Overview of the management of advanced cutaneous melanoma

INTRODUCTION — Most cases of malignant melanoma are diagnosed at an early stage, when surgical excision can be curative. However, patients may present with metastatic disease or develop metastases after their initial definitive treatment.

Studies have led to the development of immunotherapy using checkpoint inhibitors (the programmed cell death 1 [PD-1] inhibitors [eg, pembrolizumab, nivolumab], cytotoxic T lymphocyte-associated protein 4 [CTLA-4] inhibitors [eg, ipilimumab], and LAG-3 inhibitors [eg, relatlimab]) and targeted therapy (BRAF plus MEK inhibitors). Both checkpoint inhibitor immunotherapy and targeted therapy prolong progression-free and overall survival compared with chemotherapy.

This topic provides an overview of treatment options for patients with advanced and metastatic cutaneous melanoma, along with their applications in different clinical settings. More detailed discussions of each of the specific treatment options are presented separately:

●(See "Metastatic melanoma: Surgical management".)

●(See "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)

●(See "Systemic treatment of metastatic melanoma lacking a BRAF mutation".)

●(See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)

●(See "Management of brain metastases in melanoma".)

●(See "Interleukin 2 and experimental immunotherapy approaches for advanced melanoma".)

●(See "Cytotoxic chemotherapy for metastatic melanoma".)

TREATMENT OPTIONS — Approaches that can provide clinically important benefits for appropriately chosen subsets of patients with metastatic melanoma include surgical metastasectomy, immunotherapy, targeted inhibition of the mitogen-activated protein kinase (MAPK) pathway, and radiation therapy to symptomatic sites of metastases (algorithm 1). Although cytotoxic chemotherapy was widely used prior to the development of checkpoint inhibition immunotherapy and targeted therapies, it does not have an established role for patients with metastatic melanoma.

The choice and sequencing of these approaches based upon patient-specific factors are discussed below. Additional novel approaches are under active development. Patients should be encouraged to enroll in clinical trials whenever possible. (See 'Choice and sequence of therapy' below.)

Surgical metastasectomy — In patients with one or a very limited number of metastases, surgical excision of all metastatic disease can occasionally produce durable benefit. Surgical resection may be particularly important for patients with brain metastases, in appropriately selected patients. (See "Metastatic melanoma: Surgical management" and "Management of brain metastases in melanoma".)

Adjuvant systemic therapy may be offered to patients who have undergone definitive resection of all metastatic disease (algorithm 2). (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'Metastatic disease (stage IV)'.)

Immunotherapy — Checkpoint inhibitor immunotherapy is an important systemic treatment modality for metastatic melanoma (algorithm 1). Responses to immunotherapy may develop slowly, and patients may have a transient worsening of disease before disease stabilizes or tumor regresses; delayed responses are most commonly seen with ipilimumab-containing regimens. (See "Principles of cancer immunotherapy", section on 'Immunotherapy response criteria'.)

Checkpoint immunotherapy inhibition with a programmed cell death 1 (PD-1) inhibitor (pembrolizumab, nivolumab) in combination with ipilimumab has better efficacy (response rates, progression-free survival) than single-agent anti-PD-1 therapy in patients with advanced melanoma who are candidates for systemic therapy. In a randomized trial, the combination of nivolumab plus ipilimumab also improved survival compared with ipilimumab [1,2]. Combination immunotherapy is also effective as initial therapy in patients with a BRAF V600 mutation. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Nivolumab plus ipilimumab (preferred)' and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Nivolumab plus ipilimumab (preferred)'.)

Available data suggest that checkpoint inhibitor immunotherapy can also extend treatment-free survival. These data are discussed separately. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Treatment-free survival'.)

Treatment with ipilimumab and, to a lesser extent, the anti-PD-1 antibodies is associated with a variety of clinically significant autoimmune side effects. (See "Toxicities associated with immune checkpoint inhibitors".)

Targeted therapy

BRAF mutations (MAPK pathway) — Approximately one-half of cutaneous melanomas have a V600 mutation in the BRAF gene. In combination with downstream MEK, BRAF activates the mitogen-activated protein kinase (MAPK) pathway, resulting in oncogenesis. In a majority of patients with BRAF V600 mutation-positive melanoma, BRAF inhibition produces rapid tumor regression. The addition of MEK inhibition reduces resistance and decreases cutaneous toxicity seen with single-agent BRAF inhibition [3].

Combined BRAF plus MEK inhibitor therapy has replaced the use of single-agent BRAF inhibitors (algorithm 1). Options include dabrafenib plus trametinib, vemurafenib plus cobimetinib, and encorafenib plus binimetinib. Simultaneous inhibition of BRAF and MEK improves response rates and survival compared with BRAF inhibition alone. The rapid tumor regression is especially important for patients with extensive tumor burden and disease-related symptoms. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)

In a retrospective analysis of survival data from two large phase III trials, 34 percent of patients with BRAF V600 mutations treated with the combination of dabrafenib and trametinib were alive at five years, and approximately 20 percent were progression free at five years [4]. Lactate dehydrogenase (LDH) appears to be a critical prognostic factor. As an example, 43 percent of patients with normal LDH were alive at five years. Other prognostic factors for improved survival include higher performance status and <3 organ sites with metastases. Further details regarding long-term treatment outcomes for combined BRAF plus MEK inhibitor therapy are discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Dabrafenib plus trametinib'.)

KIT mutations — Approximately 10 percent of acral melanomas and up to 5 percent of mucosal melanomas harbor activating mutations in BRAF, and another 15 percent have somatic mutations or amplification of KIT. Only approximately one-third of melanomas with KIT mutations are responsive to targeted therapy, and patients with activating mutations in KIT have had clinically meaningful responses in clinical trials with imatinib. Those with amplifications of KIT have typically not responded to KIT inhibitors. (See "Locoregional mucosal melanoma: Epidemiology, clinical diagnosis, and treatment" and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'KIT mutations (acral and mucosal melanoma)'.)

Radiation therapy — Radiation therapy may have a palliative role for symptomatic localized areas of disease. Radiation therapy, especially stereotactic radiosurgery, may be particularly important for patients with brain metastases. (See "Radiation therapy in the management of melanoma", section on 'Palliative RT' and "Management of brain metastases in melanoma".)

Cytotoxic chemotherapy — Cytotoxic chemotherapy (single agent or combination) has not been shown to improve overall survival in patients with advanced melanoma. Response rates are typically less than 20 percent, and median response durations are four to six months. Consequently, the role of chemotherapy (eg, dacarbazine, temozolomide, carboplatin/paclitaxel, fotemustine) is limited to patients who have progressed after optimal treatment with other systemic therapy options. (See "Cytotoxic chemotherapy for metastatic melanoma".)

INITIAL EVALUATION — Patients with metastatic melanoma should undergo a detailed evaluation prior to treatment to assess the extent of disease because the likelihood of detecting additional unsuspected lesions is high. This includes pathologic confirmation of metastatic disease, whole body imaging (eg, computed tomography [CT] of the chest, abdomen, and pelvis [and neck for those with primary tumors or nodal involvement of the head and neck region]; positron emission tomography (PET)-CT; and magnetic resonance imaging [MRI] of the brain), and serum lactate dehydrogenase (LDH), which is incorporated into the staging system for melanoma (table 1A-B). (See "Staging work-up and surveillance of cutaneous melanoma" and "Imaging studies in melanoma", section on 'Approach to patient imaging based on disease site'.)

In addition, all patients with advanced cutaneous melanoma should have their tumors rapidly assayed for the presence or absence of a driver mutation at the V600 site in BRAF. For patients in whom a BRAF V600 mutation is not identified, next-generation DNA sequencing (NGS) may be obtained to maximize the chances of identifying other actionable mutations. Patients with an acral or mucosal primary tumor that does not contain a BRAF mutation should have their tumor assessed for the presence of other driver mutations, such as KIT or TRK fusions. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Approach to genetic assay'.)

CHOICE AND SEQUENCE OF THERAPY — For patients with disseminated metastases, immunotherapy (particularly checkpoint inhibition with anti-programmed cell death 1 [PD-1] antibodies alone or in combination with ipilimumab) and targeted therapy (inhibiting the mitogen-activated protein kinase [MAPK] pathway) have established clinical roles based upon significant rates of durable remission or prolongation of overall survival (algorithm 1).

Whenever possible, the tumor should be assayed for the presence of driver mutations. The presence of such a mutation is an important factor in choosing and sequencing therapies for patients with advanced melanoma. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Assessment of actionable mutations'.)

In contrast to immunotherapy and targeted therapy, cytotoxic chemotherapy has not been shown to increase survival or to induce durable remissions. Chemotherapy, thus, is generally limited to patients who are not candidates for further treatment with either immunotherapy or targeted therapy and for whom there is no appropriate clinical trial. (See "Cytotoxic chemotherapy for metastatic melanoma".)

Therapeutic approach

Neoadjuvant and adjuvant therapy — Immunotherapy and targeted therapies are used in the adjuvant setting for patients at high risk for recurrence following initial surgery. Immunotherapy is also used in the neoadjuvant setting for select patients with high-risk disease prior to definitive surgery (algorithm 2). Further details on the selection of adjuvant and neoadjuvant therapy for cutaneous melanoma are discussed separately. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)

For patients who recur with metastatic disease after initial adjuvant therapy, the approach to systemic therapy is discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Prior adjuvant systemic therapy' and "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Prior treatment with single-agent PD-1 inhibitors (including adjuvant therapy)'.)

Oligometastatic disease — For patients with oligometastatic disease (ie, in only one or a very limited number of sites), the optimal role, timing, and outcome of surgery in the contemporary era of targeted and checkpoint inhibitor immunotherapy remain to be determined. (See "Metastatic melanoma: Surgical management".)

Patients may be evaluated by a surgical oncologist is indicated to determine whether complete resection of all metastatic disease is feasible as the initial treatment. Although widespread metastatic disease develops in most cases, complete resection of metastatic disease is associated with prolonged survival in select cases. (See 'Surgical metastasectomy' above.)

Adjuvant systemic therapy may be offered to patients who have undergone definitive resection of all metastatic disease. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'Metastatic disease (stage IV)'.)

Systemic therapy is indicated for patients in whom surgical metastasectomy is not appropriate. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation" and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)

BRAF V600 mutation negative — Checkpoint inhibitor immunotherapy is the preferred initial therapy in most patients with metastatic melanoma lacking a driver mutation in BRAF V600 (algorithm 1). Options include single-agent PD-1 inhibitors (eg, pembrolizumab, nivolumab) and combination immunotherapy (eg, nivolumab plus ipilimumab, nivolumab-relatlimab). Targeted therapy with BRAF plus MEK inhibitors is not indicated in patients without a characteristic BRAF V600 mutation. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Treatment-naive patients'.)

BRAF V600 mutation positive — Immunotherapy is the preferred approach to initial therapy for patients with a BRAF V600 driver mutation as this approach improves overall survival and provides a greater opportunity for long-term treatment-free survival (algorithm 1). Immunotherapy given after progression on a BRAF inhibitor also appears to be relatively less effective than when it is given as initial therapy. Randomized clinical trials evaluating the optimal treatment sequence for patients with BRAF-mutant melanoma are discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Previously untreated patients'.)

Other molecular alterations — Molecular alterations other than BRAF V600 may be present in metastatic melanoma, such as BRAF non-V600 mutations, NRAS, TRK fusions, and KIT mutations, among others. The approach to systemic therapy in these patients is discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Other molecular alterations' and "TRK fusion-positive cancers and TRK inhibitor therapy" and "Treatment of metastatic mucosal melanoma".)

Desmoplastic melanoma — Desmoplastic melanoma is a rare variant that comprises less than 5 percent of melanoma cases. Patients with desmoplastic melanoma tend to present with more advanced local disease, but the overall prognosis is better with desmoplastic melanomas compared with other types of melanoma at the same stage. (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites", section on 'Desmoplastic melanoma'.)

Patients who do develop disseminated metastases appear to be particularly responsive to checkpoint inhibitor immunotherapy. A multicenter analysis of 1058 patients identified 60 patients with desmoplastic melanoma who were treated with either a PD-1 or programmed cell death ligand 1 (PD-L1) inhibitor (predominantly pembrolizumab and nivolumab) [5]. Extrapulmonary visceral metastases or elevated lactate dehydrogenase (LDH; M1c disease) was present in 35 cases (58 percent). At a median follow-up of 22 months, objective responses were observed in 42 patients (70 percent), including 19 complete and 23 partial responses. Responses appeared durable, and median progression-free and overall survival had not been reached in this series. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation".)

The high response to these checkpoint inhibitors may be attributable to the high mutation burden and frequent PD-L1 expression in desmoplastic melanomas [5].

Acral melanoma — Acral melanoma develops on the palms, soles, or nail apparatus. It accounts for approximately 5 percent of all melanomas. (See "Melanoma: Clinical features and diagnosis", section on 'Acral lentiginous melanoma'.)

In contrast to cutaneous melanoma, acral melanoma has a lower tumor mutational burden, more aggressive biologic behavior, and distinct genetic profile. Both BRAF and KIT variants occur at a low frequency of approximately 10 to 22 percent and 10 to 20 percent, respectively [6-8].

Acral melanoma is treated similarly to other cutaneous melanomas. However, efficacy of immunotherapy is lower when compared with cutaneous melanoma [9]. In patients with KIT mutations response rates to c-KIT inhibitors such as imatinib are around 22 percent [10].

There are several ongoing investigational approaches to improve the response rate to therapy. These include combinations of immune checkpoint inhibitors, tyrosine kinase inhibitors, vascular endothelial growth factor receptors, and other agents [11]. Patients with metastatic acral melanoma should be considered for clinical trials when possible.

Brain metastases — Brain metastases are a frequent complication in patients with advanced regional and metastatic melanoma and are an important cause of both morbidity and mortality. The approach to patients with melanoma brain metastases is rapidly evolving (algorithm 3) and should be distinguished from the current approach for patients with other types of central nervous system (CNS) metastases. (See "Management of brain metastases in melanoma".)

Historically, control of CNS lesions was considered the initial priority. Systemic therapy utilizing advances in immunotherapy and targeted therapy has dramatically improved the prognosis for patients with metastatic melanoma. These systemic agents have activity at all sites of disease, including the brain, and the CNS can be considered another site of metastatic disease. The long survival for many patients after receiving immunotherapy and/or targeted therapy has led to approaches to minimize the long-term impact of radiation therapy. These systemic therapy approaches can be integrated into a multidisciplinary management plan (algorithm 3).

Locoregional therapy — In selected situations, locoregional therapy may play an important role in the management of patients with advanced melanoma. For patients with cutaneous, subcutaneous, or nodal metastases with only limited visceral involvement, intralesional therapy with talimogene laherparepvec (an attenuated oncolytic herpes simplex virus that contains the granulocyte macrophage colony stimulating factor gene) may be useful. (See "Cutaneous melanoma: Management of local recurrence", section on 'Talimogene laherparepvec'.)

PEDIATRIC AND ADOLESCENT PATIENTS

Metastatic melanoma — There are limited data for the treatment of pediatric patients (age 12 years or older) with unresectable or metastatic melanoma. Our approach is to enroll them in formal clinical trials whenever possible, or to pattern therapy after that in adults. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation" and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)

In pediatric patients with unresectable or metastatic melanoma, treatment options that are specifically approved by the US Food and Drug Administration (FDA) include nivolumab [12] and ipilimumab [13], either in combination or as single agents. The use of combination immunotherapy (nivolumab plus ipilimumab) and nivolumab monotherapy in pediatric patients is extrapolated from clinical studies of these regimens in adults with advanced melanoma (CheckMate-067) [14]. Additional pharmacokinetic studies in pediatric patients also demonstrate similar exposure to nivolumab [15] and ipilimumab [16] as that reported in adults. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Treatment-naive patients'.)

Although single-agent ipilimumab is also approved based on early phase clinical trials of pediatric patients with advanced melanoma [13,16,17], it is less preferred since more effective and well-tolerated agents are available. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Less preferred options'.)

The FDA has also approved the combination of dabrafenib and trametinib for patients with BRAF V600E or V600K melanoma and this includes pediatric patients one year and older [18,19]. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Dabrafenib plus trametinib'.)

Resected melanoma — The use of adjuvant therapy in pediatric patients with resected melanoma at increased risk for disease recurrence is discussed separately. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'Pediatric and adolescent patients'.)

SURVEILLANCE — The primary objective of surveillance during and after treatment for melanoma is to identify locoregional recurrences that are potentially curable, second primary melanomas, and distant metastatic disease that can be treated with systemic therapy. The approach to surveillance in patients with melanoma is discussed separately. (See "Staging work-up and surveillance of cutaneous melanoma".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melanoma screening, prevention, diagnosis, and management".)

SUMMARY AND RECOMMENDATIONS

●Oligometastatic disease – For patients with oligometastatic melanoma (ie, metastases limited to one or a limited number of sites), the optimal role, timing, and outcome of surgery in the contemporary era of targeted and checkpoint inhibitor immunotherapy remain to be determined. (See 'Oligometastatic disease' above and 'Surgical metastasectomy' above.)

•Patients may be evaluated by a surgical oncologist as indicated to determine whether complete resection of all metastatic disease is feasible as the initial treatment. Although widespread metastatic disease develops in most cases, complete resection of metastatic disease is associated with prolonged survival in select cases. (See "Metastatic melanoma: Surgical management".)

Surgical resection may be particularly important for select patients with brain metastases (algorithm 3). (See "Management of brain metastases in melanoma".)

•Adjuvant systemic therapy may be offered to patients who have undergone definitive resection of all metastatic disease (algorithm 2). (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'Metastatic disease (stage IV)'.)

•Systemic therapy is indicated for patients in whom surgical metastasectomy is not appropriate (algorithm 1). (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation" and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)

●Systemic therapy for metastatic disease – The primary options for systemic therapy options in patients with metastatic melanoma are checkpoint inhibitor immunotherapy and targeted therapy against the mitogen-activated protein kinase (MAPK) pathway (algorithm 1).

•Selection of therapy – The choice of therapy is based upon factors such as the extent of disease, the molecular characteristics of the tumor (eg, presence of a driver mutation in BRAF V600), and patient performance status and comorbidity. (See 'Treatment options' above.)

•Immunotherapy – Options for immunotherapy primarily include a programmed cell death 1 (PD-1) inhibitor alone (eg, pembrolizumab (table 2) or nivolumab (table 3)), nivolumab plus ipilimumab (table 4), a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, and nivolumab-relatlimab, a LAG-3 inhibitor (algorithm 1). (See 'Immunotherapy' above.)

•Targeted therapy – Options for targeted therapy with BRAF plus MEK inhibition include dabrafenib plus trametinib, vemurafenib plus cobimetinib, and encorafenib plus binimetinib. (See 'BRAF mutations (MAPK pathway)' above.)

●Assessing for molecular alterations – Patients with advanced cutaneous melanoma should have their tumors rapidly assessed for the presence of a BRAF V600 mutation to help guide the choice of systemic therapy. (See 'Initial evaluation' above.)

•For patients in whom a BRAF V600 mutation is not identified, we obtain next-generation DNA sequencing (NGS), which maximizes the chances of identifying other actionable mutations. Acral or mucosal melanomas that do not contain a BRAF V600 mutation should also be assessed for the presence of a KIT mutation whenever possible. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Assessment of actionable mutations'.)

●BRAF mutation-negative disease – For patients with treatment-naive BRAF V600 mutation-negative disease (algorithm 1), options for systemic therapy include nivolumab (table 3), pembrolizumab (table 2), nivolumab and ipilimumab (table 4), and nivolumab-relatlimab. (See 'BRAF V600 mutation negative' above and "Systemic treatment of metastatic melanoma lacking a BRAF mutation".)

●BRAF mutation-positive disease – For patients with treatment-naive BRAF V600 mutation-positive disease, the optimal sequencing of immunotherapy or molecularly targeted therapy is evolving (algorithm 1). (See 'BRAF V600 mutation positive' above and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)

•In most patients, our general approach is to use immunotherapy as initial therapy, rather than targeted therapies with BRAF plus MEK inhibitors, as this approach improves overall survival and provides a greater opportunity for long-term treatment-free survival. The combination of nivolumab plus ipilimumab (table 4) is the preferred initial treatment option in those able to tolerate the potential toxicities of this combination regimen. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Nivolumab plus ipilimumab (preferred)'.)

•Patients who progress on (or are ineligible for) immunotherapy are candidates for targeted therapy with a combination of BRAF plus MEK inhibitors. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Prior immunotherapy' and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Ineligible for immunotherapy (targeted therapy)'.)

●Pediatric patients – For pediatric patients (age 12 years or older) with unresectable or metastatic melanoma, we offer enrollment in clinical trials whenever possible, or pattern therapy after that in adults. (See 'Pediatric and adolescent patients' above.)