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Home > Health Library > Melanoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Melanoma is a malignant tumor of melanocytes, which are the cells that make the pigment melanin and are derived from the neural crest. Although most melanomas arise in the skin, they may also arise from mucosal surfaces or at other sites to which neural crest cells migrate, including the uveal tract. Uveal melanomas differ significantly from cutaneous melanoma in incidence, prognostic factors, molecular characteristics, and treatment. (Refer to the PDQ summary on Intraocular (Uveal) Melanoma Treatment for more information.)
Incidence and Mortality
Estimated new cases and deaths from melanoma in the United States in 2019:
Skin cancer is the most common malignancy diagnosed in the United States, with 5.4 million cancers diagnosed among 3.3 million people in 2012. Invasive melanoma represents about 1% of skin cancers but results in most deaths.[1,2] The incidence has been increasing over the past 30 years. Elderly men are at highest risk; however, melanoma is the most common cancer in young adults aged 25 to 29 years and the second most common cancer in those aged 15 to 29 years. Ocular melanoma is the most common cancer of the eye, with approximately 2,000 cases diagnosed annually.
Risk factors for melanoma include both intrinsic (genetic and phenotype) and extrinsic (environmental or exposure) factors:
(Refer to the PDQ summaries on Skin Cancer Prevention and the Genetics of Skin Cancer for more information about risk factors.)
Schematic representation of normal skin. Melanocytes are also present in normal skin and serve as the source cell for melanoma. The relatively avascular epidermis houses both basal cell keratinocytes and squamous epithelial keratinocytes, the source cells for basal cell carcinoma and squamous cell carcinoma, respectively. The separation between epidermis and dermis occurs at the basement membrane zone, located just inferior to the basal cell keratinocytes.
Refer to the PDQ summary on Skin Cancer Screening for more information.
Melanoma occurs predominantly in adults, and more than 50% of the cases arise in apparently normal areas of the skin. Although melanoma can occur anywhere, including on mucosal surfaces and the uvea, melanoma in women occurs more commonly on the extremities, and in men it occurs most commonly on the trunk or head and neck.
Early signs in a nevus that would suggest a malignant change include the following:
Melanomas with characteristic asymmetry, border irregularity, color variation, and large diameter.
A biopsy, preferably by local excision, should be performed for any suspicious lesions. Suspicious lesions should never be shaved off or cauterized. The specimens should be examined by an experienced pathologist to allow for microstaging.
Studies show that distinguishing between benign pigmented lesions and early melanomas can be difficult, and even experienced dermatopathologists can have differing opinions. To reduce the possibility of misdiagnosis for an individual patient, a second review by an independent qualified pathologist should be considered.[5,6] Agreement between pathologists in the histologic diagnosis of melanomas and benign pigmented lesions has been studied and found to be considerably variable.[5,6]
Evidence (discordance in histologic evaluation):
Prognosis is affected by the characteristics of primary and metastatic tumors. The most important prognostic factors have been incorporated into the revised 2009 American Joint Committee on Cancer staging and include the following:[4,7,8,9]
Patients who are younger, who are female, and who have melanomas on their extremities generally have better prognoses.[4,7,8,9]
Microscopic satellites, recorded as present or absent, in stage I melanoma may be a poor prognostic histologic factor, but this is controversial. The presence of tumor infiltrating lymphocytes, which may be categorized as brisk, nonbrisk, or absent, is under study as a potential prognostic factor.
The risk of relapse decreases substantially over time, although late relapses are not uncommon.[12,13]
Other PDQ summaries containing information related to melanoma include the following:
The descriptive terms for clinicopathologic cellular subtypes of malignant melanoma should be considered of historic interest only; they do not have independent prognostic or therapeutic significance. The cellular subtypes are the following:
The Cancer Genome Atlas (TCGA) Network performed an integrative multiplatform characterization of 333 cutaneous melanomas from 331 patients. Using six types of molecular analysis at the DNA, RNA, and protein levels, the researchers identified four major genomic subtypes:
Genomic subtypes may suggest drug targets and clinical trial design, as well as guide clinical decision-making for targeted therapies. Refer to Table 1 for more information.
To date, targeted therapies have demonstrated efficacy and received the U.S. Food and Drug Administration approval for the BRAF-mutant subtype of melanoma only. Combination therapies with a BRAF plus a MEK inhibitor have shown improvement in outcomes over a single-agent inhibitor alone; yet, virtually all patients acquire resistance to therapy and relapse. (Refer to the individual treatment sections of this summary for more information). Therefore, clinical trials remain an important option for patients with BRAF-mutant subtype, as well as other genomic subtypes of melanoma.
A variety of immunotherapies have been approved for the treatment of melanoma regardless of genetic subtype. (Refer to the individual treatment sections of this summary for more information.) The benefit of immunotherapy has not been associated with a specific mutation or molecular subtype. The TCGA analysis identified immune markers (in a subset within each molecular subtype) that were associated with improved survival and that may have implications for immunotherapy. Identification of predictive biomarkers remains an active area of research.
Uveal melanomas differ significantly from cutaneous melanomas. ln one series, 83% of 186 uveal melanomas were found to have a constitutively active somatic mutation in GNAQ or GNA11.[2,3] (Refer to the PDQ summary on Intraocular (Uveal) Melanoma Treatment for more information.)
Clinical staging is based on whether the tumor has spread to regional lymph nodes or distant sites. For melanoma that is clinically confined to the primary site, the chance of lymph node or systemic metastases increases as the thickness and depth of local invasion increases, which worsens the prognosis. Melanoma can spread by local extension (through lymphatics) and/or by hematogenous routes to distant sites. Any organ may be involved by metastases, but lungs and liver are common sites.
The microstage of malignant melanoma is determined on histologic examination by the vertical thickness of the lesion in millimeters (Breslow classification) and/or the anatomic level of local invasion (Clark classification). The Breslow thickness is more reproducible and more accurately predicts subsequent behavior of malignant melanoma in lesions thicker than 1.5 mm and should always be reported.
Accurate microstaging of the primary tumor requires careful histologic evaluation of the entire specimen by an experienced pathologist.
Clark Classification (Level of Invasion)
AJCC Stage Groupings and TNM Definitions
The American Joint Committee on Cancer (AJCC) has designated staging by TNM (tumor, node, metastasis) classification to define melanoma.
Cancers staged using this staging system include cutaneous melanoma. Cancers not staged using this system include melanoma of the conjunctiva, melanoma of the uvea, mucosal melanoma arising in the head and neck, mucosal melanoma of the urethra, vagina, rectum, and anus, Merkel cell carcinoma, and squamous cell carcinoma.
AJCC Prognostic Stage Groups-Clinical (cTNM)
AJCC Prognostic Stage Groups-Pathological (pTNM)
Surgical excision remains the primary modality for treating melanoma. Cutaneous melanomas that have not spread beyond the site at which they developed are highly curable. The treatment for localized melanoma is surgical excision with margins proportional to the microstage of the primary lesion.
Lymph node management
Sentinel lymph node biopsy (SLNB)
Lymphatic mapping and SLNB can be considered to assess the presence of occult metastasis in the regional lymph nodes of patients with primary tumors larger than 1 to 4 mm, potentially identifying individuals who may be spared the morbidity of regional lymph node dissections and individuals who may benefit from adjuvant therapy.[1,2,3,4,5,6]
To ensure accurate identification of the sentinel lymph node, lymphatic mapping and removal of the SLN should precede wide excision of the primary melanoma.
Multiple studies have demonstrated the diagnostic accuracy of SLNB, with false-negative rates of 0% to 2%.[1,6,7,8,9,10,11] If metastatic melanoma is detected, a complete regional lymphadenectomy can be performed in a second procedure.
Complete lymph node dissection (CLND)
Patients can be considered for CLND if the sentinel node(s) is microscopically or macroscopically positive for regional control or considered for entry into the Multicenter Selective Lymphadenectomy Trial II (NCT00297895) to determine whether CLND affects survival. SLNB should be performed before wide excision of the primary melanoma to ensure accurate lymphatic mapping.
High-dose interferon alpha-2b was approved by the U.S. Food and Drug Administration (FDA) in 1995 for the adjuvant treatment of patients with melanoma who have undergone a complete surgical resection but are considered to be at a high risk of relapse (stages IIB, IIC, and III). However, prospective, randomized, multicenter treatment trials have demonstrated that high-dose interferon alpha-2b and pegylated interferon improve relapse-free survival but do not improve overall survival (OS).
Therapies that have improved OS in patients with recurrent or metastatic disease are now being tested as adjuvant therapy in clinical trials, including NCT01274338, NCT01667419, and NCT01682083.
A completed, multicenter, phase III randomized trial (SWOG-8593) of patients with high-risk primary stage I limb melanoma did not show a disease-free survival or OS benefit from isolated limb perfusion with melphalan, when compared with surgery alone.
Systematic Treatment for Unresectable Stage III, Stage IV, and Recurrent Disease
Although melanoma that has spread to distant sites is rarely curable, treatment options are rapidly expanding. Two approaches—checkpoint inhibition and targeting the mitogen-activated protein kinase pathway—have demonstrated improvement in OS in randomized trials in comparison to dacarbazine (DTIC). Although none appear to be curative when used as single agents, early data of combinations are promising. Given the rapid development of new agents and combinations, patients and their physicians are encouraged to consider treatment in a clinical trial for initial treatment and at the time of progression.
Three checkpoint inhibitors—pembrolizumab, nivolumab, and ipilimumab—are now approved by the FDA. Each has demonstrated the ability to impact OS against different comparators in unresectable or advanced disease. (Refer to the Pembrolizumab, the Nivolumab, and the Ipilimumab sections in the Unresectable Stage III, Stage IV, and Recurrent Melanoma Treatment section of this summary for more information.) Multiple phase III trials are in progress to determine optimal sequencing of immunotherapies, immunotherapy with targeted therapy, and whether combinations of immunotherapies or immunotherapy plus targeted therapy are superior for increasing OS.
IL-2 was approved by the FDA in 1998 because of durable complete response (CR) rates in a minority of patients (6%–7%) with previously treated metastatic melanoma in eight phase I and II studies. Phase III trials comparing high-dose IL-2 with other treatments and providing an assessment of relative impact on OS have not been conducted.
Studies to date indicate that both BRAF and MEK inhibitors can significantly impact the natural history of melanoma, although they do not appear to be curative as single agents.
Vemurafenib, approved by the FDA in 2011, has demonstrated an improvement in progression-free survival (PFS) and OS in patients with unresectable or advanced disease. Vemurafenib is an orally available, small-molecule, selective BRAF V600E kinase inhibitor, and its indication is limited to patients with a demonstrated BRAF V600E mutation by an FDA-approved test.
Dabrafenib, an orally available, small-molecule, selective BRAF inhibitor that was approved by the FDA in 2013, showed improvement in PFS when compared with DTIC in an international, multicenter trial (BREAK-3 [NCT01227889]).
Trametinib is an orally available, small-molecule, selective inhibitor of MEK1 and MEK2 that was approved by the FDA in 2013 for patients with unresectable or metastatic melanoma with BRAF V600E or K mutations. Trametinib demonstrated improved PFS over DTIC.
Cobimetinib is an orally available, 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 signal-transduction inhibitor therapy section of this summary for more information.)
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.[12,13,14] Phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-KIT mutation.
Combination signal-transduction inhibitor therapy
In 2014, the combination of dabrafenib and trametinib received accelerated approval from the FDA for patients with unresectable or metastatic melanomas that carry the BRAF V600E or V600K mutation. The combination demonstrated improved durable response rates over single-agent dabrafenib. Full approval is pending completion of ongoing clinical trials and demonstration of clinical benefit on OS.
In 2015, the combination of vemurafenib and cobimetinib was also approved by the FDA for patients with unresectable or metastatic melanomas that carry the BRAF V600E or V600 K mutation. Published phase III data support improved PFS using another combination of BRAF and MEK inhibitors versus BRAF inhibitor plus placebo—dabrafenib plus trametinib compared with dabrafenib plus placebo. OS data are immature.
DTIC was approved in 1970 on the basis of overall response rates. Phase III trials indicate an overall response rate of 10% to 20%, with rare CRs observed. An impact on OS has not been demonstrated in randomized trials.[15,16,17,18] 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, appeared to be similar to intravenous DTIC in a randomized phase III trial with a primary endpoint of OS; however, because the trial was designed to demonstrate the superiority of temozolomide, which was not achieved, the trial was left with a sample size that was inadequate to provide statistical proof of noninferiority.
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.[19,20,21]
Standard Treatment Options for Stage 0 Melanoma
Standard treatment options for stage 0 melanoma include the following:
Patients with stage 0 disease may be treated by excision with minimal, but microscopically free, margins.
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.
Standard Treatment Options for Stage I Melanoma
Standard treatment options for stage I melanoma include the following:
Evidence suggests that lesions no thicker than 2 mm may be treated conservatively with radial excision margins of 1 cm.
Depending on the location of the melanoma, most patients can now have the excision performed on an outpatient basis.
Elective regional lymph node dissection is of no proven benefit for patients with stage I melanoma.
Lymphatic mapping and sentinel lymph node biopsy (SLNB) for patients who have tumors of intermediate thickness and/or ulcerated tumors may identify individuals with occult nodal disease. These patients may benefit from regional lymphadenectomy and adjuvant therapy.[6,9,10,11]
Evidence (immediate lymphadenectomy vs. observation with delayed lymphadenectomy):
Treatment Options Under Clinical Evaluation for Stage I Melanoma
Treatment options under clinical evaluation for patients with stage I melanoma include the following:
Standard Treatment Options for Stage II Melanoma
Standard treatment options for stage II melanoma include the following:
For melanomas with a thickness between 2 mm and 4 mm, surgical margins need to be 2 cm to 3 cm or smaller.
Few data are available to guide treatment in patients with melanomas thicker than 4 mm; however, most guidelines recommend margins of 3 cm whenever anatomically possible.
Depending on the location of the melanoma, most patients can have the excision performed on an outpatient basis.
Lymphatic mapping and sentinel lymph node biopsy (SLNB)
Lymphatic mapping and SLNB have been used to assess the presence of occult metastasis in the regional lymph nodes of patients with stage II disease, potentially identifying individuals who may be spared the morbidity of regional lymph node dissections (LNDs) and individuals who may benefit from adjuvant therapy.[3,4,5,6,7]
With the use of a vital blue dye and a radiopharmaceutical agent injected at the site of the primary tumor, the first lymph node in the lymphatic basin that drains the lesion can be identified, removed, and examined microscopically. Multiple studies have demonstrated the diagnostic accuracy of SLNB, with false-negative rates of 0% to 2%.[3,8,9,10,11,12] If metastatic melanoma is detected, a complete regional lymphadenectomy can be performed in a second procedure.
No published data on the clinical significance of micrometastatic melanoma in regional lymph nodes are available from prospective trials. Some evidence suggests that for patients with tumors of intermediate thickness and occult metastasis, survival is better among patients who undergo immediate regional lymphadenectomy than it is among those who delay lymphadenectomy until the clinical appearance of nodal metastasis. This finding should be viewed with caution because it arose from a post hoc subset analysis of data from a randomized trial.
Evidence (regional lymphadenectomy):
High-dose interferon alpha-2b was approved in 1995 for the adjuvant treatment of patients with melanoma who have undergone a complete surgical resection but are at a high risk of relapse. Evidence was based on a significantly improved relapse-free survival (RFS) and marginally improved overall survival (OS) that were seen in EST-1684.
Subsequent large, randomized trials have not been able to reproduce a benefit in OS. Ongoing trials are testing therapies that have demonstrated improved OS in patients with stage IV disease.
Clinicians should be aware that the high-dose regimens have significant toxic effects.
Evidence (high-dose interferon alpha-2b):
Treatment Options Under Clinical Evaluation for Stage II Melanoma
Postsurgical adjuvant treatment (e.g., with interferons) has not been shown to affect survival.
Treatment options under clinical evaluation for patients with stage II melanoma include the following:
Standard Treatment Options for Resectable Stage III Melanoma
Standard treatment options for resectable stage III melanoma include the following:
The primary tumor may be treated with wide local excision with 1-cm to 3-cm margins, depending on tumor thickness and location.[1,2,3,4,5,6,7] Skin grafting may be necessary to close the resulting defect.
Lymphatic mapping and SLNB can be considered to assess the presence of occult metastases in the regional lymph nodes of patients with primary tumors larger than 1 mm to 4 mm, potentially identifying individuals who may be spared the morbidity of regional lymph node dissections and individuals who may benefit from adjuvant therapy.[3,8,9,10,11,12]
To ensure accurate identification of the sentinel lymph node (SNL), lymphatic mapping and removal of the SLN should precede wide excision of the primary melanoma.
Multiple studies have demonstrated the diagnostic accuracy of SLNB, with false-negative rates of 0% to 2%.[8,12,13,14,15,16,17] If metastatic melanoma is detected, a complete regional lymphadenectomy can be performed in a second procedure.
Patients can be considered for CLND if the sentinel node(s) is microscopically or macroscopically positive for regional control or considered for entry into the Multicenter Selective Lymphadenectomy Trial II (NCT00297895) to determine whether CLND affects survival. SLNB should be performed prior to wide excision of the primary melanoma to ensure accurate lymphatic mapping.
Adjuvant therapeutic options for patients at high risk of recurrence after complete resection are expanding, building on advances seen with both immunotherapy and targeted therapies in the metastatic setting. Prospective, randomized, multicenter treatment trials have demonstrated a clinically significant impact on relapse-free survival (RFS) with checkpoint inhibitors (ipilimumab, nivolumab, and pembrolizumab) and combination signal transduction inhibitor therapy (dabrafenib plus trametinib).
Data on the results of adjuvant therapies are early, but ipilimumab, which has a median follow-up of 5.3 years, shows an improved overall survival (OS) when compared with placebo. Treatment takes longer than a year, however, and toxicity is significant (grade 3 and 4 adverse events [AEs], death, and discontinuation of therapy due to AEs). Other completed adjuvant trials have also used placebo as a control arm, except for trials of nivolumab, which used an active control, ipilimumab, with 1-year treatment for both arms or until disease recurrence or unacceptable toxicity. Nivolumab demonstrated a statistically significant improved RFS, with less toxicity than ipilimumab. The benefit of immunotherapy with ipilimumab, nivolumab, and pembrolizumab has been seen regardless of programmed death-ligand 1 (PD-L1) expression or BRAF mutations. Combination signal transduction inhibitor therapy is an additional option for patients with BRAF mutations.
Although some trials of interferon alpha-2b have demonstrated an effect on RFS, both adjuvant high-dose and pegylated interferon have been shown to not improve OS in randomized trials.
Participation in clinical trials to identify treatments that will further extend RFS and OS with less toxicity is an important option for all patients.
A total of 906 patients were randomly assigned: 453 patients to nivolumab and 453 patients to ipilimumab. Baseline characteristics were balanced. Approximately 81% of patients had stage III disease, 32% had ulcerated primary melanoma, 48% had macroscopic lymph node involvement, 62% had less than a 5% PD-L1 expression, and 42% harbored BRAF mutations.
A total of 1,019 patients were randomly assigned: 514 to pembrolizumab and 505 to placebo. Baseline characteristics were balanced. Approximately 40% had ulcerated primary melanoma, 66% had macroscopic lymph node involvement, 84% had positive PD-L1 expression (melanoma score >2 by 22C3 antibody assay), and 44% harbored BRAF mutations.
The optimal dose of ipilimumab in the adjuvant setting is unknown. Patients are fully accrued and data are pending from an intergroup trial, E1609 (NCT01274338), testing high-dose (10 mg) versus low-dose (3 mg) ipilimumab versus interferon. For patients with metastatic disease, the recommended dose is 3 mg/kg.
Evidence (high-dose interferon alpha):
Approval of pegylated interferon alpha-2b was based on EORTC-18991 (NCT00006249), which randomly assigned 1,256 patients with resected stage III melanoma to observation or weekly subcutaneous pegylated interferon alpha-2b for up to 5 years.[Level of evidence: 1iiDii]
Combination signal transduction inhibitors
Dabrafenib plus trametinib
Evidence (dabrafenib plus trametinib):
Treatment Options Under Clinical Evaluation for Resectable Stage III Melanoma
Treatment options under clinical evaluation for patients with resectable stage III melanoma include the following:
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:
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:
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.
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.
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 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:
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.
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.
Anti–cytotoxic T-lymphocyte antigen-4 (CTLA-4)
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]
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.
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):
Strategies to improve this therapy are an active area of investigation.
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. 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):
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.[Level of evidence: 1iiA]
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.
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.
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.[15,16,17,18]
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.
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.
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.
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.)
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.[23,24,25] Phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-KIT mutation.
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
Vemurafenib plus cobimetinib
Evidence (vemurafenib plus cobimetinib):
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):
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.[6,19,33,34,35] 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.
The objective response rate to DTIC and the nitrosoureas, carmustine and lomustine, is approximately 10% to 20%.[33,36,37,38] 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.[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.[Level of evidence: 1iiA]
Two randomized, phase III trials in previously untreated patients with metastatic melanoma (resulting in FDA approval for vemurafenib  and ipilimumab ) 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,[42,43,44] and combinations of chemotherapy and immunotherapy [9,10,40,45,46,47,48]) 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.[Level of evidence:1iiA]
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.[46,47,48]
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]
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
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.
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:
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:
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.
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.
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Last Revised: 2019-04-11
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