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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 2020:
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.
Adjuvant therapy options are expanding for patients at high risk of recurrence after complete resection, with data still emerging on optimal therapy. Ipilimumab was the first checkpoint inhibitor to be approved by the U.S. Food and Drug Administration (FDA) as adjuvant therapy, and has demonstrated improved overall survival (OS) at 10 mg/kg (ipi10) compared with placebo (EORTC 18071 [NCT00636168]). However, ipilimumab has significant toxicity at this dose. The North American Intergroup Trial E1609 (NCT01274338) tested ipi10 and ipilimumab at a lower dose of 3 mg/kg (ipi3) (approved for metastatic melanoma) and compared them with high-dose interferon (HDI). Ipi3 showed a significant improvement in OS whereas ipi10 did not. These data remove support for HDI as adjuvant treatment of melanoma. As newer checkpoint inhibitors emerge, the role of ipi3 remains to be defined.
Large randomized trials with the newer checkpoint inhibitors (nivolumab and pembrolizumab) and with combination signal-transduction inhibitors (dabrafenib plus trametinib) demonstrate a clinically significant impact on relapse-free survival (RFS) with less toxicity than with ipilimumab. CheckMate 238 (NCT02388906) compared nivolumab with ipi10 and nivolumab was superior in RFS and the safety profile. Data on OS are maturing for all of these trials.
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.
Participation in clinical trials designed to identify treatments that will further extend RFS and OS with less toxicity and shorter treatment schedules is an important option for all patients.
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. 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.
Dual checkpoint inhibition
The combination of anti–programmed death-1 (PD-1) and anti–cytotoxic T-lymphocyte antigen-4 (CTLA-4) immunotherapies (nivolumab and ipilimumab) has demonstrated prolongation of progression-free survival (PFS) and OS compared with ipilimumab monotherapy, but the combination is associated with significant toxicity.
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. Two combination regimens of BRAF and MEK inhibitors have demonstrated improved PFS and OS compared with BRAF inhibitor monotherapy.
Vemurafenib, approved by the FDA in 2011, has demonstrated an improvement in 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 dacarbazine 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 dacarbazine.
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.[15,16,17] 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
Two combination regimens, dabrafenib plus trametinib and vemurafenib plus cobimetinib, are approved by the FDA on the basis of improved PFS and OS when compared with a single-agent BRAF inhibitor (either dabrafenib or vemurafenib) in patients with unresectable or metastatic melanomas that carry the BRAF V600E or V600K mutation as confirmed by an FDA-approved test.
Combination signal-transduction inhibitor therapy plus anti-PD-L1 therapy
The triplet regimen of cobimetinib (MEK inhibitor), vemurafenib (BRAF kinase inhibitor), and atezolizumab (PD-L1 inhibitor) showed improved PFS over the combination of cobimetinib and vemurafenib.
Dacarbazine 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.[19,20,21,22] When used as a control arm for recent registration trials of ipilimumab and vemurafenib in previously untreated patients with metastatic melanoma, dacarbazine was shown to be inferior for OS.
Temozolomide, an oral alkylating agent, appeared to be similar to intravenous dacarbazine 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.[14,23,24]
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):
Treatment Options Under Clinical Evaluation for Stage II Melanoma
Postsurgical systemic adjuvant treatment has not been adequately studied in patients with stage II disease; therefore, clinical trials are an important therapeutic option for patients at high risk of relapse.
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 (SLN), 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, with data still emerging on optimal therapy. Ipilimumab was the first checkpoint inhibitor to be approved by the U.S. Food and Drug Administration (FDA) as adjuvant therapy, and has demonstrated improved overall survival (OS) at 10 mg/kg (ipi10) compared with placebo (EORTC 18071 [NCT00636168]). However, ipi10 has significant toxicity at this dose. The North American Intergroup Trial E1609 (NCT01274338) compared ipi10 and ipilimumab at a lower dose of 3 mg/kg (ipi3) (approved for metastatic disease) with high-dose interferon (HDI). Ipi3 showed a significant improvement in OS whereas ipi10 did not. These data remove support for HDI as adjuvant treatment for melanoma. As newer checkpoint inhibitors emerge, the role of ipi3 remains to be defined.
Large randomized trials with the newer checkpoint inhibitors (nivolumab and pembrolizumab) and with combination signal-transduction inhibitors (dabrafenib plus trametinib) demonstrate a clinically significant impact on relapse-free survival (RFS) with less toxicity than with ipilimumab. CheckMate 238 (NCT02388906) compared nivolumab with ipi10 and nivolumab was superior in RFS and the safety profile. Data on OS are maturing for all of these trials.
Participation in clinical trials to identify treatments that will further extend RFS and OS with less toxicity and shorter treatment schedules 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 trial was designed with two coprimary endpoints, RFS and OS, with a hierarchic analysis to evaluate ipi3 versus HDI followed by ipi10 versus HDI. The time to event was longer than anticipated and the design was amended for a final analysis at a data cutoff date giving a median follow-up time of 57.4 months (range, 0.03 months−86.6 months).
Toxicity with ipi3 was lower than with ipi10; however, both had treatment-related discontinuations and death.
The study concluded that evidence no longer supports a role for HDI as adjuvant therapy for patients with high-risk melanoma. Further, ipi3 provides OS data superior to ipi10 compared with HDI. The role of ipilimumab as adjuvant monotherapy is unclear because CheckMate 238 demonstrated that nivolumab was superior to ipi10 in improving RFS, with OS data still maturing.
An updated analysis was performed at a median follow-up of 5.3 years.
Data from this trial (EORTC 18071), which tested high-dose ipilimumab at 10 mg/kg compared with placebo, served as the basis for the approval of ipilimumab in the adjuvant setting. However, the subsequent intergroup trial, E1609 (described above), demonstrated better outcomes with low-dose (3 mg/kg) ipilimumab, which is also the dose approved for metastatic disease.
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. The efficacy seen with immunotherapy is independent of BRAF mutation status.
Combinations of BRAF and MEK inhibitors have consistently shown superior efficacy compared with BRAF monotherapy. Improved PFS was seen when a PD-L1 inhibitor (atezolizumab) was added to the combination of a BRAF plus MEK inhibitor (vemurafenib plus cobimetinib); however, data on OS is immature. Further questions remain regarding triplet therapy, including how it compares with monotherapy checkpoint inhibition and if the concurrent administration is superior to sequential therapy (NCT02224781).
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 the following:
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.[7,8]
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 co-blockade 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.
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 CR, PR, 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.[16,17,18,19]
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.[24,25,26] Phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-KIT mutation.
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):
Combination signal-transduction inhibitor therapy plus PD-L1 inhibitor
Cobimetinib and vemurafenib plus atezolizumab
Evidence (cobimetinib and vemurafenib plus atezolizumab):
After all patients in both arms received a 28-day cycle of cobimetinib and vemurafenib, patients received atezolizumab (840 mg IV every 2 weeks) or placebo in addition to the combination BRAF-MEK inhibitor therapy. The primary efficacy endpoint was investigator-assessed PFS per RECIST 1.1 criteria.
The impact of triplet therapy on OS, or when compared with checkpoint inhibitor monotherapy, or to sequential therapy with combination BRAF-MEK inhibitor therapy, preceded or followed by checkpoint inhibition (ongoing trial NCT02224781) is unknown.
Dacarbazine 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.[7,20,35,36,37] When used as a control arm for recent registration trials of ipilimumab and vemurafenib in previously untreated patients with metastatic melanoma, dacarbazine was shown to be inferior for OS.
Temozolomide, an oral alkylating agent that hydrolyzes to the same active moiety as dacarbazine, appeared to be similar to dacarbazine (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 dacarbazine and the nitrosoureas, carmustine and lomustine, is approximately 10% to 20%.[35,38,39,40] 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.[38,40]
A randomized trial compared IV dacarbazine with temozolomide, an oral agent; OS was 6.4 months for dacarbazine versus 7.7 months for temozolomide (HR, 1.18; 95% CI, 0.92–1.52). While these data suggested similarity between dacarbazine and temozolomide, no benefit in survival has been demonstrated for either dacarbazine 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 dacarbazine 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 dacarbazine.[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 dacarbazine as the standard therapy arm. Both vemurafenib (in BRAF V600 mutant melanoma) and ipilimumab showed superior OS compared with dacarbazine in the two separate trials.
Other agents with modest, single-agent activity include vinca alkaloids, platinum compounds, and taxanes.[38,39]
Attempts to develop combination regimens that incorporate chemotherapy (e.g., multiagent chemotherapy,[42,43] combinations of chemotherapy and tamoxifen,[44,45,46] and combinations of chemotherapy and immunotherapy [10,11,42,47,48,49,50]) 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.[48,49,50]
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:[52,53]
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
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Editorial changes were made to this summary.
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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:
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Levels of Evidence
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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]
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Last Revised: 2021-01-12
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