv] Patients were required to have unresectable or metastatic melanoma that had progressed after treatment with ipilimumab and, if BRAF V600 mutation-positive, a BRAF inhibitor. The trial excluded patients with an autoimmune disease, a condition requiring immunosuppression, or a history of severe irAEs from treatment with ipilimumab.
    • Median age of patients was 58 years; 65% of patients were male; and, ECOG PS was 0 in 58% of patients. BRAF V600 mutation was present in 22% of patients; 76% had M1c disease; 56% had an elevated LDH; 18% had a history of brain metastases; and, 68% had received two or more systemic therapies previously for metastatic disease.
    • ORR and OS were coprimary endpoints. ORR was 32% (95% CI, 23–41) with four CRs and 34 PRs as assessed by RECIST 1.1 criteria and an independent central review. Among the 38 patients with responses, 33 (87%) had ongoing responses with durations from 2.6+ to 10.0+ months.
    • Responses were seen in patients with and without BRAF V600 mutations.
    • Safety analysis is based on 268 patients. Nivolumab was discontinued because of AEs in 9% of patients. Serious AEs occurred in 41% of patients and grade 3 and grade 4 AEs occurred in 42% of patients. The most common AEs were rash, cough, upper respiratory tract infection, and peripheral edema. Other important AEs included ventricular arrhythmia, iridocyclitis, increased amylase and lipase, dizziness, and neuropathy.
    The FDA label provides recommendations for suspected irAEs, including withholding the drug and administering corticosteroids.
  2. Previously untreated patients. A total of 418 patients with unresectable stage III or stage IV melanoma without a BRAF mutation were randomly assigned (1:1) in a double-blind multicenter trial to receive nivolumab (3 mg/kg q 2 weeks) and a DTIC-matched placebo (q 3 weeks) or DTIC (1,000 mg/m2 q 3 weeks with a nivolumab-matched placebo q 2 weeks). The primary endpoint was OS.[4][Level of evidence: 1iA ] The trial was conducted in 80 centers in Europe, Israel, Australia, Canada, and South America, which are countries where DTIC had been a standard first-line treatment in patients without a BRAF mutation.
    • The DMSB noted a potential difference in OS during safety review. On June 10, 2014, an abbreviated report from an unplanned interim–database lock was reviewed showing a significant difference in OS in favor of nivolumab. The DMSB recommended that the study be unblinded and allow patients on DTIC to receive nivolumab. The intended sample size was approximately 410 patients; a total of 418 patients had been entered.
    • Results from the double-blind portion of the study before the crossover amendment showed that median OS was not reached in the nivolumab group and was 10.8 months (95% CI, 9.3–12.1) in the DTIC group. The OS rate at 1 year was 72.9% (95% CI, 65.5–78.9) in the nivolumab group and 42.1% (95% CI, 33.0–50.9) in the DTIC group. The HRdeath was 0.42; 99.79% CI, 0.25–0.73; P < .001.
    • The most common AEs in the nivolumab group were fatigue (19.9%), pruritus (17%), nausea (16.5%), and diarrhea (16%). In the nivolumab group, 6.8% of patients discontinued study treatment because of AEs compared with 11.7% of patients discontinuing study treatment in the DTIC group. AEs with potential immunologic etiology that occurred included gastrointestinal, hepatic, pulmonary, renal, endocrine, and skin; however, the majority resolved with a delay in study treatment, glucocorticoid administration, or both per management guidelines for nivolumab. No deaths were attributed to drug-related AEs in either group.
  3. Change in dosing regimen for nivolumab in metastatic melanoma.
    • In a population pharmacokinetic response analysis and a dose/exposure-response analysis, the flat dose of 240 mg of nivolumab every 2 weeks was considered pharmacokinetically equivalent to the dosing regimen of 3 mg/kg. Clinical safety and efficacy at the two doses appeared similar across body weight and tumor types in melanoma, non-small cell lung cancer and renal cell carcinoma.[5]
    • The dosing regimen approved by the FDA for monotherapy has changed from 3 mg/kg to 240 mg IV every 2 weeks until disease progression or intolerable toxicity. The dosing regimen of 1 mg/kg of IV nivolumab when combined with ipilimumab will remain unchanged until after therapy with ipilimumab is complete when the regimen will change to a 240 mg dose every 2 weeks until disease progression or intolerable toxicity.
Anti–cytotoxic T-lymphocyte antigen-4 (CTLA-4)
Ipilimumab
Ipilimumab is a human monoclonal antibody that binds to CTLA-4, thereby blocking its ability to downregulate T-cell activation, proliferation, and effector function.
Ipilimumab has demonstrated clinical benefit by prolonging OS in randomized trials and was approved by the FDA in 2011. Two prospective, randomized, international trials, one each in previously untreated and treated patients, supported the use of ipilimumab.[6,7]
Evidence (ipilimumab):
  1. Previously treated patients: A total of 676 patients with previously treated, unresectable stage III or stage IV disease, and who were HLA-A*0201-positive, entered into a three-arm, multinational, randomized (3:1:1), double-blind, double-placebo trial. A total of 403 patients were randomly assigned to receive ipilimumab (3 mg/kg q 3 weeks for 4 doses) with glycoprotein 100 (gp100) peptide vaccine. One hundred thirty-seven patients received ipilimumab (3 mg/kg q 3 weeks for 4 doses), and 136 patients received the gp100 vaccine. Patients were stratified by baseline metastases and previous receipt or nonreceipt of IL-2 therapy. Eighty-two of the patients had metastases to the brain at baseline.[7][Level of evidence: 1iA]
    • The median OS was 10 months among patients who received ipilimumab alone and 10.1 months among those receiving ipilimumab with the gp100 vaccine, compared with 6.4 months for patients who received the vaccine alone (HR of ipilimumab alone vs. gp100 alone, 0.66; P < .003; HR of ipilimumab plus vaccine vs. gp100 alone, 0.68; P < .001).
    • An analysis at 1 year showed that among patients treated with ipilimumab, 44% of those treated with ipilimumab and 45% of those treated with ipilimumab and the vaccine were alive, compared with 25% of the patients who received the vaccine only.
    • Grade 3 or grade 4 irAEs occurred in 10% to 15% of patients treated with ipilimumab. These irAEs most often included diarrhea or colitis, and endocrine-related events (e.g., inflammation of the pituitary). These events required cessation of therapy and institution of anti-inflammatory agents such as corticosteroids or, in four cases, infliximab (an antitumor necrosis factor-alpha antibody).
    • There were 14 drug-related deaths (2.1%), and seven deaths were associated with irAEs.
  2. 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 receive ipilimumab (10 mg/kg) plus DTIC (850 mg/m2) or placebo plus DTIC (850 mg/m2) at weeks 1, 4, 7, and 10 followed by DTIC alone every 3 weeks through week 22. 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 ECOG 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 patients had stage M1c disease.[6][Level of evidence: 1iA]
    • The median OS was 11.2 months (95% CI, 9.4–13.6) for the ipilimumab-DTIC group versus 9.1 months (95% CI, 7.8–10.5) for the placebo-DTIC group. Estimated survival rates in the ipilimumab-DTIC group were 47.3% at 1 year, 28.5% at 2 years, and 20.8% at 3 years (HRdeath, 0.72; P < .001); and in the placebo-DTIC group, the rates were 36.3% at 1 year, 17.9% at 2 years, and 12.2% at 3 years.
    • The most common study-drug–related AEs were those classified as immune related. Grade 3 or grade 4 irAEs were seen in 38.1% of patients treated with ipilimumab plus DTIC versus 4.4% of patients treated with placebo plus DTIC, the most common events were hepatitis and enterocolitis.
    • No drug-related deaths occurred.
Clinicians and patients should be aware that immune-mediated adverse reactions may be severe or 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, are necessary.[8]
High-dose IL-2
IL-2 was approved by the FDA in 1998 because of durable CRs in eight phase I and II studies. Phase III trials comparing high-dose IL-2 to other retreatments, providing an assessment of relative impact on OS, have not been conducted.
Evidence (high-dose IL-2):
  1. Based on a pooled analysis of 270 patients from eight single- and multi-institutional trials in 22 institutions conducted between 1985 and 1993:
    • High-dose IL-2 demonstrated a 6% to 7% CR rate.[9]
    • With a median follow-up time for surviving patients of at least 7 years, the median duration of CRs was not reached but was at least 59 months.[10]
Strategies to improve this therapy are an active area of investigation.
Dual immunomodulation
T-cells coexpress several receptors that inhibit T-cell function. Preclinical data and early clinical data suggest that coblockade of the two inhibitory receptors, CTLA-4 and PD-1, may be more effective than blockade of either alone.[11] This has led to a phase III trial (NCT01844505) comparing each single agent with the combination.
Dual checkpoint inhibition
CTLA-4 inhibitor plus PD-1 inhibitor
Evidence (ipilimumab plus nivolumab):
  1. Previously untreated patients. In an international, randomized, double-blind trial (CheckMate 067), 945 previously untreated patients with unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio to:
    • Arm 1: nivolumab alone 3 mg/kg q 2 weeks plus placebo;
    • Arm 2: nivolumab (1 mg/kg q 3 weeks) plus ipilimumab (3 mg/kg q 3 weeks for 4 doses) followed by 3 mg of nivolumab q 2 weeks; or
    • Arm 3: ipilimumab alone (3 mg/kg q 3 weeks for 4 doses plus placebo).
    PFS and OS were coprimary endpoints. The study was powered to compare the combination of nivolumab plus ipilimumab with ipilimumab monotherapy, and nivolumab monotherapy with ipilimumab monotherapy; the study was not powered to compare combination ipilimumab plus nivolumab with nivolumab.
    Patients were stratified according to tumor PD-L1 status assessed in a central laboratory by immunohistochemical testing (positive vs. negative or indeterminate), BRAF mutation status (V600 mutation-positive vs. wild-type), and American Joint Committee on Cancer stage.[12][Level of evidence: 1iiA]
    1. Characteristics at baseline included 74% of patients with an ECOG PS of 0; 36% had elevated LDH; 31.5% had a BRAF mutation; and 58% had M1c disease. A minority of patients (23.6%) had a PD-L1–positive tumor.
    2. The prospectively defined coprimary analysis of PFS occurred after all patients had at least 9 months of follow-up. Treatment with nivolumab alone or in combination with ipilimumab resulted in significantly longer PFS than with ipilimumab alone. Results were consistent across the prespecified stratification factors. Median PFS was 6.9 months (95% CI, 4.3–9.5) with nivolumab, 11.5 months (95% CI, 8.9–16.7) with nivolumab plus ipilimumab, and 2.9 months (95% CI, 2.8–3.4) with ipilimumab.
    3. The prospectively specified coprimary analysis of OS was to occur at 28 months. With 467 deaths, the rate of OS at this time point was 59% in the nivolumab group, 64% in the combination group, and 45% in the ipilimumab group (HRdeath for the combination vs. ipilimumab, 0.55 [98% CI, 0.42–0.72; P< .001]; HRdeath with nivolumab vs. ipilimumab 0.63 [98% CI, 0.48–0.81; P< .001]).[13]
    4. In a descriptive analysis with a minimum follow-up of 36 months, the following data were found:
      • OS rates were 52% in the nivolumab group, 58% in patients treated with the combination, and 34% in the ipilimumab group.
      • The median OS was not reached in the combination arm (95% CI, 38.2 months–not reached). Median OS in the single-agent nivolumab and ipilimumab groups were 37.6 months (95% CI, 29.1–not reached) and 19.9 months (95% CI, 16.9–24.6), respectively.
      • The HRdeath for the combination versus ipilimumab was 0.55 (99.5% CI, 0.45–0.69; P < .001); for nivolumab versus ipilimumab, the HR was 0.65 (99.5% CI, 0.53–0.80; P < .001).
    5. AEs were highest in the combination arm and need to be monitored carefully. Grade 3 to 4 treatment-related AEs occurred in 16.3% of patients in the nivolumab group, 27.3% of patients in the ipilimumab group, and 55% of patients in the combination group. The most frequent reason for treatment discontinuation was disease progression in the two monotherapy arms—49% with nivolumab and 65% with ipilimumab. The most frequent reason for discontinuation in the combination group was toxicity (38%).
    6. Four therapy-related deaths were reported, which were attributed to neutropenia (nivolumab group), colon perforation (ipilimumab group), liver necrosis, and autoimmune myocarditis (combination ipilimumab and nivolumab).
    7. Analyses of PD-L1 expression level associated with OS at 3 years indicated that the level of expression alone is a poor predictive biomarker of OS.
  2. Melanoma metastatic to the brain. Patients with at least one measurable, nonirradiated brain metastasis were eligible for treatment with systemic dual immunotherapy in an open-label, multicenter phase II trial (CheckMate 204 [NCT02320058]).[14][Level of evidence: 3iiiDiv] Eligibility required no need for immediate intervention, an absence of neurologic signs or symptoms, and no glucocorticoids within 14 days of study treatment. Patients may have received previous stereotactic radiosurgery or excision of up to three brain metastases. Positive PD-L1 expression was not required.
    Treatment consisted of nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for up to 4 doses, followed by nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxicity.
    The primary endpoint was rate of intracranial clinical benefit assessed by the investigator per RECIST criteria and defined as the percentage of patients with complete response, partial response, or stable disease for at least 6 months. A total of 28 sites in the United States enrolled 101 patients, of whom 94 had a minimum follow-up of 6 months; the data on that population are reported below.
    • Clinical benefit (in the brain) was seen in 57% of patients (95% CI, 47–68); 24 patients (26%) had a CR, 28 patients (30%) had a PR, and 2 patients (2%) had stable disease that lasted for 6 months or longer. Similar rates of objective response (50%) were seen in patients with extracranial lesions, although fewer patients had a CR (7%).
    • A subgroup analysis indicated responses in both PD-L1–positive and PD-L1–negative patients (baseline status not known in 20/94 patients).
    • The median follow-up of the 94 patients was 14 months. Median time to intracranial response was 2.3 months (range, 1.1 to 10.8), and time to extracranial response was 2.1 months (range, 1.1 to 15.0).
    • The most common treatment-related AE of any grade in the nervous system was headache (21 patients [22%]), with 3 patients (3%) having headache of grade 3 or 4. Other treatment-related neurologic AEs of grade 3 or 4 were brain edema (2 patients [2%]), intracranial hemorrhage (1 patient [1%]), peripheral motor neuropathy (1 patient [1%]), and syncope (1 patient [1%]). Each of these AEs led to treatment discontinuation, and the one reported case of peripheral motor neuropathy was irreversible. One death was evaluated by the investigator as related to the study treatment (grade 5 immune-related myocarditis).
    • Progression was documented in 33 patients (35%); 17 patients (18%) had intracranial progression only, 4 patients (4%) had extracranial progression only, and 12 patients (13%) had progression in both intracranial and extracranial sites.

Signal-transduction inhibitors

Studies to date indicate that both BRAF and MEK (mitogen-activated ERK-[extracellular signal-regulated kinase] activating kinase) inhibitors, as single agents and in combination, can significantly impact the natural history of melanoma, although they do not appear to provide a cure.
BRAF inhibitors
Treatment with BRAF inhibitors is discouraged in wild-type BRAF melanoma because data from preclinical models have demonstrated that BRAF inhibitors can enhance rather than downregulate the mitogen-activated protein kinase (MAPK) pathway in tumor cells with wild-type BRAF and upstream RAS mutations.[15-18]
Vemurafenib
Vemurafenib is an orally available, small-molecule, selective BRAF kinase inhibitor that was approved by the FDA in 2011 for patients with unresectable or metastatic melanoma who test positive for the BRAF V600E mutation.
Evidence (vemurafenib):
  1. 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 via the Cobas 4800 BRAF V600 Mutation Test.[19] Patients were randomly assigned to receive either vemurafenib (960 mg PO bid) or DTIC (1,000 mg/m2 IV q 3 weeks). Coprimary endpoints were rates of OS and PFS. At the planned interim analysis, the DMSB 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 DTIC group be allowed to cross over to receive vemurafenib.[19][Levels of evidence: 1iiA and 1iiDiii]
    • 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 DTIC arm.
    • The HRdeath 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, LDH, 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 in the vemurafenib arm versus 1.6 months in the DTIC arm.
    • Twenty patients had non-BRAF V600E mutations: 19 with BRAF V600K and 1 with BRAF 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 DTIC. 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 DTIC were fatigue, nausea, vomiting, and neutropenia. (Refer to the PDQ summaries on Supportive and Palliative Care for more information on coping with cancer.)
  2. 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 PO bid. Of the enrolled patients, 61% had stage M1c disease, and 49% had an elevated LDH level. All patients had received one or more previous therapies for advanced disease. Median follow-up was 12.9 months.[20][Level of evidence: 3iiiDiv]
    • 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 after receiving therapy for more than 6 months.
Dabrafenib
Dabrafenib is an orally available, small-molecule, selective BRAF inhibitor that was approved by the FDA in 2013 for patients with unresectable or metastatic melanoma who test positive for the BRAF V600E mutation as detected by an FDA-approved test. Dabrafenib and other BRAF inhibitors are not recommended for treatment of BRAF wild-type melanomas, as in vitro experiments suggest there may be a paradoxical stimulation of MAPK signaling resulting in tumor promotion.
Evidence (dabrafenib):
  1. An international, multicenter trial (BREAK-3 [NCT01227889]) compared dabrafenib with DTIC. A total of 250 patients with unresectable stage III or IV melanoma and BRAFV600E mutations were randomly assigned in a 3:1 ratio (dabrafenib 150 mg PO qd or DTIC 1,000 mg/m2 IV q 3 weeks). IL-2 was allowed as a previous 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.[21][Level of Evidence: 1iiDiii]
    • 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 for dabrafenib versus 2.7 months for DTIC. OS data are limited by the median duration of follow-up and crossover. The PR rate was 47% and the CR rate was 3% in patients receiving dabrafenib versus a 5% PR rate and a 2% CR rate for those receiving DTIC.
    • The most frequent AEs in patients treated with dabrafenib were cutaneous findings (i.e., hyperkeratosis, papillomas, palmar-plantar erythrodysesthesia), pyrexia, fatigue, headache, and arthralgia. Cutaneous SCC or keratoacanthoma occurred in 12 patients, basal cell carcinoma occurred in four patients, mycosis fungoides occurred in one patient, and new melanoma occurred in two patients.
MEK inhibitors
Trametinib
Trametinib is an orally available, small-molecule, selective inhibitor of MEK1 and MEK2. BRAF activates MEK1 and MEK2 proteins, which in turn, activate MAPK. Preclinical data suggest that MEK inhibitors can restrain growth and induce cell death of some BRAF-mutated human melanoma tumors.
In 2013, trametinib was approved by the FDA for patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as determined by an FDA-approved test.
Evidence (trametinib):
  1. A total of 1,022 patients were screened for BRAF mutations, resulting in 322 eligible patients (281 with BRAF V600E, 40 with BRAF V600K, and one with both mutations).[22] One previous treatment (biologic or chemotherapy) was allowed; however, no previous treatment with a BRAF or MEK inhibitor was permitted. Patients were randomly assigned in a 2:1 ratio to receive trametinib (2 mg qd) or IV chemotherapy (either DTIC 1,000 mg/m2 q 3 weeks or paclitaxel 175 mg/m2 q 3 weeks). Crossover for patients randomly assigned to chemotherapy was allowed; therefore, 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). A radiology review blinded-to-treatment arm resulted in similar outcomes. Median OS has not 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 who received trametinib and in 10% of those who received chemotherapy.
    • The most common AEs included rash, diarrhea, nausea, vomiting, fatigue, peripheral edema, alopecia, hypertension, and constipation. Cardiomyopathy (7%), interstitial lung disease (2.4%), central serous retinopathy (<1%), and retinal-vein occlusion (<1%) are uncommon but serious AEs associated with trametinib. On-study cutaneous SCCs were not observed. (Refer to the PDQ summaries on Supportive and Palliative Care for more information on coping with cancer.)
Cobimetinib
Cobimetinib is a small-molecule, selective MEK inhibitor that was approved by the FDA in 2015 for use in combination with the BRAF inhibitor vemurafenib. (Refer to the Combination therapy with signal-transduction inhibitors section of this summary for more information.)
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.[23-25] Phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-KIT mutation.
Multikinase inhibitors
Sorafenib
The multikinase inhibitor sorafenib has activity against both the vascular endothelial growth-factor signaling and the Raf/MEK/ERK pathway.
This agent had minimal activity as a single agent in melanoma treatment. Two large, multicenter, placebo-controlled, randomized trials of carboplatin and paclitaxel with or without sorafenib showed no improvement over chemotherapy alone as either first-line treatment or second-line treatment.[21,26]
Combination therapy with signal-transduction inhibitors
Results from phase III trials comparing three different combinations of BRAF-MEK inhibitors with BRAF inhibitor monotherapy have consistently shown efficacy superior to BRAF monotherapy.
Secondary resistance to BRAF inhibitor monotherapy, in patients with BRAF V600 mutations, may be associated with reactivation of the MAPK pathway. Therefore, combinations of signal-transduction inhibitors that block different sites in the same pathway or sites in multiple pathways are an active area of research.
BRAF inhibitor plus MEK inhibitors
Dabrafenib plus trametinib
Evidence (dabrafenib plus trametinib):
  1. Previously untreated. An international, double-blind, phase III trial without crossover randomly assigned 423 previously untreated patients with unresectable stage IIIC or stage IV melanoma with BRAF V600E or V600K mutations to receive the combination of dabrafenib (150 mg PO bid) plus trametinib (2 mg PO qd) or dabrafenib plus placebo. The primary endpoint was investigator-assessed PFS. The protocol included a prespecified interim analysis for OS at the time of analysis of the primary endpoint. Patients were stratified by baseline LDH and BRAF genotype.[27][Level of Evidence: 1iDiii]
    • Median PFS was 9.3 months for the combination versus 8.8 months for dabrafenib plus placebo. The HRdeath or progression was 0.75 (95% CI, 0.57–0.99; P = .03). Updated data at the time of final analysis of OS revealed a median PFS of 11.0 months for the combination versus 8.8 months for dabrafenib plus placebo. The HR for PFS or death was 0.67 (95% CI, 0.53–0.84; P= .0004; unadjusted for multiple testing).[28]
    • A prespecified final analysis of OS was conducted at 70% of events. Median OS was 25.1 months in the dabrafenib-plus-trametinib group (66% events) versus 18.7 months in the dabrafenib-plus-placebo group (76% events). The HR was 0.71 (95% CI, 0.55–0.92; P = 0.01).
    • Permanent discontinuations of study drugs were reported in 9% of patients on the combination and in 5% of patients treated with dabrafenib only.
    • The incidence of grade 3 to grade 4 AEs was similar between the groups: a 35% incidence with the combination and a 37% incidence with dabrafenib only. Pyrexia occurred more frequently with the combination and was treated with immediate temporary cessation of the study drug in either group; prophylactic glucocorticoids may prevent recurring episodes. Hyperproliferative cutaneous events, including cutaneous SCCs, which were considered related to paradoxical activation of the MAPK pathway and occurred less frequently with the addition of the MEK inhibitor. Rare, but serious, AEs included decreased ejection fraction and chorioretinopathy.
  2. Previously untreated. An international, open-label, phase III trial randomly assigned 704 previously untreated patients with metastatic melanoma with a BRAF V600 mutation to receive standard doses of either the combination of dabrafenib plus trametinib or vemurafenib as first-line therapy. The primary endpoint was OS.[29][Level of evidence: 1iiA]
    • An interim analysis for OS was planned when 202 of the final 288 events occurred. Per protocol, the DMSB used adjusted efficacy boundaries for actual events (222) (2-sided P < .0214 for efficacy and P > .2210 for futility). The DMSB recommended stopping for efficacy, and the interim analysis is considered to be the final analysis of OS. A protocol amendment was issued to allow crossover to the combination therapy arm.
    • A total of 100 patients (28%) in the combination arm and 122 (35%) in the vemurafenib group had died (HR, 0.69; 95% CI, 0.53–0.89; P = .005). Median OS for patients treated with vemurafenib was 17.2 months; the median has not been reached in the combination therapy arm.
Vemurafenib plus cobimetinib
Evidence (vemurafenib plus cobimetinib):
  1. Previously untreated. An international phase III trial randomly assigned 495 patients with previously untreated, unresectable stage IIIC or stage IV melanoma with BRAFV600 mutation-positive melanoma to receive the combination of vemurafenib (960 mg PO qd) and cobimetinib (60 mg PO qd for 21 days followed by a 7-day rest period) or vemurafenib plus placebo. The primary endpoint was investigator-assessed PFS. Crossover at time of PFS was not allowed. Patients were stratified by stage and geographic region. Two interim analyses of OS were prespecified, with the first specified at the time of analysis of the primary endpoint.[30][Level of evidence: 1iDiii]
    • Median PFS was 9.9 months for the combination versus 6.2 months in patients treated with vemurafenib plus placebo. The HRdeath or progression was 0.51 (95% CI, 0.39–0.68; P = .001).
    • The first interim analysis of OS is immature because of the few events in both arms; therefore, median survival was not reached in either study group.
    • Rate of withdrawal of therapy caused by AEs was similar between the groups: a 13% rate was found with patients treated with the combination, and a 12% rate was found with patients treated with vemurafenib only. Six deaths were attributed to AEs in the combination group, and three deaths were attributed to AEs in the vemurafenib-only group.
    • The incidence of grade 3 to grade 4 AEs was similar between the groups: a 62% incidence rate was found in patients treated with the combination, and a 58% rate was found in patients treated with vemurafenib alone. Rare, but serious, AEs included chorioretinopathy, retinal detachment, decreased ejection fraction, and QT prolongation. Hyperproliferative cutaneous events, including cutaneous SCC, was considered to be related to paradoxical activation of the MAPK pathway,and occurred less frequently with the addition of the MEK inhibitor.
Encorafenib plus binimetinib
Encorafenib is a small-molecule BRAF inhibitor that is approved in combination with binimetinib, a small-molecule MEK inhibitor, for the treatment of unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test. The combination has demonstrated improved PFS and OS compared with vemurafenib; however, neither is approved as single-agent therapy.
Evidence (encorafenib plus binimetinib):
  1. Previously untreated or progression on or after first-line immunotherapy. An international, open-label, phase III trial (COLUMBUS [NCT01909453]) randomly assigned 577 patients with stage IIIB, IIIC, or IV melanoma with BRAF V600 mutation–positive melanoma in a 1:1:1 ratio to receive encorafenib (450 mg qd) plus binimetinib (45 mg bid) or encorafenib monotherapy (300 mg qd) or vemurafenib monotherapy (960 mg bid).[31,32] The primary endpoint was PFS for the combination versus vemurafenib as assessed by a blinded IRC with a secondary endpoint of OS.
    • A minority of patients (approximately 5%) had received previous checkpoint inhibitor therapy.
    • With a median follow-up of 16.6 months, median PFS was 14.9 months (95% CI, 11.0–18.5) with the combination versus 7.3 months (95% CI, 5.6–8.2) with vemurafenib. The HRprogression or death was 0.54 (95% CI, 0.41–0.71; 2-sided P < .0001).
    • With a median follow-up of 36.8 months for the secondary endpoint of OS, patients in the combination arm had a median OS of 33.6 months (95% CI, 24.4–39.2) versus 16.9 months (95% CI, 14.0–24.5) for patients treated with vemurafenib (HR, 0.61; 95% CI, 0.47–0.79; P < .0001). Subsequent treatments received after discontinuation of the study drug were received by 42% of patients in the combination group and 62% of patients in the vemurafenib group.[31,32][Level of evidence: 1iiA]
    • The incidence of grade 3 to 4 AEs was 58% with combination therapy and 63% with vemurafenib. Serious AEs occurred in 34% of the combination group and 37% of the vemurafenib group. The most common AEs in the combination group included gastrointestinal symptoms and elevation of gamma-glutamyl transferase (GGT), elevation of creatine phosphokinase (CPK), left ventricular dysfunction (8%) and serous retinopathy (20%), mostly grade 1 to 2 (monitoring guidelines are provided in the drug label). Patients who received vemurafenib had more pyrexia and cutaneous toxicities. Study drug discontinuations from AEs were 15% in the combination group and 17% with vemurafenib. No deaths were considered to be related to treatment; however, one death from suicide occurred in the combination arm.

Chemotherapy

DTIC was approved in 1970 on the basis of ORRs. Phase III trials indicate an ORR of 10% to 20%, with rare CRs observed. An impact on OS has not been demonstrated in randomized trials.[6,19,33-35] When used as a control arm for recent registration trials of ipilimumab and vemurafenib in previously untreated patients with metastatic melanoma, DTIC was shown to be inferior for OS.
Temozolomide, an oral alkylating agent that hydrolyzes to the same active moiety as DTIC, appeared to be similar to DTIC (IV administration) in a randomized, phase III trial with a primary endpoint of OS; however, the trial was designed for superiority, and the sample size was inadequate to prove equivalency.[34]
The objective response rate to DTIC and the nitrosoureas, carmustine and lomustine, is approximately 10% to 20%.[33,36-38] Responses are usually short-lived, ranging from 3 to 6 months, although long-term remissions can occur in a limited number of patients who attain a CR.[36,38]
A randomized trial compared IV DTIC with temozolomide, an oral agent; OS was 6.4 months for DTIC versus 7.7 months for temozolomide (HR, 1.18; 95% CI, 0.92–1.52). While these data suggested similarity between DTIC and temozolomide, no benefit in survival has been demonstrated for either DTIC or temozolomide; therefore, demonstration of similarity did not result in approval of temozolomide by the FDA.[34][Level of evidence: 1iiA]
An extended schedule and escalated dose of temozolomide was compared with DTIC in a multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) (EORTC-18032 [NCT00101218]) randomly assigning 859 patients. No improvement was seen in OS or PFS for the temozolomide group, and this dose and schedule resulted in more toxicity than standard-dose, single-agent DTIC.[39][Level of evidence: 1iiA]
Two randomized, phase III trials in previously untreated patients with metastatic melanoma (resulting in FDA approval for vemurafenib [19] and ipilimumab [6]) included DTIC as the standard therapy arm. Both 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.[36,37]
Attempts to develop combination regimens that incorporate chemotherapy (e.g., multiagent chemotherapy,[40,41] combinations of chemotherapy and tamoxifen,[42-44] and combinations of chemotherapy and immunotherapy [9,10,40,45-48]) have not demonstrated an improvement in OS.
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) reported no impact on OS.[49][Level of evidence:1iiA]

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.[46-48]
Although melanoma is a relatively radiation-resistant tumor, palliative radiation therapy may alleviate symptoms. Retrospective studies have shown that symptom relief and some shrinkage of the tumor with radiation therapy may occur in patients with the following:[50,51]
  • Multiple brain metastases.
  • Bone metastases.
  • Spinal cord compression.
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. (Refer to the PDQ summary on Cancer Pain for more information.)

Treatment Options Under Clinical Evaluation for Unresectable Stage III, Stage IV, and Recurrent Melanoma

  1. Immunotherapy—single agent, and combination immunomodulation.
  2. Targeted therapy—single-agent and combination therapy.
    1. Signal-transduction inhibitors, including P13K (phosphoinositide-3 kinase) and Akt (protein kinase B) inhibitors, CDK (cyclin-dependent kinase) in addition to BRAF and MEK inhibitors.
    2. Antiangiogenesis agents. Preclinical data suggest that increased vascular endothelial growth factor production may be implicated in resistance to BRAF inhibitors.[52]
    3. Targeted therapy for specific melanoma populations.
      • 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 the pathways activated by these mutations are currently in clinical trials.
  3. Combinations of immunotherapy and targeted therapy.
  4. Intralesional injections (for example, oncolytic viruses).
  5. Complete surgical resection of all known disease versus best medical therapy.
  6. Isolated limb perfusion for unresectable extremity melanoma.
  7. Systemic therapy for unresectable disease.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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  43. Hancock BW, Wheatley K, Harris S, et al.: Adjuvant interferon in high-risk melanoma: the AIM HIGH Study--United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon Alfa-2a in high-risk resected malignant melanoma. J Clin Oncol 22 (1): 53-61, 2004. [PUBMED Abstract]
  44. Koops HS, Vaglini M, Suciu S, et al.: Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol 16 (9): 2906-12, 1998. [PUBMED Abstract]
  45. Lee ML, Tomsu K, Von Eschen KB: Duration of survival for disseminated malignant melanoma: results of a meta-analysis. Melanoma Res 10 (1): 81-92, 2000. [PUBMED Abstract]
  46. Leo F, Cagini L, Rocmans P, et al.: Lung metastases from melanoma: when is surgical treatment warranted? Br J Cancer 83 (5): 569-72, 2000. [PUBMED Abstract]
  47. Ollila DW, Hsueh EC, Stern SL, et al.: Metastasectomy for recurrent stage IV melanoma. J Surg Oncol 71 (4): 209-13, 1999. [PUBMED Abstract]
  48. Gutman H, Hess KR, Kokotsakis JA, et al.: Surgery for abdominal metastases of cutaneous melanoma. World J Surg 25 (6): 750-8, 2001. [PUBMED Abstract]
  49. Ives NJ, Stowe RL, Lorigan P, et al.: Chemotherapy compared with biochemotherapy for the treatment of metastatic melanoma: a meta-analysis of 18 trials involving 2,621 patients. J Clin Oncol 25 (34): 5426-34, 2007. [PUBMED Abstract]
  50. Rate WR, Solin LJ, Turrisi AT: Palliative radiotherapy for metastatic malignant melanoma: brain metastases, bone metastases, and spinal cord compression. Int J Radiat Oncol Biol Phys 15 (4): 859-64, 1988. [PUBMED Abstract]
  51. Herbert SH, Solin LJ, Rate WR, et al.: The effect of palliative radiation therapy on epidural compression due to metastatic malignant melanoma. Cancer 67 (10): 2472-6, 1991. [PUBMED Abstract]
  52. Martin MJ, Hayward R, Viros A, et al.: Metformin accelerates the growth of BRAF V600E-driven melanoma by upregulating VEGF-A. Cancer Discov 2 (4): 344-55, 2012. [PUBMED Abstract]

Changes to This Summary (04/11/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of melanoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Melanoma Treatment are:
  • Russell S. Berman, MD (New York University School of Medicine)
  • Alison Martin, MD (Martin and Associates Consulting)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Melanoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/skin/hp/melanoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389469]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.
  • Updated: April 11, 2019
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