Sections

Treatment

Approach Considerations

Surgery is the definitive treatment for early-stage melanoma. In patients with solitary or acutely symptomatic brain metastases, surgical management or treatments such as gamma knife radiation may alleviate symptoms and provide local control of disease.^[35]

Because the definitive treatment of cutaneous melanoma is surgery, medical management is reserved for adjuvant therapy of patients with advanced melanoma. Less than one half of patients with deep primaries (> 4 mm) or regional lymph node involvement have long-term disease-free survival; consequently, these patients are classified as high risk and should be considered for adjuvant therapy.

By stage, standard treatment options for melanoma are as follows^[1]

Stage 0 - Excision
Stage I - Excision, with or without lymph node management
Stage II - Excision, with or without lymph node management
Resectable stage III - Excision, with or without lymph node management; adjuvant therapy and immunotherapy
Unresectable stage III, stage IV, and recurrent melanoma - Intralesional therapy, immunotherapy, signal transduction inhibitors, chemotherapy, palliative local therapy

Multiple options for adjuvant treatment of node-positive melanoma have become available. A critical question for guiding the choice of regimens is whether the tumor contains a BRAF V600 mutation. BRAF and BRAF/MEK inhibitor combinations are useful in some patients to slow the progression of disease.

In patients with no BRAF mutation (ie, wild-type BRAF), current guidelines from the National Comprehensive Cancer Network (NCCN) recommend single-agent immunotherapy with the programmed cell death–1 (PD-1) inhibitor pembrolizumab or nivolumab or combination therapy with nivolumab plus ipilimumab.^[21]

For patients with a BRAF mutation, the NCCN recommends targeted combination therapy with dabrafenib/trametinib or vemurafenib/cobimetinib.^[21] Targeted therapy is preferred if clinically needed for early response. Current targeted therapies can slow tumor growth (eg, BRAF inhibition) or release the brakes on the immune response, resulting in tumor lysis (eg, PD-1 inhibition).

Interferon alfa-2b was approved in 1995 for adjuvant treatment after excision in patients who are free of disease but are at high risk for recurrence. However, while high-dose interferon alfa-2b and pegylated interferon have been shown to improve relapse-free survival, neither improves overall survival.^[1]This is not currently offered to patients unless there are contraindications to giving PD-1 inhibitors or BRAF/MEK inhibitor combinations.

Neoadjuvant therapy for high-risk resectable melanoma has demonstrated significant efficacy in early clinical trials.^{[36, 37]}Current NCCN guidelines recommend consideration of neoadjuvant therapy, preferably in the context of a clinical trial, in patients with gross resectable nodal disease and the following:^[21]

Very high risk of recurrence after complete resection
High risk of perioperative morbidity due to extent of resection or underlying comorbidities
Uncertain likelihood of achieving gross complete resection of nodal disease

Also see Lentigo Maligna Melanoma, Oral Malignant Melanoma, and Head and Neck Mucosal Melanomas.

Regional Lymph Node Dissection

A joint practice guideline from the American Society of Clinical Oncology and the Society of Surgical Oncology recommends completion lymph node dissection (CLND) for patients with a positive sentinel lymph node biopsy (SLNB), but the risk of morbidity must be weighed for each patient. CLND has not been shown to affect overall survival, but does help with regional disease control. Careful observation with removal of enlarged nodes is an option.The second Multicenter Selective Lymphadenectomy Trial (MSLT-II) confirmed that immediate CLND in patients with metastases found on SLNB increases the rate of regional disease control and provides prognostic information. However, immediate CLND did not increase melanoma-specific survival.^[38]

In MSLT-II, patients who had sentinel node metastases detected via standard pathologic assessment or a multimarker molecular assay were randomized to receive either immediate CLND (n = 971) or nodal observation with ultrasonography (n = 968). At a median follow-up of 43 months, the mean 3-year rate of melanoma-specific survival (the primary endpoint for the study) was similar in the dissection group and the observation group (86 ± 1.3% and 86 ± 1.2%, respectively; P = 0.42).^[38]

Secondary endpoints slightly favored CLND over observation, with 3-year rates of disease control of 92 ± 1.0% versus 77 ± 1.5%, respectively (P < 0.001) and 3-year disease-free survival of 68 ± 1.7% versus 63 ± 1.7%, respectively (P = 0.05). However, lymphedema developed in 24.1% of the dissection group versus 6.3% of the observation group (P< 0.001). Lymphedema was mild in 64% of cases, moderate in 33%, and severe in 3%.^[38]

In patients whose SLNB reveals micrometastases, a randomized phase III trial by Steiner et al found no survival benefit with CLND. No statistically significant differences (ie, 10% or higher) in 5-year recurrence-free survival, distant metastases–free survival, or melanoma-specific survival were evident between 242 patients who underwent CLND and 241 patients who received observation only. At a median follow-up of 35 months, however, regional lymph node metastases developed in 14.6% of patients in the observation group versus 8.3% of those in the CLND group.^[39]

Adjuvant Therapy

Adjuvant therapy is used for locally advanced melanoma (stage III) melanoma, and most recently, resected advanced-stage disease. Although observation rather than adjuvant therapy is standard for stage II melanoma at this time, those patients are encouraged to enroll in clinical trials. Gould Rothberg et al developed and validated a multimarker prognostic assay for determining survival in stage II melanoma, which these researchers suggest might be beneficial in improving the selection of patients for adjuvant therapy.^[40]

Immune therapy and targeted therapy (eg, in cases with BRAF mutations) are preferred for treatment of unresectable or distant metastatic disease.^{[41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52]} Isolated limb perfusion and intralesional therapy with talimogene laherparepvec (T-VEC) therapy may be appropriate for some patients with localized metastases.^{[53, 54, 55, 56]}

Dabrafenib plus trametinib

In 2018, the US Food and Drug Administration (FDA) approved dabrafenib in combination with trametinib for adjuvant treatment, following complete resection, of patients with melanoma with BRAF V600E or V600K mutations and involvement of lymph node(s).

Approval was based on COMBI-AD, an international, multicenter, randomized, double-blind, placebo-controlled trial in 870 patients with stage III melanoma with BRAF V600E or V600K mutations and regional lymph node involvement. Patients in the treatment arm (dabrafenib 150 mg twice daily in combination with trametinib 2 mg once daily) had significantly longer relapse-free survival (RFS) compared with those in the placebo arm. The estimated median RFS was not reached for patients who received the combination therapy, compared with 16.6 months (95% confidence interval [CI]: 12.7, 22.1) for those receiving placebo. Patients in the treatment arm also had experienced fewer recurrences/deaths by the time of data cutoff: 38% (n=166), compared with 57% (n=248) in the placebo arm (hazard ratio [HR] 0.47; 95% CI 0.39, 0.58; P < 0.0001).^[57]

Five-year follow-up of COMBI-AD confirmed the long-term benefit of dabrafeinb plus trametinib in this setting. RFS was 53% in the treatment arm versus 36% in the placebo arm. Distant metastasis-free survival rates were 65% versus 54%, respectively.^[58]

Pembrolizumab

Pembrolizumab, a monoclonal antibody to programmed cell death-1 protein (PD-1), has FDA approval for adjuvant treatment of resected, high-risk stage III melanoma. Approval was based on data from the EORTC1325/KEYNOTE-054 trial (n=1019) showing a significantly prolonged 1-year RFS compared with placebo (75.4% vs 61%; P < 0.001).^[59]

On 3-year median follow-up of KEYNOTE-054, pembrolizumab continued to produce a sustained, clinically meaningful improvement in RFS across subgroups. In the overall population, the 3-year cumulative incidence of distant metastasis as the first recurrence was 22.3% with pembrolizumab versus 37.3% with placebo group (HR 0.55, 95% CI 0.44-0.69). In the pembrolizumab arm, 3-year RFS was superior in PD-L1 positive patients, at 65%, versus 57% for PD-L1 negative patients.^[60]

In 2021, the FDA expanded the approval of pembrolizumab to the adjuvant treatment of stage IIB or IIC melanoma following complete resection, in patients age 12 years and older. Approval was based on data from the KEYNOTE-716 trial, which demonstrated a statistically significant improvement in RFS at the time of the first interim analysis for patients randomized to the pembrolizumab arm compared with placebo, with an HR of 0.65 (95% CI 0.46-0.92; P=0.0132). The median RFS was not reached in either arm.^[61]

Pembrolizumab is also indicated for first-line treatment of unresectable or metastatic melanoma.

Nivolumab

The PD-1 inhibitor nivolumab (Opdivo) is approved for adjuvant treatment in patients with lymph node involvement or metastatic melanoma who have undergone complete resection. Approval was based on findings from the phase III CheckMate-238 trial, in which 906 patients with completely resected stage IIIB/C or stage IV melanoma received either nivolumab or ipilimumab for up to 1 year. The 12-month RFS rate was 70.5% in the nivolumab arm compared with 60.8% in the ipilimumab arm (HR for disease recurrence or death, 0.65; 97.56% CI, 0.51-0.83; P < 0.001).^[62]Based on this study, nivolumab is the current drug of choice in the adjuvant setting.

A study by Weber et al in patients with advanced melanoma that had progressed after treatment with ipilimumab or ipilimumab and a BRAF inhibitor reported a greater proportion of patients achieving an objective response and fewer toxic effects in patients treated with nivolumab (n=272) than in those treated with dacarbazine, or paclitaxel plus carboplatin (objective response rates 31.7 versus 10.6, respectively).^[4]

Ipilimumab

In a phase III trial in patients with high-risk stage III melanoma, adjuvant therapy with the checkpoint inhibitor ipilimumab resulted in significantly higher rates of RFS, overall survival, and distant metastasis–free survival compared with placebo.^[63]The study included 951 patients with stage III cutaneous melanoma who had adequate resection of lymph nodes and were randomized to receive ipilimumab at 10 mg/kg (IV) or placebo every 3 weeks for 4 doses, then every 3 months for up to 3 years, or until disease recurrence or unacceptable toxicity.

Median RFS—the primary endpoint—was 26.1 months with ipilimumab versus 17.1 months with placebo. However, 52% of patients (245 of 475) who started ipilimumab discontinued treatment due to adverse events—38.6% within 12 weeks. Grade 3-4 immune-related adverse events occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. Five patient deaths were linked to immune-related adverse events in the ipilimumab arm.^[63]

Intralesional therapy

In 2015, the FDA approved the oncolytic immunotherapeutic vaccine talimogene laherparepvec (Imlygic) for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery. It is administered by injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound guidance.^[64]

Talimogene laherparapvec is a live-attenuated herpes simplex type I virus that has been genetically modified by deleting the gene that encodes infected cell protein 34.5(ICP 34.5) and replacing it with the coding sequence for the immune stimulatory protein granulocyte-macrophage colony-stimulating factor (GM-CSF). Once injected into a tumor, the modified virus replicates and produces GM-CSF.

A phase III clinical trial by Andtbacka et al demonstrated therapeutic benefit of talimogene laherparepvec against melanoma. The study compared 295 patients treated with talimogene laherparepvec and141 patients treated with GM-CSF. The primary endpoint was the durable response rate (DRR), defined as the rate of complete response plus partial response continuously lasting ≥6 months and beginning within the first 12 months. Secondary endpoints included overall survival (OR) and the overall response rate (ORR).^[65]

The DRR was significantly higher among patients who received talimogene laherparepvec compared with those given GM-CSF (16.3% vs 2.1%; odds ratio, 8.9; P < 0.001). Of the patients who experienced a durable response, 29.1% had a durable complete response and 70.8% had a durable partial response. The median time to response was 4.1 (range: 1.2 to 16.7) months in the arm receiving talimogene laherparepvec.^[65]

The ORR was also higher with talimogene laherparepvec (26.4% vs 5.7%; P < 0.001). In all, 32 (10.8%) patients receiving talimogene laherparepvec experienced a complete response, compared with just one (< 1%) patient receiving GM-CSF. The median time to treatment failure was 8.2 months with talimogene laherparepvec and 2.9 months with GM-CSF (hazard ratio [HR], 0.42). Median OS was 23.3 months and 18.9 months, respectively (HR, 0.79; P = 0.051), which just missed being statistically significant.^[65]

The use of talimogene laherparepvec in combination with immune checkpoint inhibitors is currently being assessed. Early results indicate that the combination of talimogene laherparepvec with ipilimumab or pembrolizumab has greater efficacy in melanoma than either therapy alone, and without additional safety concerns above those expected for each monotherapy.^[66]

Interferon alfa

This drug is mentioned for completeness. It is no longer prescribed for melanoma.

Interferon (IFN) alfa-2b was the first drug approved by the FDA, in 1995, for adjuvant treatment of melanoma after excision in patients who are free of disease but are at high risk for recurrence. Approval was based on the results of Eastern Cooperative Group (ECOG) 1684, a large multicenter study of high-dose IFN that showed improvement in disease-free survival and survival benefit (time to progression improvement of 8 months, with a 1-year survival benefit).^[67]A subsequent pooled analysis of 1016 patients and 716 observational controls from all ECOG trials showed a significant increase in relapse-free survival (P = 0.006) but not overall survival (P = 0.42).^[68]

To investigate the possibility that the survival benefit seen in ECOG-1684 had to do with its incorporation of an induction phase of maximally tolerated dosages of IFN given intravenously for the initial 4 weeks, Pectasides et al conducted a prospective, randomized study in 364 patients with stage IIB, IIC, or III melanoma who had undergone curative surgery. Patients were randomized to receive IFN-alpha-2b IV for 5/7 days weekly for 4 weeks (arm A) versus the same induction regimen followed by IFN-alpha-2b administered subcutaneously 3 times a week for 48 weeks (arm B). At a median follow-up of 63 months, there were no significant differences in overall survival and relapse-free survival between the 2 arms, and patients in arm B had more grade 1 to 2 hepatotoxicity, nausea/vomiting, alopecia, and neurologic toxicity.^[69]

On the other hand, Hauschild et al found that the addition of a 4-week modified high-dose IFN-alpha induction phase to a 2-year low-dose adjuvant IFN-alpha-2b treatment schedule did not improve the clinical outcome.^[70]

Hauschild et al also studied optimal duration of treatment of malignant melanoma with low-dose IFN alfa-2a and concluded that prolonging treatment with conventional low-dose IFN alfa-2a from 18 to 60 months showed no clinical benefit in patients with intermediate- and high-risk primary melanoma. Patients with resected cutaneous melanoma of at least 1.5 mm tumor thickness and lymph node negative were included in this prospective, randomized, multicenter trial (n=850). Patients were randomly assigned to receive 3 MU IFN alfa-2a SC 3 times/wk for either 18 or 60 months. Median follow-up was 4.3 years. Relapse-free survival and distant-metastasis-free survival did not differ between the 2 groups.^[71]

Meta-analysis data show that ulceration and tumor stage are important predictors of response to interferon alfa/pegylated-interferon.^[72]

Peginterferon alfa-2b is an immunomodulatory cytokine that enhances phagocyte and lymphocyte activity. It was approved by the FDA in 2011 as adjuvant therapy following definitive surgical resection, including complete lymphadenectomy. The drug’s approval was based on a 5-year, open-label, multicenter trial in which cancer recurrence was delayed about 9 months longer in patients who took peginterferon alfa-2b than in patients who did not take the drug.^[2]

Granulocyte-macrophage colony-stimulating factor

In addition to its approved indication—accelerating bone marrow recovery in diverse settings of bone marrow failure—granulocyte-macrophage colony-stimulating factor (GM-CSF) has been used as adjuvant treatment of high-risk melanoma.^[73]GM-CSF is no longer used in this setting, due to the availability of more effective treatments.^[74]However, GM-CSF continues to be studied for its possible benefit as an immune modulator when used in combination with conventional therapies.^[75]

Treatment of Advanced-Stage Melanoma (Stage IV)

In addition to intralesional therapy with talimogene laherparepvec (see Treatment/Adjuvant Therapy), increasing numbers of biologic therapies are available for the treatment of patients with advanced-stage (stage IV) melanoma. Chemotherapy is used less frequently due to the more efficacious drugs have been developed, including immunotherapy and BRAF and MEK inhibitors. The use of immune checkpoint inhibitors for the treatment of advanced melanoma has evolved beyond monotherapies to combination strategies.

Treatment of melanoma with BRAF mutations

BRAF mutations are present in 40-60% of cutaneous melanomas, and of those, about 90% are BRAF V600E mutations. Detection of BRAF mutations is important prior to starting treatment in any melanoma patient. First-line treatment of patients with BRAF V600 wild-type or mutation-positive, unresectable or metastatic melanoma is with nivolumab as a monotherapy or in combination with ipilimumab.^{[76, 77]}

Vemurafenib

Vemurafenib (Zelboraf) was approved by the US Food and Drug Administration (FDA) in 2011. It is an inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF V600E. This agent is indicated for the treatment of unresectable or metastatic melanoma with the BRAF V600 mutation as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems). Vemurafenib has not been studied with wild-type BRAF melanoma.

Phase III trial results for vemurafenib included a 63% relative reduction in the risk of death as well as a 74% relative reduction in the risk of tumor progression in patients with previously untreated metastatic melanoma with the BRAF V600E mutation, compared with dacarbazine. In addition, the overall survival rate at 6 months in the vemurafenib group was 84%, versus 64% in the dacarbazine group.^[78] Despite the short follow-up period, these results have significant clinical implications, given the frequency of BRAF V600E mutations in cutaneous melanomas. Moreover, a response to vemurafenib in four of 10 patients with the BRAF V600K mutation was noted, suggesting sensitivity of this mutation variant to vemurafenib.^[78]

Vemurafenib was generally well tolerated, with cutaneous events (squamous cell carcinoma, keratoacanthoma, or both; all were treated with simple excision), arthralgia, fatigue, and photosensitivity the most common adverse events; such events led to dose modification or interruption in 38% of patients.^[78] Adverse events seen with dacarbazine were primarily fatigue, nausea, vomiting, and neutropenia and led to dose modification or interruption in 16% of patients.

Dabrafenib

In 2013 the FDA approved dabrafenib (Taflinar), a BRAF inhibitor in the same class as vemurafenib, for patients with unresectable or metastatic melanoma with BRAF V600E mutation confirmed by the THxID BRAF mutation test.^[79] In a multicenter, open-label, phase III randomized controlled trial, treatment with dabrafenib significantly improved progression-free survival (PFS) in patients with BRAF-mutated metastatic melanoma, compared with dacarbazine (5.1 vs 2.7 mo).^[80]

Trametinib

Trametinib (Mekinist) is a mitogen-activated, extracellular signal-regulated kinase (MEK) inhibitor that was approved by the FDA in 2013 for unresectable or metastatic melanoma with BRAF V600E or V600K mutations confirmed by the THxID BRAF mutation test.^[79] Approval was based on a phase III open-label trial in which median PFS was 4.8 months with trametinib versus 1.5 months in patients receiving dacarbazine or paclitaxel. At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% confidence interval [CI], 0.32 to 0.92).^[81]

Dabrafenib plus trametinib

In 2014, the FDA approved trametinib for use in combination with dabrafenib for treating patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. Approval was based on the demonstration of response rate and median duration of response in a phase I/II study. Median PFS in the full-dose combination therapy group was 9.4 months, compared with 5.8 months in the dabrafenib monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval [CI], 0.25 to 0.62). The rate of complete or partial response with combination therapy was 76%, compared with 54% with monotherapy. Improvement in disease-related symptoms or overall survival was demonstrated for this combination.^{[82, 83]}

Cobimetinib

In 2015, the FDA approved cobimetinib, a MEK1 and MEK2 inhibitor, for unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation, in combination with vemurafenib. Approval was based on results in 495 patients with advanced melanoma from the phase III coBRIM study, in which median PFS was longer with cobimetinib plus vemurafenib than with vemurafenib monotherapy (12.3 vs 7.2 months; HR, 0.58; 95% CI, 0.46 - 0.72). Additionally, the objective response rate was higher with the combination than with vemurafenib alone (70% vs 50%; P < 0.0001).^[84]

Binimetinib plus encorafenib

The combination of binimetinib (Mektovi), a MEK inhibitor, plus encorafenib (Braftovi), a BRAF inhibitor, was approved by the FDA in 2018 for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. Approval was based on results from the phase III COLUMBUS trial, which demonstrated that the combination doubled median PFS compared with vemurafenib alone (14.9 months versus 7.3 months, respectively (P < 0.0001).^[85]

Triple therapy

In 2020, the FDA approved the triple-therapy combination of the programmed cell death ligand–1 protein (PD-L1) inhibitor atezolizumab (Tecentriq), the MEK inhibitor cobimetinib (Cotellic), and vemurafenib for the treatment of BRAF V600 mutation–positive advanced melanoma. Approval was based on results of the double-blind, randomized, placebo-controlled, multicenter trial IMspire150 trial (n=514) in which median PFS was 15.1 months (95% CI: 11.4-18.4) with triple therapy, versus 10.6 months (95% CI: 9.3-12.7) with cobimetinib/vemurafenib plus placebo.^[86]

The most common adverse reactions (≥ 20%) with atezolizumab in combination with cobimetinib and vemurafenib in patients with melanoma were rash, musculoskeletal pain, nausea, fatigue, hepatotoxicity, pyrexia, nausea pruritus, edema, stomatitis, hypothyroidism, and photosensitivity reaction.

The recommended atezolizumab dose, following completion of a 28-day cycle of cobimetinib and vemurafenib, is 840 mg every 2 weeks with cobimetinib 60 mg orally once daily (21 days on /7 days off) and vemurafenib 720 mg orally twice daily.

Treatment of BRAF V600 wild-type melanoma

For patients with BRAF V600 wild-type, unresectable or metastatic melanoma, nivolumab plus ipilimumab is a preferred choice for first-line treatment.^[21]The FDA approved nivolumab plus ipilimumab for this indication in 2015. Approval was based on results from the phase II CheckMate 069 study. Of the 142 patients enrolled, 109 had BRAF wild-type melanoma. In patients with BRAF wild-type melanoma treated with the combination regimen, the objective response rate (the primary study endpoint) was 61% (95% CI: 48-71), compared with 11% (95% CI: 3-25) in patients given ipilimumab monotherapy (P < 0.001).^[87]

Additional analysis of CheckMate 069 showed that complete responses were seen in 22% of patients in the combination therapy arm but in none of the patients in the ipilimumab arm. Partial responses were seen in 43% of the combination group and 11% of the ipilimumab monotherapy group. The combination group had a 60% reduction in the risk of progression compared with ipilimumab alone (HR=0.40; 95% CI: 0.22-0.71; P < 0.002). Median PFS was 8.9 months with the combination (95% CI: 7.0-NA) and 4.7 months with ipilimumab alone (95% CI: 2.8-5.3).^[87]

Additional analysis showed that complete responses were seen in 22% of patients. Partial responses were seen in 43% of the combination group and 11% of the ipilimumab monotherapy group. The combination group had a 60% reduction in the risk of progression compared with ipilimumab alone (HR=0.40; 95% CI: 0.22-0.71; P < 0.002). Median PFS was 8.9 months with the combination (95% CI: 7.0, NA) and 4.7 months with ipilimumab alone (95% CI: 2.8-5.3).^[94]

In pharmacovigilance studies, myocarditis occurred in 0.27% of patients treated with the combination of ipilimumab and nivolumab. Johnson et al reported fatal myocarditis in two patients with melanoma who were receiving treatment with ipilimumab and nivolumab. Both patients developed myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates.^[88]

The phase III CheckMate 067 study in previously untreated patients with unresectable or metastatic melanoma randomized patients into three arms: combination therapy with nivolumab plus ipilimumab, monotherapy with nivolumab, and ipilimumab monotherapy. On 6.5-year follow-up, overall survival in patients with BRAF wild-type tumors was 46% in the nivolumab-plus-ipilimumab group, compared with 42% in the nivolumab group and 22% in the ipilimumab group. OS rates in patients with BRAF-mutant tumors were 57%, 43%, and 25%, respectively.^[89]

Nivolumab monotherapy

Nivolumab was first approved for use in melanoma in 2014, when the FDA granted accelerated approval for treatment of unresectable or metastatic melanoma unresponsive to other drugs. Approval was based on interim results of a randomized clinical trial in patients with unresectable or metastatic melanoma that had progressed after ipilimumab. Interim analysis confirmed objective responses in 38 of the first 120 patients treated with nivolumab (31.7%; 95% CI 23.5-40.8) versus five of 47 patients who received investigator's choice of chemotherapy (10.6%; CI, 3.5-23.1).^[4]

Nivolumab monotherapy was approved in 2015 on the basis of data from the randomized phase III CheckMate-066 trial, which compared nivolumab monotherapy with dacarbazine in the first-line treatment of 418 patients with advanced BRAF wild-type melanoma. In an interim analysis, nivolumab demonstrated superior overall survival, which was the primary outcome. The overall survival rate at 1 year with nivolumab versus dacarbazine was 72.9% versus 42.1%, respectively. In addition, median progression-free survival was longer in the nivolumab-treated patients compared with dacarbazine (5.1 vs 2.2 months; HR, 0.43; P < 0.001).^[90]In 2016, the indication for nivolumab was expanded to include mutation-positive metastatic melanoma, making nivolumab effective across BRAF status.^[76]

Pembrolizumab

Programmed cell death–1 protein (PD-1) and the related target PD-ligand 1 (PD-L1) are expressed on the surface of activated T cells under normal conditions. The PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound. This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation. Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PD-L1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells.

In 2014, the FDA granted accelerated approval for pembrolizumab (Keytruda). Pembrolizumab is the first monoclonal antibody for inhibition of PD-1.^[91] It was initially indicated for unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on data including a study in which approximately 24% of patients experienced tumor shrinkage.^[3]

In 2015, the FDA approved pembrolizumab as first-line treatment for unresectable or metastatic melanoma. Approval was based on the phase 3 KEYNOTE-006 trial. Patients with advanced melanoma were randomized to receive either pembrolizumab 10 mg/kg every 2wk or every 3wk, or 4 doses of ipilimumab (3 mg/kg every 3wk). Progression-free survival for the pembrolizumab groups were 47.3% and 46.4% respectively and 26.5% for ipilimumab. Note that the trial used a higher dose of pembrolizumab than the dose that is approved by the FDA, which is 2 mg/kg every 3 wk.^[92]

Ipilimumab

Ipilimumab is an inhibitor of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4). It is a humanized antibody directed at a down-regulatory receptor on activated T cells.^[93] The proposed mechanism of action is inhibition of T-cell inactivation, allowing expansion of naturally developed melanoma-specific cytotoxic T cells.

Ipilimumab was approved by the FDA in 2011 for unresectable or metastatic melanoma. In 2017, ipilimumab was approved in adolescents aged 12 years or older for treatment of unresectable or metastatic melanoma.^[94]

Hodi et al reported improved survival with ipilimumab in patients with metastatic melanoma. In a phase III study, 676 patients with unresectable stage III or IV melanoma whose disease had progressed while receiving therapy for metastatic disease were randomly assigned in a 3:1:1 ratio to ipilimumab plus a glycoprotein 100 (gp100) peptide vaccine, ipilimumab, or gp100 alone. Ipilimumab was given at a dose of 3 mg/kg and was administered with or without gp100 every 3 weeks for up to 4 treatments; subsequently, patients would receive reinduction therapy.^[95]

The median overall survival was 10 months in patients receiving ipilimumab plus gp100, compared with 6.4 months in those receiving gp100 alone. There was no difference in survival in the other ipilimumab arm compared with the ipilimumab plus gp100 arm. Because of these findings, ipilimumab was approved as a treatment for metastatic melanoma.^[95]

In a phase III study of ipilimumab and dacarbazine compared with dacarbazine and placebo, survival in patients with metastatic melanoma was improved by 2 months (11 mo vs 9 mo) in the ipilimumab arm; however, those patients had more grade 3 and 4 toxicity.^[96]

In the MDX010-20 trial, researchers evaluated immune-related adverse events (AEs) in 676 patients previously treated for metastatic melanoma who were randomly assigned to receive 1 of the following 3 treatment regimens (in a 3:1:1 ratio): (1) ipilimumab plus gp100; (2) ipilimumab plus placebo; or (3) gp100 plus placebo.^[97] Most of the immune-related AEs developed within 12 weeks of initial dosing, typically resolving in 6-8 weeks. Fewer than 10% of patients receiving any ipilimumab treatment experienced an immune-related AE more than 70 days after their last drug dose, and all of these AEs were grade 1 or 2 in severity. Most immune-related AEs, even grade 3/4 events, were readily managed with monitoring and early corticosteroid therapy; only 5 patients needed infliximab for gastrointestinal AEs, and all 5 subsequently improved.^[97]

Ipilimumab is also approved in the adjuvant setting. See Adjuvant therapy, above.

Relatlimab plus nivolumab

Opdualag, a fixed-dose combination of nivolumab and the LAG-3-blocking antibody relatlimab, was approved by the FDA in March 2022 for treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma. Efficacy was demonstrated in the phase III RELATIVITY-047 trial, a randomized, double-blind study in 714 patients with previously untreated metastatic or unresectable stage III or IV melanoma.^[98]

In RELATIVITY-047, patients were randomized to receive nivolumab 480 mg and relatlimab 160 mg by intravenous (IV) infusion every 4 weeks or nivolumab 480 mg by IV infusion every 4 weeks until disease progression or unacceptable toxicity. Patients receiving nivolumab plus relatlimab had significantly longer PFS than those receiving nivolumab alone (10.1 versus 4.6 months, respectively), but also had a higher rate of grade 3 or 4 treatment-related adverse events (18.9% vs 9.7%). The final analysis of OS did not show a statistically significant difference (HR=0.80; 95% CI: 0.64-1.01) with median OS not reached (NR) in the Opdualag arm (95% CI: 34.2-NR) and 34.1 months (95% CI: 25.2-NR) in the nivolumab arm.^[98]

In patients receiving nivolumab plus relatlimab, the most common laboratory abnormalities (≥20%) were decreased hemoglobin, decreased lymphocytes, increased liver transaminase values, and decreased serum sodium..The recommended dosage for patients 12 years of age or older who weigh at least 40 kg is 480 mg nivolumab and 160 mg relatlimab administered intravenously every 4 weeks until disease progression or unacceptable toxicity.^[98]

KIT inhibitor therapy

In a multicenter phase II trial, targeted therapy with imatinib was effective in patients with advanced melanoma harboring mutations and/or amplification of the KIT proto-oncogene.^{[99, 100]}Hodi et al reported that in patients with metastatic melanomas arising from acral, mucosal, or chronically sun-damaged sites and containing KIT amplifications, mutations, or both, 7 of 24 patients achieved a partial response to therapy, with five patients' responses confirmed on subsequent imaging studies, for an overall confirmed response rate of 21%.^[99]These findings reinforce similar findings in two earlier studies.^{[6, 101]}Japanese researchers are currently recruiting patients for a study of imatinib combined with pembrolizumab in patients with advanced KIT-mutant melanoma that has progressed on standard therapy.^[102]

Vaccines

Various vaccines have been studied in the treatment of melanoma. A phase III trial found that multiepitope peptide vaccination did not significantly improve relapse-free survival or overall survival in patients with high-risk resected melanoma.75 In contrast, several small studies using a personalized peptide-based DNA or RNA vaccine targeting a number of tumor neoantigens reported that some treated patients remained recurrence-free for up to 25 months, while other patients experienced recurrences but responded to treatment with pembrolizumab.^[103]Phase I trials of vaccination against telomerase human telomerase reverse transcriptase (hTERT), in combination with checkpoint inhibitors, have suggested clinical efficacy with negligible added toxicity.^[104]

Less frequently used therapies

With the advent of biologic therapies—most notably, agents that inhibit PD-1, BRAF, and MEK—the role of cytotoxic and immunotherapy agents such as dacarbazine and interleukin-2 (IL-2) has steadily diminished. For example, current NCCN guidelines recommend that use of cytotoxic agents (eg, carboplatin plus paclitaxel, or single-agent temozolomide) may be considered in symptomatic patients who are not candidates for further standard, immune-based, BRAF/MEK inhibitor therapy. However, the NCCN notes that cytotoxic therapy has a limited impact on overall survival in this setting.^[21]

Dacarbazine

Dacarbazine was the first drug approved by the FDA for the treatment of metastatic melanoma. In the initial studies with dacarbazine, the overall response rate was 22%, with no impact on survival. In a phase III study of dacarbazine compared with temozolomide, the response rate was 12% versus 13%, respectively.^[105]On the basis of this trial, and the greater ease of administration of temozolomide versus dacarbazine (oral versus intravenous), most oncologists prefer temozolomide for melanoma chemotherapy. Temozolomide has orphan drug designation for treatment of advanced metastatic melanoma.

Interleukin 2

The second drug approved by the FDA for the treatment of metastatic melanoma was interleukin-2 (IL-2), a recombinant hormone of the immune system originally described as a T-cell–derived growth factor and used as a lymphokine-activated cell killer therapy. A pooled analysis of 270 patients treated with a high-dose IL-2 bolus (600,000-720,000 units/kg every 8 hours for 5 days) resulted in an objective response rate of 16% (complete response of 6%) with the best response in patients with soft tissue and lung metastases. Median overall median survival was 11.4 months.^[106]

The treatment was quite toxic, with some patients requiring intensive care unit support. The more common toxicities included hypotension (45%), vomiting (37%), diarrhea (32%), and oliguria (39%). Consequently, this therapy is offered only in centers that have adequately trained staff and facilities. To qualify for IL-2 therapy, patients must have normal results on pulmonary function testing, brain imaging, and cardiac stress testing, plus adequate kidney and liver function.

Carboplatin plus paclitaxel

Combination therapy with carboplatin and paclitaxel has been tested in two small phase II studies, and when used together with sorafenib, the response rate was 11-17%. This regimen sometimes is used by clinicians in clinical practice because of lesser toxicity than dacarbazine and also as a second- or third-line regimen.

However, a randomized, placebo-controlled phase III study by Hauschild et al found that the addition of sorafenib to carboplatin and paclitaxel did not improve outcome in patients with unresectable stage III or IV melanoma; these investigators recommend against this combination in the second-line setting for patients with advanced melanoma.^{[107, 108]}

Treatment of brain metastases

The brain is a common site of metastasis in malignant melanoma. Brain metastases are associated with a poor prognosis; they tend to progress rapidly and display resistance to conventional therapies.

Stereotactic radiosurgery is used increasingly in patients with a limited number of brain metastases (fewer than 3); it is less invasive than craniotomy. External-beam radiation alone appears effective in palliating symptoms. Chemotherapy alone is relatively ineffective, although the combination of chemotherapy with external-beam radiation is being investigated.^[35]

Investigational Treatments

In a phase Ib/II clinical trial in 24 patients with stage IV melanoma, Tobin et al reported favorable tolerability and a high response rate to treatment with the combination of all-trans retinoic acid (ATRA) and pembrolizumab. The overall response rate was 71%, with 50% of patients experiencing a complete response. Median PFS was 20.3 months and 1-year OS was 80%. The combination effectively lowered the frequency of circulating myeloid-derived suppressor cells—immature myeloid cells that accumulate in the circulation and at tumor sites, where they suppress antitumor immunity.^[109]

In a randomized, open-label phase III trial in 168 patients with unresectable stage IIIC or IV melanoma, Rohaan et al demonstrated the survival benefit of therapy with tumor-infiltrating lymphocytes (TILs), compared with ipilimumab. For this personalized autologous treatment, tumor-resident T cells from the patient undergo ex vivo outgrowth and expansion, with subsequent intravenous adoptive transfer after preparative lymphodepleting chemotherapy, supported by treatment with interleukin-2 to enhance expansion of the cells in the patient and augment their antitumor responses.^[110]

Median PFS was 7.2 months (95% CI, 4.2-13.1) in the TIL group and 3.1 months (95% CI, 3.0-4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P< 0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median OS was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8-32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab. In the TIL group, most of those events were chemotherapy-related myelosuppression.^[110]

Prevention of Malignant Melanoma

The focus of melanoma prevention is avoidance of sun exposure. Everyone, especially those individuals at high risk of developing a melanoma, should wear protective clothing, avoid peak sun hours, protect children against exposure to ultraviolet radiation, avoid tanning booths, and wear sunscreen with a sun protection factor (SPF) of at least 15.

This last recommendation is considered somewhat controversial, because no study has shown sunscreen to reduce the incidence of melanoma.^[111]Moreover, a systematic review found that sunscreen use leads to longer duration of intentional sun exposure, and sunburns tend to be more frequent among sunscreen users.^[112]

In addition, a study of 499 white children who were enrolled at birth or at age 6 and stratified colorimetrically by skin tone found no association between sunscreen use and the overall number of moles at the age of 15 years. The only significant association was for lighter-skinned children who had at least three sunburns at 12 to 14 years old, who had fewer moles if they used sunscreen. However, even that association might have occurred by chance.^[113]

First-degree relatives of a patient diagnosed with familial melanoma should be encouraged to have annual skin examinations. Individuals with other risk factors for melanoma (see Overview/Etiology) should seek regular screening or do self-screening.

Consultations

A patient with a suggestive lesion should be referred to a dermatologist or surgical oncologist for excisional biopsy.

If the diagnosis of melanoma is made, the patient should be referred to an oncologist after definitive surgery is performed.

Long-Term Monitoring

Follow-up care of a patient with melanoma is based on the stage of the primary. The follow-up examination should be performed with the knowledge that the patient has an increased risk for a second primary and that, of all solitary sites of visceral recurrence, the lungs are the most frequent.

Follow-up guidelines from the National Comprehensive Cancer Network are listed below.^[21]

Follow-up for stage 0 in situ is as follows:

At least annual skin examination for life
Educate patient in monthly self-examination of skin

Follow-up for stage IA is as follows:

History and physical examination (H&P) (with emphasis on nodes and skin) every 3-12 mo for 5 y, then annually as clinically indicated
At least annual skin examination for life
Educate patient in monthly self-examination of skin and lymph nodes

Follow-up for stage IB-IV (patients with no evidence of disease) is as follows:

H&P (with emphasis on nodes and skin) every 3-6 mo for 2 y, then every 3-12 mo for 2 y, then annually as clinically indicated
Chest radiography, lactate dehydrogenase (LDH) level, and complete blood cell count (CBC) every 6-12 mo (optional)
Routine imaging is not recommended for stage IB or IIA disease
CT scans to follow up for specific signs and symptoms
Consider CT scans to screen stage IIB and higher for recurrent/metastatic disease
At least annual skin examination for life
Educate patient in monthly self-examination of skin and lymph nodes

Neoadjuvant Immunotherapy

Investigational studies suggest that neoadjuvant therapy with checkpoint inhibitors may be superior to adjuvant therapy. Blank et al randomized 20 patients with palpable stage III melanoma to receive ipilimumab/nivolumab in either four courses after surgery (adjuvant arm) or two courses before surgery and two courses after surgery (neoadjuvant arm). Neoadjuvant therapy proved feasible, with all patients undergoing surgery at the preplanned time point; 78% of patients achieving pathological response; and on median follow-up of 25.6 months, no patient experiencing relapse. However, in both the adjuvant and neoadjuvant arms, 9 of the 10 patients experienced one or more grade 3/4 adverse events. These authors concluded that neoadjuvant therapy appears promising, but further investigation is needed into reducing toxicity while preserving efficacy.^[114]

OpACIN-neo, a multicenter phase II trial by Rozeman et al in 86 patients with macroscopic stage III melanoma, identified an effective and tolerable dosing schedule for neoadjuvant therapy. In this randomized comparison of three neoadjuvant dosing schedules, two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every 3 weeks intravenously was associated with the lowest rate of grade 3-4 immune-related adverse events (20%). Of patients receiving this schedule, 57% achieved a radiologic objective response and 77% achieved a pathological response. Rozeman et al suggest that this schedule might be suitable for broader clinical use.^[115]

Uveal Melanoma Immunotherapy

Unlike advanced cutaneous melanoma, metastatic uveal melanoma does not respond to standard immunotherapies. However, a new class of immunotherapy agents, immune-mobilizing monoclonal T-cell receptors against cancer (ImmTACs), has shown benefit. ImmTACs enhance the function of tumor-specific T cells, which otherwise tend to have weak binding with tumor antigens.^[116]

The first ImmTAC to become clinically available, tebentafusp-tebn (Kimmtrak), was approved by the FDA in 2022 for HLA-A*02:01–positive adult patients with unresectable or metastatic uveal melanoma. This agent is a bispecific fusion protein comprised of a soluble T-cell receptor fused to an anti-CD3 immune-effector function. It places T cells in proximity to melanoma cells by targeting the gp100 protein, a lineage antigen expressed in melanocytes and melanoma.

The efficacy of tebentafusp-tebn was demonstrated in IMCgp100-202 (NCT03070392), an open-label, multicenter trial in which patients with metastatic uveal melanoma were randomized to receive tebentafusp-tebn (n=252) or investigator’s choice (n=126) of pembrolizumab, ipilimumab, or dacarbazine. Median overall survival was 21.7 months for patients treated with tebentafusp-tebn versus 16 months in patients who received the investigator’s choice of therapy (hazard ratio [HR]=0.51, 95% CI: 0.37, 0.71, P < 0.0001), and progression-free survival was 3.3 versus 2.9 months (HR=0.73, 95% CI: 0.58, 0.94, P=0.0139).^[117]

In the tebentafusp-tebn arm, the most common adverse reactions (≥30%) were cytokine release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache, and vomiting. The most common laboratory abnormalities (≥50%) were decreased lymphocyte count, increased creatinine, increased glucose, increased aspartate aminotransferase, increased alanine aminotransferase, decreased hemoglobin, and decreased phosphate.

For full discussion of this form of melanoma, see Choroidal Melanoma.

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Media Gallery

A 1.5-cm melanoma with characteristic asymmetry, irregular borders, and color variation.
Malignant melanoma. Image courtesy of Hon Pak, MD.
Lentigo maligna melanoma, right lower cheek. The centrally located erythematous papule represents invasive melanoma with surrounding macular lentigo maligna (melanoma in situ). Image courtesy of Susan M. Swetter, MD.

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Author

Winston W Tan, MD, FACP Associate Professor of Medicine, Mayo Medical School; Consultant and Person-in-Charge of Genitourinary Oncology-Medical Oncology, Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic Jacksonville; Vice Chairman, Division of Hematology/Oncology Education, Chair, Cancer Survivorship Program, Associate Chair, Department of Medicine Faculty Development, Mayo Clinic Florida; Vice President, Florida Society of Clinical Oncology

Winston W Tan, MD, FACP is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, American Society of Hematology, Philippine Medical Association, Texas Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Philip Schulman, MD Chief, Medical Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center

Philip Schulman, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology, Medical Society of the State of New York

Disclosure: Nothing to disclose.

Mohsin R Mir, MD Private Practice, Mohs Micrographic Surgery and Dermatologic Surgery, Kelsey-Seybold Clinic; Assistant Professor, Baylor College of Medicine

Mohsin R Mir, MD is a member of the following medical societies: American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery

Disclosure: Nothing to disclose.

Wesley Wu, MD Mohs Surgeon, Department of Dermatology, VA Puget Sound and University of Washington School of Medicine

Wesley Wu, MD is a member of the following medical societies: American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery

Disclosure: Nothing to disclose.

Malignant Melanoma Treatment & Management

Approach Considerations

Regional Lymph Node Dissection

Adjuvant Therapy

Dabrafenib plus trametinib

Pembrolizumab

Nivolumab

Ipilimumab

Intralesional therapy

Interferon alfa

Granulocyte-macrophage colony-stimulating factor

Treatment of Advanced-Stage Melanoma (Stage IV)

Treatment of melanoma with BRAF mutations

Treatment of BRAF V600 wild-type melanoma

Nivolumab monotherapy

Pembrolizumab

Ipilimumab

Relatlimab plus nivolumab

KIT inhibitor therapy

Vaccines

Less frequently used therapies

Treatment of brain metastases

Investigational Treatments

Prevention of Malignant Melanoma

Consultations

Long-Term Monitoring

Neoadjuvant Immunotherapy

Uveal Melanoma Immunotherapy

References

Tables

Contributor Information and Disclosures

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