Malignant Melanoma Treatment & Management

Updated: Feb 17, 2019
  • Author: Winston W Tan, MD, FACP; Chief Editor: Dirk M Elston, MD  more...
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Treatment

Approach Considerations

Surgery is the definitive treatment for early-stage melanoma. Wide local excision with completion lymph node dissection (CLND) in patients with positive sentinel lymph node biopsy results is considered the mainstay of treatment for patients with primary melanoma. In patients with solitary or acutely symptomatic brain metastases, surgical management may alleviate symptoms and provide local control of disease. [26]

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. 

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]

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

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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). CLND achieves good regional disease control. Careful observation is an alternative for patients with low-risk micrometastatic disease, with due consideration of clinicopathologic factors. For higher-risk patients, however, the guidelines advise that careful observation may be considered only after a thorough discussion with patients about the potential risks and benefits of foregoing CLND. [27]

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. [28, 29]

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). [28, 29]

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%. [28, 29]

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. [30]

 

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Adjuvant Therapy

Adjuvant therapy is used for metastatic, unresectable melanoma, and most recently, resected advanced-stage disease. Although observation rather than adjuvant therapy is standard for stage II melanoma, 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. [31]

Dabrafenib plus trametinib

In 2018, the 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% 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 0.47; 95% confidence interval 0.39, 0.58; P< 0.0001). [32]

Pembrolizumab

Pembrolizumab is indicated for first-line treatment of unresectable or metastatic melanoma. In addition, in February 2019, pembrolizumab gained FDA approval for adjuvant treatment of resected, high-risk stage 3 melanoma. Approval was based on data from the EORTC1325/KEYNOTE-054 trial (n=1019) showing a significantly prolonged 1-year recurrence-free survival compared with placebo (75.4% vs 61%; P < 0.001). [33]

Nivolumab

In 2017, the FDA approved nivolumab as an adjuvant treatment for patients with lymph node involvement or metastatic disease 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 recurrence-free survival rate was 70.5% in the nivolumab arm compared with 60.8% in the ipilimumab arm (hazard ratio for disease recurrence or death, 0.65; 97.56% confidence index, 0.51 to 0.83; P< 0.001). [34] 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 recurrence-free survival, overall survival, and distant metastasis–free survival compared with placebo. [35] 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 recurrence-free survival—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. [35]

Intralesional therapy

In October 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. [36]

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). [37]

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. [37]

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. [37]

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. [38]

Interferon alfa

A large multicenter study using high-dose interferon (IFN) alfa-2b, Eastern Cooperative Group (ECOG) 1684, showed improvement in disease-free survival and survival benefit (time to progression improvement of 8 months, with a 1-year survival benefit). [39]  On the basis of ECOG-1684, the US Food and Drug Administration (FDA) approved IFN as adjuvant treatment after excision in patients who are free of disease but are at high risk for recurrence.

A 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). [40]

Concerns about toxicity associated with high-dose adjuvant interferon alfa have prompted several investigators to test lower doses of the drug. Lower-dose adjuvant interferon alfa has demonstrated less toxicity than high-dose interferon alfa but also less efficacy in delaying progression, with no survival advantage.

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. [41]

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. In their prospective, randomized, multicenter trial in 674 lymph node–negative patients with resected primary malignant melanoma of more than 1.5-mm tumor thickness, there was no significant difference in 5-year relapse-free survival and overall survival between patients who received an induction phase (IFN-alpha-2b 5 times weekly IV for 2 wk and 5 times weekly subcutaneously for another 2 wk) followed by 23 months of low-dose IFN-alpha-2b, and patients who received low-dose subcutaneous treatment 3 times a week for 24 months. [42]

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. [43]

Meta-analysis data show that ulceration and tumor stage are important predictors of response to interferon alfa/pegylated-interferon. [44]

Peginterferon alfa-2b is an immunomodulatory cytokine that enhances phagocyte and lymphocyte activity. It was approved by the FDA in March 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

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been used in the adjuvant setting to treat high-risk melanoma. In a study of 46 patients with resected stage III or IV melanoma treated with a subcutaneous dose of 125 mg/m2 for 2 weeks on and 2 weeks off for a year, progression-free survival was 37 months, vs 12 months in historical controls. [45] . This treatment is no longer used due to the availability of more effective treatments.

However, a subsequent double-blind, placebo-controlled trial that compared the effect of GM-CSF and peptide vaccination (PV) on relapse-free survival (RFS) and overall survival (OS) in 815 patients with resected high-risk melanoma (locally advanced and/or stage 4) found that neither adjuvant GM-CSF nor PV significantly improved RFS or OS. Exploratory analyses did show a trend toward improved OS in GM-CSF-treated patients with resected visceral metastases. [46]

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Treatment of Advanced-Stage Melanoma (Stage IV)

Treatment of patients with advanced-stage (stage IV) melanoma has continued to improve despite the challenges. Chemotherapy is used less frequently due to the more efficacious drugs have been developed, including immunotherapy and BRAF and MEK inhibitors.

Single-agent dacarbazine (DTIC) yields only a 10-15% response rate. [47] Two combination regimens that have been commonly used in the treatment of patients with advanced-stage melanoma are cisplatin, vinblastine, and DTIC (CVD), and the Dartmouth regimen, which consists of cisplatin, DTIC, carmustine, and tamoxifen. However, a meta-analysis found that the strength of evidence does not support the addition of tamoxifen to combined chemotherapy regimens. [48] . Due to increased toxicity it is not used today.

Dacarbazine

Dacarbazine was the first drug approved by the US Food and Drug Administration (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. [49] On the basis of this trial, and the greater ease of administration of temozolomide versus dacarbazine (oral versus intravenous), most oncologists prefer temozolomide as a first-line chemotherapy drug for 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. The overall median survival was 11.4 months. [50]

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 renal and hepatic function.

Carboplatin and paclitaxel

Carboplatin and paclitaxel have been tested in two small phase II studies, and when used in combination with sorafenib, the response rate was 11-17%. This regimen sometimes is being 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. [51, 52]

Treatment of melanoma with BRAF mutations

BRAF mutations are present in 60% of melanomas. Detection of this mutation is important prior to starting treatment in any melanoma patient. In a multicenter, phase I, dose-escalation trial, 32 patients with metastatic melanoma who had a BRAF mutation were treated with vemurafenib (PLX4032). [53] Two patients had a complete response and 24 had a partial response.

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. [54]

Vemurafenib (Zelboraf) was approved by the FDA in August 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 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.

In May 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. [55] In a multicenter, open-label, phase III randomized controlled trial, treatment with dabrafenib significantly improved progression-free survival in patients with BRAF-mutated metastatic melanoma, compared with dacarbazine (5.1 vs 2.7 mo). [56]

Phase III trial results for the BRAF inhibitor 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. [57]

In addition, the overall survival rate at 6 months in the vemurafenib group was 84%, versus 64% in the dacarbazine group. [57] Despite the short follow-up period, these results have significant clinical implications, as, of the previously mentioned 40-60% of cutaneous melanomas with BRAF mutations, about 90% involve the BRAF V600E mutation. 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. [57]

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. [57] Adverse events seen with dacarbazine were primarily fatigue, nausea, vomiting, and neutropenia and led to dose modification or interruption in 16% of patients.

Dabrafenib was shown to significantly improve progression-free survival compared with dacarbazine (5.1 vs 2.7 mo) in patients with BRAF-mutated metastatic melanoma in a multicenter, open-label, phase III randomized controlled trial. [58]

Trametinib (Mekinist) is a mitogen-activated, extracellular signal-regulated kinase (MEK) inhibitor that was approved by the FDA in May 2013 for unresectable or metastatic melanoma with BRAF V600E or V600K mutations confirmed by the THxID BRAF mutation test. [55] Approval was based on a phase III open-label trial in which median progression-free survival 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). [59]

In January 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 progression-free survival in the combination full-dose 150 mg/2 mg group was 9.4 months compared with 5.8 months in the dabrafenib monotherapy group (hazard ratio for progression or death, 0.39; 95% 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 has not been demonstrated for this combination. [60, 61, 62]

In November 2015, the FDA approved cobimetinib, an 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 3 coBRIM study, in which median progression-free survival was longer with cobimetinib plus vemurafenib than with vemurafenib monotherapy (12.3 vs 7.2 months; hazard ratio, 0.58; 95% confidence interval, 0.46 - 0.72). Additionally, the objective response rate was higher with the combination than with vemurafenib alone (70% vs 50%; P < 0.0001). [63]

The combination of binimetinib (Mektovi), a MEK inhibitor, plus encorafenib (Braftovi), a BRAF inhibitor, was approved by the FDA in June 2018 for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. Approval was based on results from the phase 3 COLUMBUS trial, which demonstrated that the combination doubled median progression-free survival  compared with vemurafenib alone (14.9 months versus 7.3 months, respectively (P< 0.0001). [64]  

Treatment of BRAF V600 wild-type melanoma

First-line treatment of patients with BRAF V600 wild-type , unresectable or metastatic melanoma is with nivolumab plus ipilimumab is the first choice .

Nivolumab (Opdivo), another PD-1 inhibitor, was granted accelerated approval in December 2014 for unresectable or metastatic melanoma and disease progression following ipilimumab treatment and, if BRAF V600 mutation positive, a BRAF inhibitor. 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% confidence interval [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 November 2015 on the basis of data from the randomized phase 3 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 was 72.9% (95% CI, 65.5 to 78.9) in the nivolumab group versus 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group. [65]

A significant benefit with respect to overall survival was observed in the nivolumab group, as compared with the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P< 0.001). Median progression-free survival was also improved in the nivolumab-treated patients compared with dacarbazine (5.1 vs 2.2 months; HR, 0.43; P < 0.001). [65]

The FDA approved the combination regimen of nivolumab plus ipilimumab on September 30, 2015 in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma. Approval was based on results from the phase 2 CheckMate-069 study Of the 142 patients enrolled, 109 had both BRAF wild-type and BRAF mutation-positive melanoma. The primary endpoint was objective response rate (ORR) in patients. In patients with BRAF wild-type melanoma treated with the combination regimen, the overall response rate was 61% (95% CI: 48-71) compared to 11% (95% CI: 3-25) in patients given ipilimumab monotherapy (P < 0.001).

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). [66]

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.  [67]

In January 2016, the indication for nivolumab was expanded to include mutation-positive melanoma, making nivolumab effective across BRAF status. [54]

 

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 September 2014, the FDA granted accelerated approval for pembrolizumab (Keytruda). Pembrolizumab is the first monoclonal antibody for inhibition of PD-1. [68]  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 December 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. [69]

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. [70]  The proposed mechanism of action is inhibition of T-cell inactivation, allowing expansion of naturally developed melanoma-specific cytotoxic T cells.

Ipilimumab has demonstrated remarkable promise in patients with metastatic melanoma. Clinical trials for monotherapy and in combination with other immunotherapies and vaccines have been concluded or are currently under way. [71]  Ipilimumab was approved by the FDA in March 2011 for unresectable or metastatic melanoma. In July 2017, ipilimumab was approved in adolescents aged 12 years or older for treatment of unresectable or metastatic melanoma. [72]

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. [71]

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. [71]

In a phase 3 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. [73]

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. [74]  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. [74]

The FDA approved the combination regimen of nivolumab plus ipilimumab on September 30, 2015 in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma. [66]  Additionally, it is indicated for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection, including total lymphadenectomy. [75]

The use of immune checkpoint inhibitors for the treatment of advanced melanoma has evolved beyond monotherapies to combination strategies. This combination approach results in response rates around 60% and superior progression-free survival compared with ipilimumab monotherapy (median 11.5 versus 2.9 months). [76]

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

External-beam radiation

The brain is a common site of metastasis in malignant melanoma. Brain metastases are associated with a poor prognosis. Management of brain metastases can be difficult due to rapid progression of disease and resistance to conventional therapies. Stereotactic radiosurgery is used increasingly in patients with a limited number of metastases; 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. [26]

KIT inhibitor therapy

In a multicenter phase II trial, targeted therapy with imatinib was an effective treatment option in patients with advanced melanoma harboring mutations or amplification of the KIT proto-oncogene. [77, 78, 79] Of 50 patients with melanomas arising from acral, mucosal, or chronically sun-damaged sites with KIT alterations, 24 evaluable patients with KIT -mutant (n = 8), KIT -amplified melanoma (n = 11), or both (n = 5) were treated with imatinib. Seven of these 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%. [77, 78]

These findings reinforce similar findings in two earlier studies. [5, 80]

Vaccines

A phase III trial found that peptide vaccination did not significantly improve relapse-free survival or overall survival in patients with high-risk resected melanoma. [46] However, in two small phase I studies, personalized treatment vaccines for melanoma generated a robust immune response and may have helped prevent recurrences. In the studies, researchers identified genetic mutations specific to each patient’s tumor and the neoantigens associated with those mutations. They then produced a peptide-based DNA or RNA vaccine targeting a number of those neoantigens. [81]

In these studies, some of the treated patients remained recurrence free for up to 25 months. Other patients experienced recurrences but responded to treatment with the checkpoint inhibitor pembrolizumab.  [81]

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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. [82] 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. [83]

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. [84]

First-degree relatives of a patient diagnosed with familial melanoma should be encouraged to have annual skin examinations.

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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.

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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

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