Treatment of metastatic mucosal melanoma

INTRODUCTION — Melanomas may arise from the mucosal epithelium lining the respiratory, alimentary, and genitourinary tracts, all of which contain melanocytes, as well as from the skin.

Mucosal melanomas generally carry a worse prognosis than those arising from cutaneous sites. Our understanding of the optimal management for malignant melanoma is limited because of the rarity of this disease, its unique biology, and clinical challenges of mucosal melanoma arising from each anatomic location.

The treatment of metastatic mucosal melanoma is discussed here. The epidemiology, clinical diagnosis, and specific management of patients with locoregional mucosal melanomas arising in the head and neck, vulvovaginal, and anorectal regions, is discussed separately. The management of patients with cutaneous melanoma as well as uveal and conjunctival melanoma is also discussed separately.

●(See "Locoregional mucosal melanoma: Epidemiology, clinical diagnosis, and treatment".)

●(See "Overview of the management of advanced cutaneous melanoma".)

●(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 "Initial management of uveal and conjunctival melanomas".)

INITIAL THERAPY

Data are limited for the optimal management of patients with metastatic melanoma arising from a mucosal site. Although systemic treatments have been extrapolated from metastatic cutaneous melanoma, these approaches are evolving as more clinical trials specifically evaluate patients with mucosal melanoma. (See 'Investigational approaches' below.)

Treatment approach — For patients with treatment-naïve mucosal melanoma, we offer enrollment in clinical trials, if available. For those who are ineligible for or are unable to access clinical trials, we suggest initial treatment with checkpoint inhibitor immunotherapy that incorporates a programmed cell death 1 (PD-1) inhibitor rather than other systemic agents. Options for immunotherapy include the combination of nivolumab plus ipilimumab (table 1) or single-agent immunotherapy such as nivolumab (table 2) or pembrolizumab (table 3). The choice of therapy is individualized based on patient performance status, ability to tolerate combination immunotherapy, and the goals of therapy. (See 'Nivolumab plus ipilimumab' below and 'Single-agent immunotherapy' below.)

Surgery and/or radiation therapy (RT) may also be used to palliate symptomatic lesions. (See "Metastatic melanoma: Surgical management" and "Radiation therapy in the management of melanoma".)

Nivolumab plus ipilimumab — For patients with metastatic mucosal melanoma and good performance status who are anticipated to tolerate the potential toxicities of combination immunotherapy, we suggest initial therapy with nivolumab plus ipilimumab (table 1) over single-agent immunotherapy, as this regimen offers the opportunity to achieve complete responses and treatment-free survival, extrapolating from the approach used for metastatic cutaneous melanoma. Of note, the clinical efficacy of nivolumab plus ipilimumab in metastatic mucosal melanoma is lower than that seen for metastatic cutaneous melanoma. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Treatment-free survival'.)

However, single-agent immunotherapy is a reasonable alternative to nivolumab plus ipilimumab in patients with metastatic mucosal melanoma. Although a subset analysis of patients with mucosal melanoma in a randomized phase III trial suggested better response rates for nivolumab plus ipilimumab, it failed to demonstrate a statistically significant overall survival (OS) or progression-free survival (PFS) benefit over single-agent immunotherapy in this population. In addition, subsequent observational data comparing single-agent immunotherapy with nivolumab plus ipilimumab in real world patient populations with mucosal melanoma also suggest similar efficacy but less toxicity with this approach. (See 'Single-agent immunotherapy' below.)

A randomized phase III trial (CheckMate-067), which confirmed the efficacy of nivolumab plus ipilimumab in metastatic melanoma, included a subgroup of 79 patients with mucosal melanoma treated with either nivolumab and ipilimumab in combination or as single agents [1]. In preliminary results of this post-hoc subset analysis, at minimum follow-up of 60 months, compared with either nivolumab or ipilimumab as single agents, nivolumab plus ipilimumab was associated with the highest five-year objective response rate (43 versus 30 versus 7 percent, respectively). Complete response rates were also higher with nivolumab plus ipilimumab (14 percent) relative to nivolumab (4 percent) or ipilimumab (0 percent) monotherapy. Although nivolumab plus ipilimumab demonstrated higher five-year PFS (29 versus 14 percent, hazard ratio [HR] 0.69, 95% CI 0.36-1.33) and five-year OS (36 versus 17, HR 0.73, 95% CI 0.38-1.39) than single-agent nivolumab, these results were not statistically significant [1]. Grade ≥3 treatment-related adverse event rates were 54, 26, and 25 percent, respectively, which were similar to the overall population.

The efficacy outcomes for nivolumab plus ipilimumab in patients with mucosal melanoma are generally less favorable than that seen in the overall population of patients with cutaneous melanoma [2,3]. (see "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Nivolumab plus ipilimumab (preferred)').

●A combined analysis of six studies identified a subset of 35 patients with advanced mucosal melanoma treated with the combination of nivolumab plus ipilimumab [2]. Compared with 326 patients with cutaneous melanoma treated with nivolumab plus ipilimumab, those with mucosal melanoma who received nivolumab plus ipilimumab demonstrated lower objective response rates (37 versus 60 percent) and PFS (median 5.9 versus 11.7 months).

●In a single-arm phase IIIb trial (CheckMate 401) of 533 patients with unresectable stage III-IV melanoma treated with nivolumab plus ipilimumab, the two-year OS was lower for patients with mucosal melanoma relative to the entire study population (38 versus 63 percent) [3].

Single-agent immunotherapy — For patients with treatment-naïve metastatic mucosal melanoma, single-agent PD-1 inhibitors (nivolumab (table 2), pembrolizumab (table 3)) are a reasonable alternative to combination immunotherapy, as observational data in real-world patient populations with mucosal melanoma suggest similar efficacy with less toxicity with this approach [4]. Single-agent immunotherapy is also an option for patients who decline or are anticipated to not tolerate the potential toxicities of combination immunotherapy.

Nivolumab and pembrolizumab prolong survival in patients with advanced cutaneous melanoma. Although there are no randomized clinical trials specifically addressing the activity of these agents in patients with mucosal melanoma, efficacy has been observed in this subset in post-hoc analyses of trials enrolling a more general population [2,5-7]. Compiled data from clinical trials focused on all subsets of patients with metastatic melanoma suggest that those with mucosal melanoma respond less well to single-agent immunotherapy than patients with cutaneous melanoma.

In an exploratory post-hoc analysis of three randomized trials (KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006) enrolling almost 1600 patients with stage III or IV melanoma, 84 patients had mucosal melanoma, of whom 33 had received prior ipilimumab [6]. Among patients with mucosal melanoma, treatment with pembrolizumab (at several doses) resulted in an overall objective response rate of 19 percent, and median PFS and OS of 2.8 and 11.3 months, respectively. Median duration of response was 27.6 months, suggesting durable antitumor activity.

Subsequent observational studies in real-world populations suggest similar efficacy but lower toxicity for single-agent immunotherapy (PD-1 inhibitors) compared with combination immunotherapy (PD-1 plus CTLA-4 inhibitors) [4,8]. As an example, a retrospective cohort study of 329 patients from Japan with advanced mucosal melanoma demonstrated no significant differences in objective response rates (26 versus 29 percent), PFS (median 6 versus 7 months), or OS (median 20 months each), but lower grade ≥3 toxicity rates (17 versus 53 percent) for single-agent immunotherapy versus combination immunotherapy [4].

SUBSEQUENT THERAPY — For subsequent-line therapy, the choice of therapy is determined by the presence or absence of an actionable molecular alterations such as BRAF V600 or KIT. Clinical trials are encouraged, where available.

Approach to mutational testing — All patients with mucosal melanoma should have their tumors assayed for the presence of a driver mutation at the V600 site in BRAF. Patients with a tumor that does not contain a BRAF mutation should be assessed using next-generation sequencing for the presence of an actionable driver mutation, such as KIT or less common driver alterations such as NTRK fusions [9]. Further details are discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Approach to genetic assay'.)

Patients with actionable mutations

KIT mutation — For those patients without a V600 BRAF mutation and with a KIT (exon 11 or 13) mutation, we offer imatinib, a KIT inhibitor, as subsequent-line therapy.

●Imatinib – Approximately 25 percent of patients with mucosal melanoma have somatic mutations or amplification of KIT [10,11]. In these patients, imatinib, a small molecule inhibitor of KIT and other tyrosine kinases, is an important treatment option, particularly those with symptomatic disease and those who have progressed on or are ineligible for immunotherapy. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'KIT mutations (acral and mucosal melanoma)' and "The molecular biology of melanoma", section on 'Acral and mucosal melanoma'.)

In initial clinical trials, imatinib was ineffective in a molecularly unselected patient population with advanced melanoma [12-14], but observational studies demonstrated rapid and durable tumor responses in patients with melanoma harboring KIT mutations [15,16]. In subsequent phase II trials of patients with KIT alterations in exon 11 (L576P) or exon 13 (K642E), overall response rates ranged from approximately 16 to 29 percent, including some with durable responses [10,17,18].

●Other KIT inhibitors – Nilotinib also has clinical efficacy in patients with KIT-mutant melanoma [19-21]. As an example, in one phase II study, the partial response rate for nilotinib was 26 percent [21].

Patients with KIT-mutant melanoma involving exon 11 or 13 have also been reported to respond to other KIT inhibitors, such as sorafenib [22], dasatinib [23], and sunitinib [24].

TRK fusions — Patients with mucosal melanoma and TRK fusion-positive disease respond to therapies such as larotrectinib and entrectinib. The efficacy of these agents in metastatic melanoma is discussed in detail separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'TRK fusions' and "TRK fusion-positive cancers and TRK inhibitor therapy".)

BRAF mutation — We offer the combination of BRAF plus MEK inhibitors to patients with metastatic mucosal melanoma harboring a BRAF V600 mutation who have progressed on or are ineligible for checkpoint inhibitor immunotherapy, using a similar approach to those with metastatic cutaneous melanoma. Such patients are uncommon, as approximately 10 percent or less of mucosal melanomas harbor activating mutations in BRAF. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Choice of BRAF plus MEK inhibitor therapy' and "The molecular biology of melanoma", section on 'Acral and mucosal melanoma'.)

Other mutations — Molecular studies have noted other potential therapeutic targets in mucosal melanoma, including SF3B1 mutation, CDK4 amplifications, and CDKN2A gene deletions, which are under investigation [25].

Patients without actionable mutations

Antiangiogenic approaches — For patients with progressive disease whose tumors lack actionable mutations, we reserve the use of regimens that incorporate antiangiogenic agents. In these patients, we suggest the addition of bevacizumab to carboplatin plus paclitaxel, which improved overall survival (OS) and progression-free survival (PFS) in a phase II trial [26]. Other antiangiogenic therapies remain investigational, and clinical trials are encouraged, where available.

Mucosal melanoma is a highly vascularized tumor suggesting that antiangiogenic therapeutic approaches may provide antitumor efficacy. Data are as follows:

●Carboplatin plus paclitaxel and bevacizumab – In a randomized phase II trial of 114 patients with advanced treatment-naive mucosal melanoma, the addition of bevacizumab to the combination of carboplatin plus paclitaxel, improved PFS (median 4.8 versus 3 months, hazard ratio [HR] 0.461, 95% CI 0.306-0.695) and OS (median 13.6 versus 9 months; HR 0.611; 95% CI 0.407-0.917) [26]. Objective response rates were 19.7 and 13.2 percent, respectively.

●Toripalimab plus axitinib – In a phase Ib trial, the combination of toripalimab (a programmed cell death 1 [PD-1] inhibitor) with axitinib (a vascular endothelial growth factor receptor inhibitor) demonstrated an objective response rate of 48 percent in patients with metastatic disease [27]. Median PFS was eight months and three-year OS was 31 percent. Although toripalimab has regulatory approval in China for patients with metastatic melanoma, the combination of toripalimab and axitinib in patients with metastatic mucosal melanoma remains investigational.

●Other antiangiogenic agents – The efficacy of other therapies in metastatic melanoma, such as lenvatinib plus pembrolizumab, are discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Pembrolizumab plus lenvatinib'.)

Agents with limited roles — In patients with metastatic mucosal melanoma, there is a limited role for chemotherapy either alone or in combination with interferon alfa-2b and/or interleukin (IL-2). Studies show minimal efficacy for this approach, similar to those with cutaneous melanoma. Access to interferon alfa-2b is also limited as the manufacturer has discontinued production. (See "Cytotoxic chemotherapy for metastatic melanoma" and "Interleukin 2 and experimental immunotherapy approaches for advanced melanoma".)

Historical outcomes with cytotoxic chemotherapy alone have been poor. In one retrospective study, 74 patients were evaluated for response to first-line and 43 were evaluated for response to second-line systemic therapy [28]. Cytotoxic therapy represented 82 and 51 percent of first-line and second-line regimens, respectively. The best response achieved in the setting of initial therapy was similar for single-agent (10 percent) and combination alkylator therapy (8 percent). Median OS from first-line treatment was 10.3 months.

Data also suggest limited clinical responses for cisplatin-based chemotherapy plus interferon alfa-2b and/or IL-2 in patients with mucosal melanoma of the anorectal [29], vulvovaginal [30], and head and neck regions [31]. Additionally, the addition of these biologic agents to chemotherapy failed to show a survival benefit and had significant toxicity in a phase III trial (E3695) of advanced cutaneous melanoma [32]. (See "Interleukin 2 and experimental immunotherapy approaches for advanced melanoma", section on 'Alternative interleukin 2 regimens'.)

INVESTIGATIONAL APPROACHES — Mucosal melanoma is rare and carries a poor prognosis, and data are limited for the optimal treatment approach. Clinical trials are encouraged, where available.

●Nemvaleukin alfa – Nemvaleukin alfa, an engineered IL-2 variant immunotherapy [33], remains under investigation for patients with mucosal melanoma previously treated with single-agent PD-1 inhibitors in the ARTISTRY-6 trial (NCT04830124).

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".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Melanoma skin cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Melanoma treatment; advanced or metastatic melanoma (Beyond the Basics)" and "Patient education: Melanoma treatment; localized melanoma (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Enrollment in clinical trials – For patients with treatment-naïve metastatic mucosal melanoma, we offer enrollment in clinical trials, if available. Mucosal melanoma is rare and carries a poor prognosis, and data are limited for the optimal treatment approach. (See 'Investigational approaches' above.)

●Initial treatment – For those who are ineligible for clinical trials, we suggest initial treatment with checkpoint inhibitor immunotherapy that incorporates a single-agent programmed cell death 1 (PD-1) inhibitor rather than other systemic agents (Grade 2C). (See 'Initial therapy' above.)

•Eligible for combination immunotherapy – For patients with metastatic mucosal melanoma and good performance status who are anticipated to tolerate the potential toxicities of combination immunotherapy, we suggest initial therapy with nivolumab plus ipilimumab (table 1) over single-agent immunotherapy (Grade 2C). Nivolumab plus ipilimumab offers the opportunity to achieve complete responses and treatment-free survival, extrapolating from the approach used for metastatic cutaneous melanoma. Of note, this regimen has less clinical efficacy in metastatic mucosal melanoma compared with metastatic cutaneous melanoma. (See 'Nivolumab plus ipilimumab' above.)

However, single-agent PD-1 inhibitors (nivolumab (table 2), pembrolizumab (table 3)) are a reasonable alternative to combination immunotherapy, as clinical trials and observational data in real-world patient populations with mucosal melanoma suggest similar efficacy but less toxicity with this approach. (See 'Single-agent immunotherapy' above.)

•Ineligible for combination immunotherapy – Single-agent immunotherapy is also an option for patients who decline or are anticipated to not tolerate the potential toxicity of combination immunotherapy with nivolumab plus ipilimumab. (See 'Single-agent immunotherapy' above.)

●Subsequent therapy – For patients with metastatic disease who progress on or are ineligible for checkpoint inhibitor immunotherapy, the choice of therapy is determined by the presence of absence of an actionable molecular alteration. (See 'Subsequent therapy' above.)

•Patients with actionable mutations – For patients without a BRAF mutation, next-generation sequencing can be used to evaluate for actionable mutations and participation into clinical trials. (See 'Patients without actionable mutations' above.)

-KIT mutation – For those with a KIT mutation, we suggest imatinib rather than other systemic agents (Grade 2C). (See 'KIT mutation' above.)

-TRK fusion-positive – For those with TRK fusion-positive disease, we offer either larotrectinib or entrectinib. (See 'TRK fusions' above.)

For the uncommon patient with a BRAF V600 mutation, we offer the combination of BRAF plus MEK inhibitors, using a similar approach to those with cutaneous melanoma. (See 'BRAF mutation' above and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Choice of BRAF plus MEK inhibitor therapy'.)

•Patients without actionable mutations – For patients without actionable mutations who progress on immunotherapy, we suggest the addition of bevacizumab to carboplatin plus paclitaxel (Grade 2C). (See 'Patients without actionable mutations' above.)