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Systemic treatment of metastatic melanoma lacking a BRAF mutation

Systemic treatment of metastatic melanoma lacking a BRAF mutation
Author:
Jeffrey A Sosman, MD
Section Editor:
Michael B Atkins, MD
Deputy Editor:
Sonali Shah, MD
Literature review current through: Jun 2022. | This topic last updated: Jun 15, 2022.

INTRODUCTION — The most common molecular alteration in patients with metastatic melanoma are mutations in the BRAF gene, in particular BRAF V600 [1-4]. In these patients, BRAF mutation status can subsequently influence management. (See "The molecular biology of melanoma" and "Overview of the management of advanced cutaneous melanoma".)

For patients with metastatic melanoma lacking a BRAF mutation, there have been important advances in systemic therapy, such as checkpoint inhibitor immunotherapy. Available options for immunotherapy include agents that inhibit cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death receptor 1 (PD-1), among others. The principles and biologic mechanism of immunotherapy in the treatment of cancer, including melanoma, is discussed separately. (See "Principles of cancer immunotherapy".)

The approach to systemic therapy in patients with metastatic melanoma lacking a BRAF mutation (ie, BRAF wild-type disease) is reviewed in this topic (algorithm 1). The management of patients with metastatic melanoma harboring a BRAF or other molecular alterations, adjuvant and neoadjuvant therapy for locally advanced cutaneous melanoma, the surgical management of melanoma, and toxicities associated with checkpoint inhibitor immunotherapy are discussed separately.

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

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

(See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites".)

(See "Toxicities associated with checkpoint inhibitor immunotherapy".)

TREATMENT-NAIVE PATIENTS — For patients with BRAF wild-type disease, we recommend initial immunotherapy that includes a programmed cell death receptor 1 (PD-1) inhibitor (ie, nivolumab, pembrolizumab), rather than other systemic agents, including single-agent ipilimumab, high-dose interleukin 2 (IL-2), or chemotherapy. Patient eligibility for checkpoint inhibitor immunotherapy is discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Defining immunotherapy eligibility'.)

Benefits of immunotherapy over chemotherapy — Systemic therapy using checkpoint inhibitor immunotherapy is established as the preferred initial treatment option in patients with metastatic melanoma compared with chemotherapy. In randomized trials of patients with BRAF wild-type metastatic melanoma, checkpoint inhibitor immunotherapy demonstrated superior overall survival (OS) and progression-free survival (PFS) benefit and comparable toxicity to chemotherapy. As an example, in a randomized phase III trial (CheckMate-066) of treatment-naïve patients with BRAF wild-type metastatic melanoma, single-agent nivolumab improved OS compared with dacarbazine (hazard ratio [HR] 0.46) [5]. Data from this trial are further discussed below. (See 'Nivolumab' below.)

In separate randomized trials, compared with chemotherapy, similar benefits for OS were seen with ipilimumab in treatment-naïve patients [6] and for PFS with single-agent pembrolizumab in those with ipilimumab-refractory disease [7,8]. Further details on the use of chemotherapy and high-dose IL-2 in patients with metastatic melanoma are discussed separately. (See "Cytotoxic chemotherapy for metastatic melanoma" and "Interleukin 2 and experimental immunotherapy approaches for advanced melanoma".)

Patients with features of aggressive disease

Nivolumab plus ipilimumab (preferred) — For patients with treatment-naïve metastatic melanoma without a BRAF V600 mutation and aggressive disease, we suggest combination immunotherapy with nivolumab plus ipilimumab (table 1) rather than a single-agent PD-1 inhibitor or nivolumab-relatlimab (algorithm 1). Clinical features that suggest aggressive disease include elevated lactate dehydrogenase (LDH); acral primary; and brain metastases, liver metastases, and/or other symptomatic systemic metastases [9].

In patients with treatment-naïve advanced or metastatic melanoma (regardless of BRAF status), compared with single-agent nivolumab, the combination of nivolumab plus ipilimumab improved PFS and treatment-free interval, and trended toward improved OS and melanoma-specific survival (MSS). Most of the benefit of the combination relative to nivolumab monotherapy was confined to patients with BRAF-mutant disease. In patients with BRAF wild-type melanoma, relative to nivolumab, there was a nonstatistically significant trend for PFS and OS benefit for nivolumab plus ipilimumab [10,11]. However, both nivolumab plus ipilimumab and single-agent nivolumab improved PFS, OS, and MSS compared with single-agent ipilimumab [10-15]. (See 'All patients' below and 'BRAF wild-type disease' below.)

The overall data for nivolumab plus ipilimumab also showed a strong advantage over single-agent immunotherapy (either nivolumab or ipilimumab) in extending the time off treatment. These data suggest that nivolumab plus ipilimumab may offer many patients an opportunity for curative-intent therapy [16]. (See 'Treatment-free survival' below.)

Dosing considerations — We administer nivolumab (1 mg/kg) in combination with ipilimumab (3 mg/kg) every three weeks for four doses, followed by maintenance nivolumab (table 1).

Alternative dosing schedules have also been evaluated. Data are as follows:

Alternative dosing of nivolumab and ipilimumab – The standard dosing of this combination is four doses of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every three weeks (table 1). However, four doses of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every three weeks is an acceptable off-label alternative.

In a randomized phase IIIb/IV study (CheckMate 511) of 360 patients with previously untreated, unresectable stage III or IV melanoma, an alternative dosing strategy of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg reduced toxicity compared with a standard dosing strategy of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg [17,18]. In preliminary results, at median follow-up of 44 months, compared with standard dosing, the alternative dosing decreased treatment-related grade ≥3 adverse events (34 versus 48 percent, odds ratio 0.55, 95% CI 0.36-0.84) [18].

In descriptive analyses, objective response rates, three-year PFS and OS, and median treatment-free intervals were similar between the two treatment arms. However, the study was not adequately powered to confirm noninferiority of the alternative versus the standard dosing regimen. Therefore, clinicians who offer this approach must discuss with patients that this alternative regimen was not evaluated for noninferiority compared with the standard dosing of nivolumab plus ipilimumab.

Is there a role for reducing the number of doses of nivolumab plus ipilimumab? – In patients with advanced or metastatic melanoma, initial data are promising for reducing the number of doses of nivolumab plus ipilimumab to less than the established standard of four doses. Although preliminary results from a phase II trial suggest that most of the efficacy occurs within the first two doses [19], further randomized trials are needed to identify which patients treated with nivolumab plus ipilimumab are best suited for this approach and confirm that it reduces toxicity without compromising long-term outcomes.

All patients — Based on results from phase I and II studies [15,20], a double-blind, placebo-controlled phase III trial (CheckMate 067) was conducted to evaluate the efficacy of nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone [10-13]. In this trial, 945 treatment-naïve patients were randomly assigned to one of the following treatments:

Combination nivolumab (1 mg/kg every three weeks for four doses) plus ipilimumab (3 mg/kg every three weeks for four doses), followed by nivolumab 3 mg/kg every two weeks

Nivolumab 3 mg/kg every two weeks

Ipilimumab 3 mg/kg every three weeks for four doses

PFS and OS were the co-primary endpoints of the trial. The trial was powered to compare each of the nivolumab-containing arms with ipilimumab, but it was not powered to compare the combination with nivolumab alone.

For the entire study population, at a minimum follow-up of 6.5 years, objective response rates for the combination, nivolumab alone, and ipilimumab alone were 58, 45, and 19 percent, respectively; complete response rates were 23, 19, and 6 percent, respectively [10,11].

Nivolumab-containing arms versus ipilimumab alone – Relative to ipilimumab alone, results for the two nivolumab-containing arms for the entire study population were as follows [10,11]:

Progression-free survival – The 6.5-year PFS rates for the combination and nivolumab alone were superior (for nivolumab plus ipilimumab versus ipilimumab, 34 versus 7 percent, HR 0.42, 95% CI 0.35-0.51; for nivolumab versus ipilimumab, 29 versus 7 percent, HR 0.53, 95% CI 0.44-0.64).

Overall survival – The 6.5-year OS rates for the combination and nivolumab alone were also superior (for nivolumab plus ipilimumab versus ipilimumab, 49 versus 23 percent, HR 0.52, 95% CI 0.43-0.64; for nivolumab versus ipilimumab, 42 versus 23 percent, HR 0.63, 95% CI 0.52-0.76).

Melanoma-specific survival – In a post-hoc analysis, the 6.5-year MSS rates for the combination and nivolumab alone were also superior (for nivolumab plus ipilimumab versus ipilimumab, 56 versus 27 percent, HR 0.48, 95% CI 0.39-0.60; for nivolumab versus ipilimumab, 48 versus 27 percent, HR 0.59, 95% CI 0.48-0.73).

Nivolumab plus ipilimumab versus nivolumab alone – Relative to nivolumab alone, results for the combination for the entire study population were as follows:

Progression-free survival – The 6.5-year PFS was increased with nivolumab plus ipilimumab compared with nivolumab alone (34 versus 29 percent, HR 0.79, 95% CI 0.65-0.97).

Overall survival – The 6.5-year OS for nivolumab plus ipilimumab was 49 percent, compared with 42 percent with nivolumab (HR 0.84, 95% CI 0.67-1.04).

Melanoma-specific survival – In a post-hoc analysis, the 6.5-year MSS for nivolumab plus ipilimumab was 56 percent, compared with 48 percent with nivolumab (HR 0.81, 95% CI 0.64-1.03) [11].

BRAF wild-type disease — In results from CheckMate-067, among the subgroup of 644 patients with BRAF wild-type disease, at minimum follow-up of 6.5 years, the combination of nivolumab plus ipilimumab improved PFS and OS relative to ipilimumab [10,11], similar to the results seen for the entire study population. (See 'All patients' above.)

Nivolumab-containing arms versus ipilimumab alone – Relative to ipilimumab alone, results for the two nivolumab-containing arms for those with BRAF wild-type disease were as follows [10,11]:

Progression-free survival – The 6.5-year PFS rates for the combination and nivolumab alone were superior (for nivolumab plus ipilimumab versus ipilimumab, 33 versus 6 percent, HR 0.41, 95% CI 0.33-0.52; for nivolumab versus ipilimumab, 31 versus 6 percent, HR 0.47, 95% CI 0.38-0.59).

Overall survival – The 6.5-year OS rates for the combination and nivolumab alone were also superior (for nivolumab plus ipilimumab versus ipilimumab, 46 versus 22 percent, HR 0.58, 95% CI 0.45-0.74; for nivolumab versus ipilimumab, 42 versus 22 percent, HR 0.63, 95% CI 0.50-0.80).

Nivolumab plus ipilimumab versus nivolumab alone – Relative to nivolumab alone, the combination of nivolumab plus ipilimumab demonstrated a nonstatistically significant trend toward PFS and OS benefit for those with BRAF wild-type disease [10,11]. However, this benefit may still be particularly relevant for patients with aggressive disease (eg, brain metastases, elevated LDH, symptomatic metastatic disease) where a salvage regimen may not be available.

Progression-free survival – The 6.5-year PFS with nivolumab plus ipilimumab was 33 percent, compared with 31 percent for nivolumab alone (HR 0.88, 95% CI 0.69-1.12).

Overall survival – The 6.5-year OS for nivolumab plus ipilimumab was 46 percent, compared with 42 percent with nivolumab (HR 0.92, 95% CI 0.71-1.18).

Aggressive disease and other populations — In subgroup analyses, certain subsets of patients (eg, those with clinical features suggesting aggressive disease, BRAF-mutant tumors) appeared to derive greater benefit with the combination relative to nivolumab:

Elevated LDH – Approximately one-third of patients with elevated LDH, a risk factor for aggressive disease, also benefit from the combination of ipilimumab plus nivolumab. In these patients, five-year OS and PFS were numerically higher for those treated with nivolumab plus ipilimumab compared with nivolumab alone (five-year OS 38 versus 28 percent, HR 0.82, 95% CI 0.52-1.13; five-year PFS 28 versus 18 percent, HR 0.77, 95% CI 0.56-1.05) [10].

Brain metastases – The efficacy of nivolumab plus ipilimumab in patients with brain metastases are discussed separately. (See "Management of brain metastases in melanoma", section on 'Nivolumab plus ipilimumab'.)

BRAF-mutant tumors – The magnitude of benefit for nivolumab plus ipilimumab appeared to be greater among those with BRAF-mutated tumors. These data are discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Nivolumab plus ipilimumab (preferred)'.)

Toxicity — Treatment-related toxicities and the need for treatment discontinuation are more frequent for the combination of nivolumab plus ipilimumab compared with either nivolumab or ipilimumab as single agents [21-23]. Patients receiving this combination should be offered appropriate monitoring and treatment for immune-related adverse events. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)

In extended follow-up of the phase III CheckMate 067 trial, rates of grade ≥3 treatment-related adverse events for the combination, nivolumab alone, and ipilimumab alone were 59, 24, and 28 percent, respectively, with no new toxicity signals noted [10,11]. Gastrointestinal toxicity was the most common grade ≥3 adverse event (15, 4, and 12 percent for combination therapy, nivolumab alone and ipilimumab alone, respectively) [10].

Grade ≥3 treatment-related adverse events led to discontinuation in 31, 8, and 13 percent of patients treated with the combination, nivolumab alone, or ipilimumab alone, respectively [10,11]. However, other data suggest that discontinuing nivolumab plus ipilimumab due to adverse events is not associated with worse clinical outcomes [21]. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Relationship between immunotherapy toxicities and efficacy'.)

Decision-making regarding resumption of immunotherapy after immune-related toxicities is discussed separately. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Retreatment after prior toxicity'.)

Nivolumab-relatlimab — For patients with aggressive disease who are anticipated to not tolerate the toxicities of nivolumab plus ipilimumab, we suggest nivolumab-relatlimab rather than single-agent PD-1 inhibitors. In a phase III trial (RELATIVITY-047), nivolumab-relatlimab improved PFS over single-agent nivolumab [24] and had a more favorable toxicity profile compared with that reported for nivolumab plus ipilimumab in other studies [10-13]. (See 'All patients' below.)

Dosing considerations — Nivolumab-relatlimab is a fixed-dose combination of two IgG4 kappa monoclonal antibodies, nivolumab and relatlimab. For adult and pediatric patients 12 years of age or older who weigh at least 40 kg, 480 mg of nivolumab and 160 mg of relatlimab are administered intravenously and simultaneously every four weeks until disease progression or unacceptable toxicity [25].

All patients — Relatlimab is a human IgG4 LAG-3-blocking antibody that restores effector function of exhausted T cells. Further details on the mechanism of action for relatlimab are discussed separately. (See "Principles of cancer immunotherapy", section on 'LAG3'.)

Nivolumab-relatlimab was evaluated in a double-blind phase III trial (RELATIVITY-047) of 714 patients with treatment-naive advanced melanoma [24,26]. In preliminary results, at median follow-up of 19 months, compared with single-agent nivolumab, nivolumab-relatlimab demonstrated the following [26]:

Improved PFS (median 10 versus 5 months, two-year PFS 39 versus 29 percent, HR 0.78, 95% CI 0.64-0.94). PFS benefit was also seen across multiple subgroups indicating high-risk disease (ie, elevated LDH and acral primary) [24].

A non-statistically significant trend towards improved OS, which would be clinically meaningful if true (median not reached versus 34 months, three-year OS 56 versus 48 percent, HR 0.80, 95% CI 0.64-1.01).

Higher objective response rates (43 versus 33 percent) and similar complete response (CR) rates (16 versus 14 percent).

Nivolumab-relatlimab had a more favorable toxicity profile compared with that reported in other studies for nivolumab plus ipilimumab [10-13,24]. Grade ≥3 toxicities were higher for the combination versus nivolumab alone (21 versus 11 percent); common symptoms of any grade included pruritus, fatigue, rash, arthralgias, hypothyroidism, diarrhea, and vitiligo [26]. Common grade ≥3 immunotherapy-related adverse events (irAEs) for nivolumab-relatlimab included hepatitis (4 percent), adrenal insufficiency (2 percent), rash, diarrhea, nephritis and kidney dysfunction, pneumonitis, and hypophysitis (approximately 1 percent each). Myocarditis occurred more frequently with nivolumab-relatlimab (two versus one percent) and patients were serially monitored with troponins for the first two months of therapy.

Based on these data [24], the US Food and Drug Administration (FDA) approved nivolumab-relatlimab for patients with unresectable or metastatic melanoma ages 12 and older [25].

BRAF wild-type disease — Nivolumab-relatlimab also improved PFS for the subset of patients with BRAF wild-type disease. A randomized phase III trial (RELATIVITY-047) included a subset of 439 patients with BRAF wild-type disease [24]. Among these patients, at median follow-up of 19 months, the combination improved PFS compared with single-agent nivolumab (HR 0.78, 95% CI 0.61-0.99) [26]. The PFS benefit seen for patients with BRAF wild-type disease was similar to that seen for the entire study population. (See 'All patients' above.)

The efficacy of nivolumab-relatlimab in treatment-naïve patients with BRAF-mutant disease is discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Nivolumab-relatlimab'.)

Patients lacking features of aggressive disease

Nivolumab-relatlimab (preferred) — For patients with treatment-naive BRAF wild-type disease who lack features of aggressive disease, we suggest nivolumab-relatlimab rather than single-agent PD-1 inhibitors.

In subset analyses of a randomized phase III trial (RELATIVITY-047), nivolumab-relatlimab improved PFS compared with single-agent nivolumab in patients without features of aggressive disease. Such patients included those with LDH less than or equal to the upper limit of normal (HR 0.70, 95% CI 0.54-0.91) and cutaneous non-acral disease (HR 0.73, 95% CI 0.57-0.93) [24].

Further data on the efficacy and toxicity of nivolumab-relatlimab in the entire study population are discussed above. (See 'Nivolumab-relatlimab' above.)

Pembrolizumab — For patients with BRAF wild-type disease and who lack features of aggressive disease, or those who are unable to tolerate the potential toxicities of combination immunotherapy (ie, nivolumab plus ipilimumab or nivolumab-relatlimab), we offer a single-agent PD-1 inhibitor as a suitable alternative (algorithm 1). Options include pembrolizumab (table 2) or nivolumab (table 3). (See 'Nivolumab' below.)

Dosing considerations — Pembrolizumab is administered intravenously at either 200 mg every three weeks or 400 mg every six weeks (table 2). Data from a phase I trial (KEYNOTE-555) and pharmacokinetic studies [27] suggest comparable efficacy and safety between the two schedules. In this study, pembrolizumab administered at 400 mg every six weeks was evaluated in a cohort of 100 patients with advanced or metastatic melanoma without prior exposure to immunotherapy [28]. In an interim analysis of 44 patients with median follow-up of approximately seven months, the overall response rate was 39 percent. This was comparable to a response rate of 35 percent calculated from three separate trials previously evaluating pembrolizumab administered every three weeks in a similar population of patients, including KEYNOTE-001, KEYNOTE-006, and KEYNOTE-252 [29,30]. Grade ≥3 toxicities were seen in 11 patients (25 percent), which are also comparable to previous pembrolizumab trials.

Based on these data, the US Food and Drug Administration (FDA) approved pembrolizumab at a dose of 400 mg every six weeks across all approved adult indications, including patients with advanced or metastatic melanoma. Clinicians may offer pembrolizumab on an every-six-week schedule as a convenient and alternative dosing to the every-three-week schedule. Although the studies above only evaluated this schedule in treatment-naïve patients, we consider it to be an acceptable alternative in patients receiving either front-line or subsequent-line therapy with pembrolizumab.

All patients — Based on data from early-phase clinical trials [29,31,32] and initial randomized studies of patients with disease refractory to ipilimumab [7,8], the efficacy of single-agent pembrolizumab was established in a randomized phase III trial. In this study, pembrolizumab (table 2) improved both PFS and OS relative to ipilimumab among immunotherapy-naïve patients [33-36].

In a phase III trial (KEYNOTE-006), 834 patients were randomly assigned to pembrolizumab at 10 mg/kg, administered either every two weeks or every three weeks, versus four doses of ipilimumab 3 mg/kg every three weeks. Treatment with pembrolizumab was typically continued for two years in the absence of toxicity or progressive disease. However, patients were allowed, per investigator discretion, to discontinue pembrolizumab after at least six months in the setting of a complete response. Approximately 35 percent of patients had a BRAF V600 mutation, and approximately one-half of these had received prior BRAF or MEK inhibitor therapy. Approximately 3 percent of patients had received prior immunotherapy.

At a median follow-up of 58 months, relative to ipilimumab, pembrolizumab demonstrated the following [33]:

Improved median OS (33 versus 16 months; five-year OS 39 versus 31 percent; hazard ratio [HR] 0.73, 95% CI 0.61-0.88).

Improved median PFS (8.4 versus 3.4 months; four-year PFS 23 versus 7 percent; HR 0.57, 95% CI 0.48-0.67).

Higher objective (42 versus 17 percent) and complete response rates (14 versus 3 percent).

Rates of grade ≥3 toxicity were similar between pembrolizumab and ipilimumab (17 versus 20 percent), as were treatment-related discontinuation rates (10 versus 9 percent). Pembrolizumab also improved quality of life and global health status in a secondary analysis based on patient-reported outcomes [36].

In subset analysis, among those who were naïve to systemic treatment (including immunotherapy, chemotherapy, and/or BRAF/MEK inhibitors), pembrolizumab also improved median OS (39 versus 17 months) and PFS (12 versus 4 months), relative to ipilimumab [33]. For patients whose tumors did not express programmed death ligand 1 (PD-L1), pembrolizumab did not demonstrate an OS benefit [37].

BRAF wild-type disease — Pembrolizumab also improved OS in patients with BRAF wild-type disease. A randomized phase III trial (KEYNOTE-006) included a subset of 525 patients with BRAF wild-type disease. Among these patients, at median follow-up of approximately five years, compared with ipilimumab, pembrolizumab improved objective response rates (43 versus 16 percent) and OS (median 28 versus 14 months, HR 0.73, 95% CI 0.58-0.93) [33]. The efficacy of pembrolizumab in treatment-naïve patients with BRAF-mutant disease is discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Alternative immunotherapy options'.)

Other data have also demonstrated activity for pembrolizumab among patients with treatment-naïve disease, regardless of BRAF status. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Alternative immunotherapy options'.)

Nivolumab — For patients with BRAF wild-type disease who lack features of aggressive disease, or those who are unable to tolerate the potential toxicities of combination immunotherapy (ie, nivolumab plus ipilimumab or nivolumab-relatlimab), we offer a single-agent PD-1 inhibitor as a suitable alternative (algorithm 1). Options include nivolumab (table 3) and pembrolizumab (table 2). (See 'Pembrolizumab' above.)

Dosing considerations — Nivolumab (table 3) is administered at either 240 mg as a flat dose every two weeks or 480 mg as a flat dose every four weeks.

The original approved dose of nivolumab was 3 mg/kg every two weeks based on initial phase III trials. (See 'All patients' above and 'BRAF wild-type disease' below.)

The FDA subsequently approved a modified dose of 240 mg as a flat dose every two weeks, which is similar to the 3 mg/kg intravenous dose based on population pharmacokinetics and dose/exposure-response analyses. An alternative schedule of nivolumab 480 mg every four weeks was also approved, based on clinical pharmacology analyses and safety assessments [38].

All patients — The efficacy of nivolumab compared with nivolumab plus ipilimumab in all patients with metastatic melanoma is discussed above. (See 'Nivolumab plus ipilimumab (preferred)' above.)

BRAF wild-type disease — Based on data from early-phase clinical trials [39-41] and initial randomized studies in patients with ipilimumab-refractory disease [42], the efficacy of single-agent nivolumab (table 3) was established in a randomized phase III trial (CheckMate 066). In this study, 418 treatment-naïve patients with BRAF wild-type disease were randomly assigned to nivolumab (3 mg/kg every two weeks) or dacarbazine (1000 mg/m2 every three weeks) [5,43,44]. At minimum follow-up of 38 months, compared with dacarbazine, nivolumab improved three-year PFS (32 versus 3 percent, HR 0.42, 95% CI 0.33-0.53), three-year OS (51 versus 22 percent, HR 0.46, 95% CI 0.36-0.59) [5], and objective response rates (43 versus 14 percent).

Nivolumab has also been compared with nivolumab plus ipilimumab in patients with metastatic melanoma. Data for those with BRAF wild-type disease are discussed above. (See 'Nivolumab plus ipilimumab (preferred)' above.)

Data for nivolumab in patients with BRAF-mutant disease are discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Alternative immunotherapy options'.)

What is the optimal duration of immunotherapy?

Single-agent immunotherapy — For patients with BRAF wild-type metastatic melanoma receiving single-agent PD-1 inhibitor immunotherapy (ie, pembrolizumab or nivolumab as monotherapy; or nivolumab as maintenance therapy after combination therapy with nivolumab plus ipilimumab) with either a partial response or stable disease, we typically administer treatment for a maximum of two years in the absence of toxicity. However, for those with a complete response, single-agent immunotherapy may be discontinued after at least six months of therapy have been completed if the complete response has been confirmed on at least two sets of restaging imaging studies. This approach is based on the efficacy of pembrolizumab in a randomized phase III trial (KEYNOTE-006) [33] and other studies [45-47]. (See 'Pembrolizumab' above.)

Early-phase clinical trials of both pembrolizumab [29,31,32] and nivolumab [39-41,48] demonstrated the ability of these agents to achieve long-term PFS in a significant number of patients. Subsequent data from a phase III trial (KEYNOTE-006) provided support for discontinuation of pembrolizumab after two years in responding patients, with an option of discontinuation after six months for complete responders. In this trial, at median follow-up of almost five years, among the 19 percent (103 patients) who had completed a two-year course of pembrolizumab, the three-year OS was 94 percent [33]. Among the 44 patients with a complete response, two-year PFS rates were similar to those who continued pembrolizumab for two years and those who discontinued prior to two years but after at least six months (85 versus 86 percent, respectively).

The duration of immunotherapy among patients with concurrent successful treatment of intracranial metastases is discussed separately. (See "Management of brain metastases in melanoma", section on 'Duration of therapy after complete response'.)

Nivolumab-relatlimab — There are no data on the optimal duration of nivolumab-relatlimab based on disease response, or switching to single-agent nivolumab in patients who experience immune-related adverse events. Nivolumab-relatlimab is typically continued until disease progression or unacceptable toxicity. (See 'Nivolumab-relatlimab' above.)

Less preferred options

Ipilimumab — Ipilimumab is a monoclonal antibody directed against cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). The combination of nivolumab plus ipilimumab is effective in patients with treatment-naïve disease. (See 'Nivolumab plus ipilimumab (preferred)' above.)

In initial randomized phase III trials, ipilimumab monotherapy improved OS in patients with metastatic melanoma [6,49-52]. However, the role of single-agent ipilimumab has become more limited with the development of PD-1 inhibitors (pembrolizumab (table 2), nivolumab (table 3)) that are more active than ipilimumab and have less toxicity in this patient population. (See 'Pembrolizumab' above and 'Nivolumab' above and "Toxicities associated with checkpoint inhibitor immunotherapy".)

In separate phase III trials, ipilimumab was directly compared with pembrolizumab (KEYNOTE-006) and nivolumab (CheckMate 067) as single agents. In these trials, the overall toxicities associated with nivolumab or pembrolizumab were less frequent and severe than those associated with ipilimumab. Nivolumab and pembrolizumab were also discontinued less frequently for toxicity than ipilimumab, but with differing side effect profiles. Further results of these studies are discussed above. (See 'Pembrolizumab' above and 'Toxicity' above.)

Chemotherapy — In the era of checkpoint inhibitor immunotherapy, the role of chemotherapy in patients with metastatic melanoma is limited. Indications for chemotherapy in metastatic melanoma are discussed separately. (See "Cytotoxic chemotherapy for metastatic melanoma".)

ASSESSING TREATMENT RESPONSE

Patterns of response — In patients with metastatic melanoma receiving checkpoint inhibitor immunotherapy, evaluating treatment response requires an understanding of the distinct patterns of response seen with immunotherapy, which differ from those seen with chemotherapy or molecularly targeted agents in several important respects:

Patients may have a transient worsening of disease, manifested either by progression of known lesions or the appearance of new lesions, before the disease stabilizes or tumor regresses (image 1).

For patients with interval tumor growth on restaging imaging studies obtained 8 to 12 weeks after initiating therapy who are asymptomatic or those who exhibit improved disease-related symptoms and/or a decline in serum lactase dehydrogenase (LDH) levels, some caution should be taken in discontinuing therapy early. In the absence of symptomatic progression, a short-term follow-up imaging study (after an additional six to eight weeks) to confirm disease status is reasonable [53]. (See 'Imaging studies' below.)

Patients with interval tumor growth on restaging imaging studies obtained 8 to 12 weeks after initiating therapy who exhibit new or persistent symptoms (symptomatic disease) or rising LDH likely have true progressive disease [54]. We do not continue therapy beyond disease progression in these patients.

Radiographic responses can take longer to become apparent compared with other systemic therapies, such as chemotherapy or targeted therapy.

Some patients who do not meet criteria for objective response can have prolonged periods of stable disease that are clinically significant. In some of these patients, positron emission tomography computed tomography (PET-CT) scans or tumor biopsies may show no evidence of residual tumor.

Immunotherapy response criteria have been developed to properly recognize these patterns of response and are discussed separately (table 4). (See "Principles of cancer immunotherapy", section on 'Immunotherapy response criteria'.)

Imaging studies — Options for imaging patents to assess treatment response include computed tomography (CT) and fludeoxyglucose (FDG)-PET-CT. PET-CT may be problematic early on in treatment, as an active immune response against tumor can increase the standardized uptake value (SUV), creating a false impression of disease progression. However, later in the treatment process (after approximately one year), a PET-CT provides a better assessment of treatment response to checkpoint inhibitor immunotherapy compared with CT, as it can identify complete metabolic responses (eg, residual tumor lesions on CT scans that are no longer FDG-avid) [55]. Such complete metabolic responses correlate with prolonged progression-free survival (PFS) [56,57] and melanoma-specific survival [47]. These data are consistent with the durable treatment-free survival observed with immunotherapy in other studies. (See 'What is the optimal duration of immunotherapy?' above and 'Treatment-free survival' below.)

TREATMENT-FREE SURVIVAL

Nivolumab plus ipilimumab — The combination of nivolumab plus ipilimumab extends treatment-free survival (ie, the time from immunotherapy cessation to subsequent therapy initiation or death) compared with nivolumab or ipilimumab as single agents.

In a long-term follow-up phase III trial (Checkmate 067), at median follow-up of 81 months, among patients assigned to nivolumab plus ipilimumab, 36 percent (112 of 314 patients) were alive and treatment free at 6.5 years, compared with 27 percent of those receiving nivolumab (84 of 316 patients) and 9 percent of those receiving ipilimumab (27 of 315 patients) [10,11]. Median treatment-free survival was approximately 28 months for the combination versus 2 months each for single-agent nivolumab and ipilimumab.

Similar promising results have been observed in other studies. In a combined analysis of the CheckMate 067 and CheckMate 069 trials, combination immunotherapy improved treatment-free survival relative to either single-agent ipilimumab or nivolumab [16,58]. Among 1077 patients with advanced or metastatic melanoma treated with nivolumab and ipilimumab, more patients who received nivolumab plus ipilimumab were treatment free at three years of follow-up (47 percent) compared with those who received nivolumab or ipilimumab (37 and 15 percent, respectively). Mean treatment-free survival at three years was also greater for the combination (11 months) than for nivolumab or ipilimumab alone (five and nine months, respectively).

SUBSEQUENT THERAPY — Most patients with BRAF wild-type metastatic melanoma who receive checkpoint inhibitor immunotherapy will experience extended durable responses to therapy. However, others may demonstrate progressive disease. The choice of subsequent therapy in these patients is based on clinical factors such as prior therapies received as well as patient performance status (table 5), comorbidities, goals, and preferences. Patients should be encouraged to enroll in clinical trials, where available.

Prior treatment with nivolumab plus ipilimumab — For patients with BRAF wild-type disease who have progressed on combination therapy with nivolumab plus ipilimumab, we offer enrollment in clinical trials, where available. Further data on investigational agents being evaluated in patients with treatment-refractory melanoma, regardless of BRAF status, are discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Investigational options'.)

For those who are ineligible for clinical trials, options include high-dose interleukin 2 [59] or chemotherapy. The use of these agents in patients with metastatic melanoma is discussed separately. (See "Interleukin 2 and experimental immunotherapy approaches for advanced melanoma" and "Cytotoxic chemotherapy for metastatic melanoma".)

Patients may also have their tumors evaluated for other actionable mutations (other than BRAF) for which standard therapies are available. Subsequent therapy for patients with metastatic melanoma harboring other actionable mutations are discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Other molecular alterations'.)

Prior treatment with single-agent PD-1 inhibitors (including adjuvant therapy)

Nivolumab plus ipilimumab — For patients with BRAF wild-type metastatic melanoma who have progressed on single-agent programmed cell death receptor 1 (PD-1) inhibitors (either in the adjuvant or metastatic setting) and have no other actionable mutations, we suggest the combination of nivolumab plus ipilimumab (table 1) rather than other available agents. Patients may alternatively be enrolled in clinical trials, where available. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Investigational options'.)

For patients with BRAF wild-type disease and resistance to PD-1 inhibitor immunotherapy, subsequent therapy with the combination of nivolumab plus ipilimumab improves progression-free survival (PFS) and objective response rates compared with single-agent ipilimumab, based on data from randomized trials [60,61] and observational studies [62,63]. In an open-label phase II trial (SWOG 1616), 92 patients with unresectable or metastatic melanoma who progressed on single-agent PD-1 or PD-L1 inhibitors and without prior exposure to a cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitor (eg, ipilimumab) were randomly assigned in a 3:1 ratio to either nivolumab plus ipilimumab for four cycles followed by maintenance nivolumab for up to two years (table 1) or single-agent ipilimumab (3 mg/kg every three weeks for four cycles) [61]. This study also enrolled patients who progressed on single-agent PD-1 or PD-L1 inhibitors in the adjuvant setting.

In preliminary results, at median follow-up of 25 months, compared with ipilimumab, nivolumab plus ipilimumab improved PFS (six-month PFS 34 versus 13 percent, HR 0.63, 90% CI 0.41-0.97). Overall survival (OS) was similar between the two treatment arms (one-year OS 63 versus 57 percent, HR 0.94, 90% CI 0.45-1.62). Objective response rates were higher for the combination compared with ipilimumab (28 versus 9 percent). Grade ≥3 toxicity rates were also higher for nivolumab plus ipilimumab compared with ipilimumab alone (57 versus 35 percent) but consistent with known safety profiles of these agents.

Is there a role for pembrolizumab plus ipilimumab? — Pembrolizumab plus ipilimumab is clinically effective in patients with disease refractory to single-agent PD-1 inhibitors, with clinical responses seen in up to one-third of patients [64,65]. However, the use of this combination remains investigational since it does not have regulatory drug approval in metastatic melanoma.

As an example, in an open-label, nonrandomized phase II trial, 70 patients with advanced or metastatic melanoma with disease progression on prior PD-1 inhibitor therapy and without prior exposure to ipilimumab were treated with the combination of pembrolizumab (200 mg) plus ipilimumab (1 mg/kg) every three weeks for four doses followed by up to two years of maintenance pembrolizumab [65]. At median follow-up of 12 months, the objective response rate (based on iRECIST criteria) was 29 percent, including five complete responses (7 percent) and 15 partial responses (21 percent). Median PFS and OS were 5 and 25 months, respectively. The grade ≥3 toxicity rate for the combination was 27 percent.

Is there a role for PD-1 inhibitor rechallenge? — We do not retreat patients with single-agent PD-1 inhibitors, as data suggest minimal clinical efficacy with this approach.

In the second part of a placebo-controlled phase III trial (KEYNOTE-054) of adjuvant pembrolizumab for resected Stage III melanoma, patients with disease recurrence were treated with pembrolizumab at 200 mg every three weeks for a maximum of two years [66]. Patients who received adjuvant pembrolizumab and recurred six months or more after completing one year of adjuvant therapy were rechallenged with pembrolizumab, and those who received placebo crossed over to pembrolizumab. In preliminary results, among the 20 patients rechallenged with pembrolizumab, response rates were limited and median PFS was four months.

By contrast, among the 155 patients who crossed over to pembrolizumab, the objective response rate was 39 percent, and three-year PFS was 32 percent [66]. These data are comparable to the responses seen in patients with treatment-naïve metastatic disease treated with pembrolizumab. (See 'Pembrolizumab' above.)

Further details on this study and the use of adjuvant pembrolizumab in resected cutaneous melanoma are discussed separately. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'Pembrolizumab'.)

Prior treatment with single-agent ipilimumab — For patients who progress on single-agent ipilimumab, we offer single-agent PD-1 inhibitors such as nivolumab (table 3) or pembrolizumab (table 2), as these agents were both superior to ipilimumab in randomized trials [7,8,42]. However, such patients are rare since initial therapy with ipilimumab is less preferred due to toxicity profile and the availability of other effective treatments. (See 'Ipilimumab' above.)

INVESTIGATIONAL AGENTS — Other systemic therapies have been evaluated in patients with metastatic melanoma, and their use remains investigational. Further prospective studies are necessary.

Pembrolizumab plus ipilimumab – There is no established role for the combination of pembrolizumab plus ipilimumab as initial therapy in patients with advanced or metastatic melanoma, mostly due to lack of randomized trials. Nonetheless, early-phase studies (KEYNOTE-129) show robust efficacy and suggest less toxicity than what has previously been observed with standard-dose nivolumab plus ipilimumab [67,68].

GM-CSF plus immunotherapy – In a randomized phase II trial (E1608), the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to high doses of ipilimumab improved overall survival (OS) and decreased pulmonary and gastrointestinal toxicity [69]; these results require further prospective validation. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Combining or sequencing immunotherapy with other therapies'.)

Fecal microbiota transplantation – Data suggest that gastrointestinal microbiome composition (and therapies that influence it) may be associated with response to immunotherapy in melanoma [70,71]. As an example, in early-phase clinical trials, fecal microbiota transplantation (FMT) overcame disease resistance and promoted treatment responses in patients with metastatic melanoma who progressed on immunotherapy [72,73].

Intralesional T-VEC plus immunotherapy – Although the combination of the oncolytic virus talimogene laherparepvec (T-VEC) with immunotherapy demonstrated clinical efficacy in early-phase clinical trials of patients with metastatic melanoma [74-77], a randomized phase III trial showed no benefit for this approach [78].

The use of T-VEC in patients with cutaneous melanoma is discussed separately. (See "Cutaneous melanoma: Management of local recurrence", section on 'Talimogene laherparepvec' and "Cutaneous melanoma: In-transit metastases", section on 'Intralesional therapy (T-VEC)'.)

Other agents – Other systemic therapies, such as pembrolizumab plus lenvatinib and adoptive cell therapy (eg, lifileucel), are under investigation as initial and subsequent therapy in melanoma. These data are discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Investigational options'.)

SPECIAL CONSIDERATIONS

Brain metastases — For select patients with untreated brain metastases, data indicate that immunotherapy has a role in the multidisciplinary approach to patient management. (See "Management of brain metastases in melanoma".)

Noncutaneous melanoma — A majority of patients with metastatic noncutaneous (ie, mucosal and uveal) melanoma lack BRAF mutations. (See "The molecular biology of melanoma", section on 'Genetic abnormalities in melanoma'.)

The approach to systemic therapy for these patients is discussed separately.

Mucosal melanoma (see "Treatment of metastatic mucosal melanoma")

Uveal melanoma (see "Management of metastatic uveal melanoma", section on 'Systemic therapy')

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

Available immunotherapy agents – For patients with metastatic melanoma lacking a BRAF V600 mutation, there have been important advances in systemic therapy, such as checkpoint inhibitor immunotherapy. Available options for immunotherapy include agents that inhibit cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) such as ipilimumab, those that inhibit lymphocyte-activation gene 3 (LAG-3) such relatlimab, and those that inhibit the programmed cell death receptor 1 (PD-1) such as pembrolizumab (table 2) and nivolumab (table 3). (See 'Introduction' above.)

Treatment-naïve patients with BRAF wild-type disease – For treatment-naïve patients with BRAF wild-type disease, we recommend initial treatment with immunotherapy that includes a PD-1 inhibitor (nivolumab, pembrolizumab) rather than other systemic agents (Grade 1A). (See 'Treatment-naive patients' above and 'Benefits of immunotherapy over chemotherapy' above.)

Patients with features of aggressive disease – For patients with aggressive disease, we suggest using combination immunotherapy with nivolumab plus ipilimumab (table 1) rather than a single-agent PD-1 inhibitor or nivolumab-relatlimab (Grade 2C) (algorithm 1). Clinical features that suggest aggressive disease include elevated lactate dehydrogenase (LDH); acral primary; and brain metastases, liver metastases, and/or other symptomatic systemic metastases. Nivolumab plus ipilimumab showed a nonstatistically significant trend for improved progression-free survival (PFS) and overall survival (OS), and improved treatment-free survival in this population where salvage therapy may not be available. (See 'Nivolumab plus ipilimumab (preferred)' above and 'Treatment-free survival' above.)

For those who are anticipated to not tolerate the toxicities of nivolumab plus ipilimumab, we suggest nivolumab-relatlimab rather than single-agent PD-1 inhibitors (Grade 2B), as this agent improved PFS over single-agent nivolumab in a randomized trial and has a more favorable toxicity profile than nivolumab plus ipilimumab. (See 'Nivolumab-relatlimab' above.)

Patients lacking features of aggressive disease – For patients who lack features of aggressive disease, we suggest nivolumab-relatlimab rather than single-agent PD-1 inhibitors (Grade 2B). (See 'Nivolumab-relatlimab (preferred)' above.)

For those who are anticipated to not tolerate the potential toxicities of combination immunotherapy (ie, nivolumab plus ipilimumab or nivolumab-relatlimab) we offer a single-agent PD-1 inhibitor as a suitable alternative (algorithm 1). Options include pembrolizumab (table 2) or nivolumab (table 3). (See 'Pembrolizumab' above and 'Nivolumab' above.)

What is the optimal duration of immunotherapy? – For patients receiving single-agent PD-1 inhibitor immunotherapy (either as monotherapy or maintenance therapy after nivolumab plus ipilimumab) with either a partial response or stable disease, we typically administer treatment for a maximum of two years in the absence of toxicity. (See 'What is the optimal duration of immunotherapy?' above.)

However, for those with a complete response, single-agent immunotherapy may be discontinued after at least six months of therapy have been completed if the complete response has been confirmed on at least two sets of restaging imaging studies.

Patients with a BRAF V600 mutation – For patients with a BRAF V600 mutation, options for initial therapy include nivolumab plus ipilimumab, nivolumab-relatlimab, single-agent PD-1 inhibitors, and targeted therapy with BRAF plus MEK inhibitors (algorithm 1). Further treatment details in this population are discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'BRAF V600 mutant disease'.)

Assessing treatment response – In patients with metastatic melanoma receiving checkpoint inhibitor immunotherapy, specific immunotherapy response criteria have been developed to assess treatment response (table 4). (See 'Assessing treatment response' above.)

Subsequent therapy – For patients with BRAF wild-type disease who have progressed on combination therapy with nivolumab plus ipilimumab, we evaluate their tumors for other actionable mutations and offer enrollment in clinical trials, where available. For patients not eligible for clinical trials, options include high-dose interleukin 2 and chemotherapy. (See 'Prior treatment with nivolumab plus ipilimumab' above and 'Investigational agents' above.)

For those who have progressed on single-agent PD-1 inhibitors (either in the adjuvant or metastatic setting) and have no other actionable mutations, we suggest the combination of nivolumab plus ipilimumab (table 1) rather than other available agents (Grade 2C). We do not retreat these patients with single-agent PD-1 inhibitors, as data suggest minimal clinical efficacy with this approach. (See 'Prior treatment with single-agent PD-1 inhibitors (including adjuvant therapy)' above.)

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Topic 15863 Version 144.0

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