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European consensus-based interdisciplinary guideline for melanoma. Part 2: Treatment - Update 2022

Open AccessPublished:May 24, 2022DOI:https://doi.org/10.1016/j.ejca.2022.04.018

      Abstract

      A unique collaboration of multidisciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO), and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on cutaneous melanoma diagnosis and treatment, based on the systematic literature reviews and the experts' experience. Cutaneous melanomas are excised with one to 2-cm safety margins. Sentinel lymph node dissection shall be performed as a staging procedure in patients with tumor thickness ≥1.0 mm or ≥0.8 mm with additional histological risk factors, although there is as yet no clear survival benefit for this approach. Therapeutic decisions in stage III/IV patients should be primarily made by an interdisciplinary oncology team (“tumor board”). Adjuvant therapies can be proposed in stage III/completely resected stage IV patients and are primarily anti-PD-1, independent of mutational status, or alternatively dabrafenib plus trametinib for BRAF mutant patients. In distant metastases (stage IV), either resected or not, systemic treatment is always indicated. For first-line treatment particularly in BRAF wild-type patients, immunotherapy with PD-1 antibodies alone or in combination with CTLA-4 antibodies shall be considered. In stage IV melanoma with a BRAF-V600  E/K mutation, first-line therapy with BRAF/MEK inhibitors can be offered as an alternative to immunotherapy. In patients with primary resistance to immunotherapy and harboring a BRAF-V600  E/K mutation, this therapy shall be offered as second-line therapy. Systemic therapy in stage III/IV melanoma is a rapidly changing landscape, and it is likely that these recommendations may change in the near future.

      Keywords

      1. Surgical therapy

      1.1 General principles

      Tabled 1Recommendation 12 (numbers continued from Part 1)
      Primary excisionConsensus-based recommendation
      GCPWhen melanoma is suspected, the whole lesion should be completely excised with a narrow (1–3 mm) margin in order to perform a histological diagnosis.

      Incisional biopsies can be performed on large lesions such as lesions on the face (e.g., lentigo maligna), acral lesions, and on the genitalia.
      Consensus rate: 100%
      Tabled 1Recommendation 13
      Avoidance of non-surgical treatmentsConsensus-based recommendation
      GCPIf melanoma cannot be excluded, blind destructive treatments such as laser, cryotherapy, or topical drugs shall not be performed.
      Consensus rate: 100%

      1.2 Primary melanoma

      Excision with a safety margin remains a standard of care in melanoma patients. The current recommendations are based on both prospective, randomized studies and international consensus guidelines [
      • Eggermont A.M.
      • Spatz A.
      • Robert C.
      Cutaneous melanoma.
      ,
      • Coit D.G.
      • Andtbacka R.
      • Bichakjian C.K.
      • Dilawari R.A.
      • Dimaio D.
      • Guild V.
      • et al.
      Melanoma.
      ,
      SaNZGGW TcCAaACN
      Australian cancer network melanoma guidelines revision working party.
      ,
      • Negrier S.
      • Saiag P.
      • Guillot B.
      • Verola O.
      • Avril M.F.
      • Bailly C.
      • et al.
      Guidelines for clinical practice: standards, options and recommendations 2005 for the management of adult patients exhibiting an M0 cutaneous melanoma, full report. National Federation of cancer campaign centers. French dermatology society. Update of the 1995 consensus conference and the 1998 standards, options, and recommendations.
      ,
      • Marsden J.R.
      • Newton-Bishop J.A.
      • Burrows L.
      • Cook M.
      • Corrie P.G.
      • Cox N.H.
      • et al.
      Revised U.K. guidelines for the management of cutaneous melanoma 2010.
      ,
      • Garbe C.
      • Hauschild A.
      • Volkenandt M.
      • Schadendorf D.
      • Stolz W.
      • Reinhold U.
      • et al.
      Evidence-based and interdisciplinary consensus-based German guidelines: systemic medical treatment of melanoma in the adjuvant and palliative setting.
      ]. A randomized, open-label multicenter clinical trial comparing 1 cm vs. 3 cm margins in patients with primary cutaneous melanoma on the trunk and limbs suggested that a 1 cm excision margin is inadequate for cutaneous melanoma with Breslow thickness greater than 2 mm [
      • Hayes A.J.
      • Maynard L.
      • Coombes G.
      • Newton-Bishop J.
      • Timmons M.
      • Cook M.
      • et al.
      Wide versus narrow excision margins for high-risk, primary cutaneous melanomas: long-term follow-up of survival in a randomised trial.
      ]. A meta-analysis showed that there is a statistically significant worse melanoma-specific survival (MSS) with narrow (1–3 cm) than with wider margins (3–5 cm) with no treatment effect on recurrence-free survival (RFS) [
      • Wheatley K.
      • Wilson J.S.
      • Gaunt P.
      • Marsden J.R.
      Surgical excision margins in primary cutaneous melanoma: a meta-analysis and Bayesian probability evaluation.
      ]. However, with regard to MSS, only four trials were eligible, and the hazard ratio (HR) in favor of wider margins was largely affected by the positive trial of Hayes et al (3 cm vs. 1 cm) [
      • Hayes A.J.
      • Maynard L.
      • Coombes G.
      • Newton-Bishop J.
      • Timmons M.
      • Cook M.
      • et al.
      Wide versus narrow excision margins for high-risk, primary cutaneous melanomas: long-term follow-up of survival in a randomised trial.
      ], while another study comparing 4 cm vs. 2 cm did not show any statistical difference in thicker melanomas [
      • Gillgren P.
      • Drzewiecki K.T.
      • Niin M.
      • Gullestad H.P.
      • Hellborg H.
      • Mansson-Brahme E.
      • et al.
      2-cm versus 4-cm surgical excision margins for primary cutaneous melanoma thicker than 2 mm: a randomised, multicentre trial.
      ]. Only recently, a further meta-analysis involving 4579 patients’ data from seven randomized clinical trials revealed no significant difference between narrow (1–2 cm) and wide (3–5 cm) excision margins in locoregional or distant recurrence, metastasis, death, or death due to melanoma [
      • Hanna S.
      • Lo S.N.
      • Saw R.P.
      Surgical excision margins in primary cutaneous melanoma: a systematic review and meta-analysis.
      ]. Moreover, the usefulness of margins above 1 cm still remains unclear in patients with stage II melanoma (pT2b-pT4b, AJCC 8th edition). An ongoing clinical trial comparing 1 cm vs. 2 cm margins (MelMart-II) is expected to offer valuable data about this.
      Tabled 1Recommendation 14
      Safety margins for secondary excision (re-excision)Evidence-based recommendation
      GCPIn the case of primary melanoma, a subsequent excision should be performed in order to minimize the risk of local recurrences.

      The following safety peripheral surgical margins∗ should be considered: in situ: 5 mm

      ≤2 mm tumor thickness: 1 cm

      >2 mm tumor thickness: 2 cm

      Larger excisions are not recommended.
      Guideline adaptation [
      • Onkologie L.
      Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): Diagnostik, Therapie und Nachsorge des Melanoms, Langversion 3.1.
      ,
      • Pflugfelder A.
      • Kochs C.
      • Blum A.
      • Capellaro M.
      • Czeschik C.
      • Dettenborn T.
      • et al.
      Malignant melanoma S3-guideline “diagnosis, therapy and follow-up of melanoma”.
      ]
      Consensus rate: 100%
      ∗Margins are to be measured clinically and not pathologically; the initial excision margin should be included in the total safety margins definition.
      Tabled 1Recommendation 15
      Safety margins for secondary excision (re-excision) in special anatomic locationsEvidence-based recommendation
      GCPNarrower margins for re-excision may be exceptionally considered for special anatomic locations in order to preserve function, maintain cosmesis, and to allow reconstruction, particularly in facial, acral, and genital lesions.
      Guideline adaptation [
      • Onkologie L.
      Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): Diagnostik, Therapie und Nachsorge des Melanoms, Langversion 3.1.
      ,
      • Pflugfelder A.
      • Kochs C.
      • Blum A.
      • Capellaro M.
      • Czeschik C.
      • Dettenborn T.
      • et al.
      Malignant melanoma S3-guideline “diagnosis, therapy and follow-up of melanoma”.
      ]
      Consensus rate: 100%

      1.3 Lentigo maligna

      Lentigo maligna is a slowly growing melanoma in situ, which occurs typically in UV-exposed areas like the face [
      • Moehrle M.
      • Dietz K.
      • Garbe C.
      • Breuninger H.
      Conventional histology vs. three-dimensional histology in lentigo maligna melanoma.
      ]. A Cochrane review about interventions in melanoma in situ failed to find randomized clinical trials of surgical interventions aiming to optimize margin control (square method, perimeter technique, “slow Mohs”, staged radial sections, staged “mapped” excisions, or Mohs micrographic surgery), which are the most widely used interventions recommended as first-line therapy [
      • Tzellos T.
      • Kyrgidis A.
      • Mocellin S.
      • Chan A.W.
      • Pilati P.
      • Apalla Z.
      Interventions for melanoma in situ, including lentigo maligna.
      ]. A retrospective study including patients with lentigo maligna melanoma treated through staged surgery with immunohistopathological control of lateral margins showed a higher clearance and a lower recurrence rate than wide excisions [
      • de Vries K.
      • Greveling K.
      • Prens L.M.
      • Munte K.
      • Koljenovic S.
      • van Doorn M.B.
      • et al.
      Recurrence rate of lentigo maligna after micrographically controlled staged surgical excision.
      ]. A single-center retrospective study compared conventional surgical excision and “slow Mohs surgery” for patients with lentigo maligna melanoma. This study concluded that surgical margins of 0.5 cm are inadequate for the treatment of a considerable number of lesions on the head, particularly if these are recurrent. “Slow Mohs” using routinely stained paraffin-embedded sections was shown to be the treatment of choice in such cases, particularly for recurrent lesions or lesions with poorly defined borders or possible subclinical extension [
      • Hilari H.
      • Llorca D.
      • Traves V.
      • Villanueva A.
      • Serra-Guillen C.
      • Requena C.
      • et al.
      Conventional surgery compared with slow Mohs micrographic surgery in the treatment of lentigo maligna: a retrospective study of 62 cases.
      ]. Because of unpredictable subclinical extension of the adjacent intraepidermal component, the management of lentigo maligna melanoma may range from a 5 mm margin to wider margins (up to 10 mm). For larger lentigo maligna and lentigo maligna melanoma, microscopically controlled surgery is a recommended option and is usually performed following any of the technical variations developed (frozen section Mohs micrographic surgery, paraffin-embedded, “slow Mohs”, and 3D-histology) [
      • Hilari H.
      • Llorca D.
      • Traves V.
      • Villanueva A.
      • Serra-Guillen C.
      • Requena C.
      • et al.
      Conventional surgery compared with slow Mohs micrographic surgery in the treatment of lentigo maligna: a retrospective study of 62 cases.
      ,
      • Krausz A.E.
      • Higgins 2nd, H.W.
      • Etzkorn J.
      • Sobanko J.
      • Shin T.
      • Giordano C.
      • et al.
      Systematic review of technical variations for Mohs micrographic surgery for melanoma.
      ].
      As for non-surgical interventions, high-quality evidence does not support the use of imiquimod as primary therapy in non-selected cases [
      • Tzellos T.
      • Kyrgidis A.
      • Mocellin S.
      • Chan A.W.
      • Pilati P.
      • Apalla Z.
      Interventions for melanoma in situ, including lentigo maligna.
      ]. However, several retrospective analyses and phase II trials support a role for topical imiquimod as a potential alternative to surgery in selected cases not eligible for surgery or radiotherapy [
      • Tio D.
      • van der Woude J.
      • Prinsen C.A.C.
      • Jansma E.P.
      • Hoekzema R.
      • van Montfrans C.
      A systematic review on the role of imiquimod in lentigo maligna and lentigo maligna melanoma: need for standardization of treatment schedule and outcome measures.
      ], as well as for incompletely excised tumors or as an adjuvant option for those treated through narrow margins [
      • Swetter S.M.
      • Chen F.W.
      • Kim D.D.
      • Egbert B.M.
      Imiquimod 5% cream as primary or adjuvant therapy for melanoma in situ, lentigo maligna type.
      ]. Recently, a 95% cure rate after a mean follow-up of three years has been reported with adjuvant imiquimod following conventional surgery with narrow margins [
      • Lallas A.
      • Moscarella E.
      • Kittler H.
      • Longo C.
      • Thomas L.
      • Zalaudek I.
      • et al.
      Real-world experience of off-label use of imiquimod 5% as an adjuvant therapy after surgery or as a monotherapy for lentigo maligna.
      ]. The complete response rate to imiquimod treatment is in the range of 75%–88% [
      • Buettiker U.V.
      • Yawalkar N.Y.
      • Braathen L.R.
      • Hunger R.E.
      Imiquimod treatment of lentigo maligna: an open-label study of 34 primary lesions in 32 patients.
      ,
      • Mahoney M.H.
      • Joseph M.G.
      • Temple C.
      Topical imiquimod therapy for lentigo maligna.
      ,
      • Cotter M.A.
      • McKenna J.K.
      • Bowen G.M.
      Treatment of lentigo maligna with imiquimod before staged excision.
      ]. Pre-treatment mapping biopsies or in vivo reflectance confocal microscopy can be used to assess the extent of the lesion [
      • Yelamos O.
      • Cordova M.
      • Blank N.
      • Kose K.
      • Dusza S.W.
      • Lee E.
      • et al.
      Correlation of handheld reflectance confocal microscopy with radial video mosaicing for margin mapping of lentigo maligna and lentigo maligna melanoma.
      ].

      1.4 Acral and mucosal melanomas

      Tabled 1Recommendation 16
      Microscopically controlled surgeryConsensus-based recommendation
      GCPIn some melanoma subtypes, such as lentigo maligna melanoma, genital and acral melanomas, and microscopically controlled surgery can be used to spare tissue and ensure complete resection.
      Consensus rate: 90%; 2 abstentions

      1.5 Sentinel lymph node biopsy

      The sentinel lymph node biopsy (SLNB) was introduced in order to allow the evaluation of the first draining lymph node(s) in the regional lymphatic system avoiding the surgical morbidity from unnecessary elective lymph node dissections [
      • Morton D.L.
      • Wen D.R.
      • Wong J.H.
      • Economou J.S.
      • Cagle L.A.
      • Storm F.K.
      • et al.
      Technical details of intraoperative lymphatic mapping for early stage melanoma.
      ]. SLNB is a staging procedure, appropriate for patients in whom neither palpation nor lymph node sonography has suggested the presence of lymph node metastases. SLNB involvement is an independent prognostic factor for MSS and is considered a standard staging procedure [
      • Gershenwald J.E.
      • Scolyer R.A.
      • Hess K.R.
      • Sondak V.K.
      • Long G.V.
      • Ross M.I.
      • et al.
      Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual.
      ]. In addition, a positive sentinel lymph node (SLN) will upstage patients with clinically negative nodes and make them eligible for adjuvant systemic therapy. As all the adjuvant trials have selected the patients on the basis of the positivity of SLNB, the SLNB status is required for the new adjuvant options. Multicenter studies have shown that despite a slight increase in RFS in patients undergoing SLNB, there is no impact on overall survival (OS) [
      • Thompson J.F.
      • Shaw H.M.
      Sentinel node mapping for melanoma: results of trials and current applications.
      ,
      • Morton D.L.
      • Cochran A.J.
      • Thompson J.F.
      • Elashoff R.
      • Essner R.
      • Glass E.C.
      • et al.
      Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial.
      ,
      • Faries M.B.
      • Thompson J.F.
      • Cochran A.J.
      • Andtbacka R.H.
      • Mozzillo N.
      • Zager J.S.
      • et al.
      Completion dissection or observation for sentinel-node metastasis in melanoma.
      ].
      Tabled 1Recommendation 17
      Sentinel lymph node biopsyEvidence-based recommendation
      Level of recommendation AFor a correct stage classification and treatment decision, a sentinel lymph node biopsy shall be offered in patients with tumor thickness ≥1.0 mm or ≥ 0.8 mm with additional histological risk factors.
      Level of evidence: 1aDe novo literature research [
      • Morton D.L.
      • Thompson J.F.
      • Cochran A.J.
      • Mozzillo N.
      • Elashoff R.
      • Essner R.
      • et al.
      Sentinel-node biopsy or nodal observation in melanoma.
      ,
      • Morton D.L.
      • Thompson J.F.
      • Cochran A.J.
      • Mozzillo N.
      • Nieweg O.E.
      • Roses D.F.
      • et al.
      Final trial report of sentinel-node biopsy versus nodal observation in melanoma.
      ]
      Consensus rate: 90%

      1.6 Procedure in patients with negative SLN

      No further lymph node surgery is required.

      1.7 Procedure in patients with micro-metastases in SLN

      Complete lymph node dissection (CLND) has previously been routinely offered to patients having micro-metastasis of the SLN. The results of the German Dermatologic Cooperative Oncology Group (DeCOG) and Multicenter Selective Lymphadenectomy Trial (MSLT-II) clinical trials led to the revision of the role of lymphadenectomy in patients with SLN metastasis. In patients with microscopic SLN metastases, both studies failed to show a survival difference between CLND and observation. In the DeCOG study, 68% of patients in the observation arm and 65% in the CLND arm were free of distant metastases after five years of follow-up [
      • Leiter U.
      • Stadler R.
      • Mauch C.
      • Hohenberger W.
      • Brockmeyer N.
      • Berking C.
      • et al.
      Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial.
      ,
      • Leiter U.
      • Stadler R.
      • Mauch C.
      • Hohenberger W.
      • Brockmeyer N.H.
      • Berking C.
      • et al.
      Final analysis of DeCOG-SLT trial: No survival benefit for complete lymph node dissection in patients with melanoma with positive sentinel node.
      ]. In the MSLT-II, 86% of the patients in both study groups (CLND or observation) were alive after three years [
      • Faries M.B.
      • Thompson J.F.
      • Cochran A.J.
      • Andtbacka R.H.
      • Mozzillo N.
      • Zager J.S.
      • et al.
      Completion dissection or observation for sentinel-node metastasis in melanoma.
      ]. Moreover, in the MSLT-II study, the percentage of patients with non-sentinel-node metastases was 20% at five years. Consequently, 80% of the CLND performed might have been avoided [
      • Faries M.B.
      • Thompson J.F.
      • Cochran A.J.
      • Andtbacka R.H.
      • Mozzillo N.
      • Zager J.S.
      • et al.
      Completion dissection or observation for sentinel-node metastasis in melanoma.
      ].
      Tabled 1Recommendation 18
      Management of micro-metastasisEvidence-based recommendation
      Level of recommendation AIn patients with sentinel lymph node micro-metastasis, complete lymphadenectomy shall no longer be performed. There is an indication for adjuvant systemic therapy.
      Level of evidence: 1aDe novo literature research [
      • Faries M.B.
      • Thompson J.F.
      • Cochran A.J.
      • Andtbacka R.H.
      • Mozzillo N.
      • Zager J.S.
      • et al.
      Completion dissection or observation for sentinel-node metastasis in melanoma.
      ,
      • Leiter U.
      • Stadler R.
      • Mauch C.
      • Hohenberger W.
      • Brockmeyer N.
      • Berking C.
      • et al.
      Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial.
      ,
      • Leiter U.
      • Stadler R.
      • Mauch C.
      • Hohenberger W.
      • Brockmeyer N.H.
      • Berking C.
      • et al.
      Final analysis of DeCOG-SLT trial: No survival benefit for complete lymph node dissection in patients with melanoma with positive sentinel node.
      ]
      Consensus rate: 100%

      1.8 Clinically identified lymph node metastases

      If lymph node metastases are diagnosed clinically or by imaging techniques (including ultrasound), therapeutic lymph node dissection (TLND) is considered standard therapy [
      • Wong S.L.
      • Faries M.B.
      • Kennedy E.B.
      • Agarwala S.S.
      • Akhurst T.J.
      • Ariyan C.
      • et al.
      Sentinel lymph node biopsy and management of regional lymph nodes in melanoma: American society of clinical oncology and society of surgical oncology clinical practice guideline update.
      ,
      • Morton D.L.
      • Wanek L.
      • Nizze J.A.
      • Elashoff R.M.
      • Wong J.H.
      Improved long-term survival after lymphadenectomy of melanoma metastatic to regional nodes. Analysis of prognostic factors in 1134 patients from the John Wayne Cancer Clinic.
      ].
      Tabled 1Recommendation 19
      Lymphadenectomy in regional lymph node metastasesConsensus-based recommendation
      GCPIf regional lymph node macro-metastases have been detected clinically or by imaging, complete lymphadenectomy shall be offered, in the absence of in-transit and distant metastasis.
      Consensus rate: 100%

      1.9 Satellite and/or in-transit metastases

      Depending on the number, size, and location of satellite and in-transit metastases, different options include surgery or other destructive therapies such as cryotherapy, laser therapy, electrochemotherapy, and radiotherapy. Systemic therapies with anti-PD-1 immunotherapy, targeted therapy, intralesional immunotherapy (talimogene laherparepvec [T-VEC] [
      • Andtbacka R.H.
      • Kaufman H.L.
      • Collichio F.
      • Amatruda T.
      • Senzer N.
      • Chesney J.
      • et al.
      Talimogene laherparepvec improves durable response rate in patients with advanced melanoma.
      ]), or IL-2 can be used. Topic therapy with imiquimod is also possible. Finally, isolated limb perfusion with melphalan ± tumor necrosis factor (TNF) might be considered [
      • Lienard D.
      • Eggermont A.M.
      • Koops H.S.
      • Kroon B.
      • Towse G.
      • Hiemstra S.
      • et al.
      Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or without interferon-gamma for the treatment of in-transit melanoma metastases: a multicentre randomized phase II study.
      ,
      • Deroose J.P.
      • Eggermont A.M.
      • van Geel A.N.
      • de Wilt J.H.
      • Burger J.W.
      • Verhoef C.
      20 years experience of TNF-based isolated limb perfusion for in-transit melanoma metastases: TNF dose matters.
      ].

      1.10 Distant metastases

      If technically feasible and reasonable (oligometastatic disease), complete surgical removal of distant metastases may be an option for selected patients. These include those with a long disease-free interval and with tumor markers LDH and protein S100B in the normal range. Nevertheless, these patients are also those who better respond to systemic therapies [
      • Weide B.
      • Elsasser M.
      • Buttner P.
      • Pflugfelder A.
      • Leiter U.
      • Eigentler T.K.
      • et al.
      Serum markers lactate dehydrogenase and S100B predict independently disease outcome in melanoma patients with distant metastasis.
      ]. Many studies show that excision of solitary or few metastases can be associated with a favorable outcome for stage IV patients [
      • Petersen R.P.
      • Hanish S.I.
      • Haney J.C.
      • Miller 3rd, C.C.
      • Burfeind Jr., W.R.
      • Tyler D.S.
      • et al.
      Improved survival with pulmonary metastasectomy: an analysis of 1720 patients with pulmonary metastatic melanoma.
      ,
      • Sanki A.
      • Scolyer R.A.
      • Thompson J.F.
      Surgery for melanoma metastases of the gastrointestinal tract: indications and results.
      ,
      • Chua T.C.
      • Saxena A.
      • Morris D.L.
      Surgical metastasectomy in AJCC stage IV M1c melanoma patients with gastrointestinal and liver metastases.
      ,
      • Wasif N.
      • Bagaria S.P.
      • Ray P.
      • Morton D.L.
      Does metastasectomy improve survival in patients with Stage IV melanoma? A cancer registry analysis of outcomes.
      ]. These patients are now eligible for adjuvant systemic therapy after resection of stage IV oligometastatic disease.
      The possibility of neoadjuvant therapy followed by surgical excision of metastatic lesions can be considered. Stereotactic radiosurgery (SRS) is also an established treatment in this clinical situation [
      • Moschos S.J.
      • Edington H.D.
      • Land S.R.
      • Rao U.N.
      • Jukic D.
      • Shipe-Spotloe J.
      • et al.
      Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses.
      ].
      Tabled 1Recommendation 20
      Surgical treatment of distant metastasesEvidence-based recommendation
      Level of recommendation CIn case of oligometastatic disease, complete resection or other destructive procedures can be considered. These can also be considered as a palliative procedure.
      Guideline adaptation [
      • Onkologie L.
      Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): Diagnostik, Therapie und Nachsorge des Melanoms, Langversion 3.1.
      ,
      • Pflugfelder A.
      • Kochs C.
      • Blum A.
      • Capellaro M.
      • Czeschik C.
      • Dettenborn T.
      • et al.
      Malignant melanoma S3-guideline “diagnosis, therapy and follow-up of melanoma”.
      ]
      Consensus rate: 100%

      2. Radiotherapy

      2.1 Primary melanoma

      Radiotherapy of the primary tumor is rarely indicated. However, in elderly or frail patients or where the surgical procedure will lead to severe disfigurement, radiotherapy can be applied with curative intent. This could be considered for lentigo maligna fulfilling these criteria [
      • Farshad A.
      • Burg G.
      • Panizzon R.
      • Dummer R.
      A retrospective study of 150 patients with lentigo maligna and lentigo maligna melanoma and the efficacy of radiotherapy using Grenz or soft X-rays.
      ].

      2.2 Regional lymph nodes

      There is no established role for adjuvant radiotherapy of draining lymph nodes after excision of the primary melanoma. Adjuvant radiotherapy after lymphadenectomy has been evaluated in a randomized clinical trial [
      • Burmeister B.H.
      • Henderson M.A.
      • Ainslie J.
      • Fisher R.
      • Di Iulio J.
      • Smithers B.M.
      • et al.
      Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial.
      ], proving the efficacy of radiotherapy in terms of increased locoregional control, but with no impact on survival. Furthermore, the increased locoregional control was accompanied by significant toxicity, with 22% of the patients receiving radiotherapy, developing grade 3–4 toxicity [
      • Henderson M.A.
      • Burmeister B.H.
      • Ainslie J.
      • Fisher R.
      • Di Iulio J.
      • Smithers B.M.
      • et al.
      Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial.
      ].

      2.3 Oligometastatic disease

      In patients with oligometastatic disease, ablative (SRS or equivalent) radiotherapy represents a treatment alternative to surgery in cases where surgical access is associated with a high risk of significant surgical complications.

      2.4 Skin metastases

      In-transit metastases, which are too extensive for a surgical approach, may be controlled by radiotherapy alone [
      • Olivier K.R.
      • Schild S.E.
      • Morris C.G.
      • Brown P.D.
      • Markovic S.N.
      A higher radiotherapy dose is associated with more durable palliation and longer survival in patients with metastatic melanoma.
      ].

      2.5 Bone metastases

      Radiotherapy is effective to palliate patients with bone metastases. The response rate (complete response and partial symptom control) is 67–85% [
      • Rate W.R.
      • Solin L.J.
      • Turrisi A.T.
      Palliative radiotherapy for metastatic malignant melanoma: brain metastases, bone metastases, and spinal cord compression.
      ,
      • Katz H.R.
      The results of different fractionation schemes in the palliative irradiation of metastatic melanoma.
      ,
      • Konefal J.B.
      • Emami B.
      • Pilepich M.V.
      Analysis of dose fractionation in the palliation of metastases from malignant melanoma.
      ,
      • Kirova Y.M.
      • Chen J.
      • Rabarijaona L.I.
      • Piedbois Y.
      • Le Bourgeois J.P.
      Radiotherapy as palliative treatment for metastatic melanoma.
      ]. The major indications for radiotherapy in these cases are pain, loss of structural stability (fracture risk), and compression of the spinal canal with or without neurological symptoms.

      2.6 Brain metastases

      Melanoma has a marked propensity to metastasize to the brain. Systemic treatment strategies for brain metastases with high response rates combined with a short time to response using combination immunotherapy [
      • Long G.V.
      • Atkinson V.
      • Lo S.
      • Sandhu S.
      • Guminski A.D.
      • Brown M.P.
      • et al.
      Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study.
      ,

      Tawbi H. Safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with advanced melanoma(MEL) metastatic to the brain: Initial Results From Phase 2 CheckMate 204. SMR2016.

      ] or targeted therapies [
      • Gaudy-Marqueste C.
      • Carron R.
      • Delsanti C.
      • Loundou A.
      • Monestier S.
      • Archier E.
      • et al.
      On demand Gamma-Knife strategy can be safely combined with BRAF inhibitors for the treatment of melanoma brain metastases.
      ] led to renewed considerations on how to plan the optimal treatment of melanoma patients with brain metastases.
      Preclinical evidence has suggested a positive effect of the combination of immunotherapy and radiotherapy [
      • Grimaldi A.M.
      • Simeone E.
      • Giannarelli D.
      • Muto P.
      • Falivene S.
      • Borzillo V.
      • et al.
      Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy.
      ,
      • Crittenden M.
      • Kohrt H.
      • Levy R.
      • Jones J.
      • Camphausen K.
      • Dicker A.
      • et al.
      Current clinical trials testing combinations of immunotherapy and radiation.
      ], and a number of clinical trials are currently in progress evaluating the possible additive effect of this combination or the combination of radiotherapy and BRAF + MEK inhibitors in BRAF mutated melanomas. Recent publications support the concomitant use immunotherapy and stereotactic radiosurgery [SRT] [
      • Lehrer E.J.
      • Peterson J.
      • Brown P.D.
      • Sheehan J.P.
      • Quinones-Hinojosa A.
      • Zaorsky N.G.
      • et al.
      Treatment of brain metastases with stereotactic radiosurgery and immune checkpoint inhibitors: an international meta-analysis of individual patient data.
      ,
      • Rauschenberg R.
      • Bruns J.
      • Brutting J.
      • Daubner D.
      • Lohaus F.
      • Zimmer L.
      • et al.
      Impact of radiation, systemic therapy and treatment sequencing on survival of patients with melanoma brain metastases.
      ,
      • Tagliaferri L.
      • Lancellotta V.
      • Fionda B.
      • Mangoni M.
      • Casà C.
      • Di Stefani A.
      • et al.
      Immunotherapy and radiotherapy in melanoma: a multidisciplinary comprehensive review.
      ]. A recent review concludes that the combination of radiotherapy and targeted therapy is safe provided a short drug holiday is introduced [
      • Ge Y.
      • Che X.
      • Gao X.
      • Zhao S.
      • Su J.
      Combination of radiotherapy and targeted therapy for melanoma brain metastases: a systematic review.
      ].
      The literature provides only limited evidence for the use of radiotherapy in the treatment of brain metastases [
      • Garsa A.
      • Jang J.K.
      • Baxi S.
      • Chen C.
      • Akinniranye O.
      • Hall O.
      • et al.
      Radiation therapy for brain metastases: a systematic review.
      ] Whole brain radiotherapy (WBRT) may cause serious long-term cognitive toxicity and therefore increased focus on SRS has emerged [
      • Brown P.D.
      • Ballman K.V.
      • Cerhan J.H.
      • Anderson S.K.
      • Carrero X.W.
      • Whitton A.C.
      • et al.
      Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC.3): a multicentre, randomised, controlled, phase 3 trial.
      ]. Clinical trials have shown increased local control in patients with 1–10 brain metastases using adjuvant SRS after surgery [
      • Mahajan A.
      • Ahmed S.
      • McAleer M.F.
      • Weinberg J.S.
      • Li J.
      • Brown P.
      • et al.
      Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial.
      ]. WBRT is no longer a standard of care for melanoma patients, because it is widely an ineffective and toxic treatment.

      3. Adjuvant therapy

      3.1 General principles

      Adjuvant therapy is offered to patients without evidence of macroscopic metastases but at a high risk of having microscopic metastases. Historically, adjuvant therapy with interferon alpha was used in patients with tumors thicker than 1.5 mm. More recently, checkpoint inhibitors and targeted therapy have been evaluated in resected stage III and stage IV disease. Prolonged RFS and distant metastases free survival (DMFS) in stage III melanoma has been reported for adjuvant therapy with ipilimumab [
      • Eggermont A.M.
      • Chiarion-Sileni V.
      • Grob J.J.
      • Dummer R.
      • Wolchok J.D.
      • Schmidt H.
      • et al.
      Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial.
      ], nivolumab [
      • Weber J.
      • Mandala M.
      • Del Vecchio M.
      • Gogas H.J.
      • Arance A.M.
      • Cowey C.L.
      • et al.
      Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma.
      ], pembrolizumab [
      • Eggermont A.M.
      • Blank C.U.
      • Mandalà M.
      • Long G.V.
      • Atkinson V.
      • Dalle S.
      • et al.
      Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: new recurrence-free survival results from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial at three-year median follow-up.
      ] and for therapy with dabrafenib and trametinib in patients with BRAF mutated melanoma [
      • Long G.V.
      • Hauschild A.
      • Santinami M.
      • Atkinson V.
      • Mandala M.
      • Chiarion-Sileni V.
      • et al.
      Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma.
      ]. Data demonstrating a significant impact on OS have been reported for ipilimumab [
      • Eggermont A.M.
      • Chiarion-Sileni V.
      • Grob J.J.
      • Dummer R.
      • Wolchok J.D.
      • Schmidt H.
      • et al.
      Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy.
      ] and for dabrafenib and trametinib. Recently, early data for adjuvant therapy with pembrolizumab in resected stage IIB and IIC melanoma also showed a significant improvement in RFS [
      • Luke PR J.J.
      • Queirolo P.
      • Del Vecchio M.
      • Mackiewicz J.
      • Chiarion Sileni V.
      • de la Cruz Merino L.
      • et al.
      LBA3 PR - pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: efficacy and safety results from the KEYNOTE-716 double-blind phase III trial.
      ]. In addition, the combination of dose modified ipilimumab and nivolumab was tested in a randomized phase III trial in stage III–IV melanoma and the standard dose combination therapy in a randomized phase II study in resected stage IV melanoma without evidence of disease following surgery or radiotherapy [
      • Zimmer L.
      • Livingstone E.
      • Hassel J.C.
      • Fluck M.
      • Eigentler T.
      • Loquai C.
      • et al.
      Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial.
      ,
      • Long G.V.
      • Robert C.
      • Butler M.O.
      • Couture F.
      • Carlino M.S.
      • Day S.
      • et al.
      Standard-dose pembrolizumab plus alternate-dose ipilimumab in advanced melanoma: KEYNOTE-029 cohort 1C, a phase 2 randomized study of two dosing schedules.
      ].

      3.2 Adjuvant immunotherapy with interferon-α

      Interferon-α was the first substance in the adjuvant therapy of melanoma to have shown a significant improvement of disease-free survival and in some prospective randomized trials, also an impact on OS, albeit with significant toxicity [
      • Pehamberger H.
      • Soyer H.P.
      • Steiner A.
      • Kofler R.
      • Binder M.
      • Mischer P.
      • et al.
      Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group.
      ,
      • Garbe C.
      • Radny P.
      • Linse R.
      • Dummer R.
      • Gutzmer R.
      • Ulrich J.
      • et al.
      Adjuvant low-dose interferon {alpha}2a with or without dacarbazine compared with surgery alone: a prospective-randomized phase III DeCOG trial in melanoma patients with regional lymph node metastasis.
      ,
      • Kleeberg U.R.
      • Suciu S.
      • Brocker E.B.
      • Ruiter D.J.
      • Chartier C.
      • Lienard D.
      • et al.
      Final results of the EORTC 18871/DKG 80-1 randomised phase III trial. rIFN-alpha2b versus rIFN-gamma versus ISCADOR M versus observation after surgery in melanoma patients with either high-risk primary (thickness >3 mm) or regional lymph node metastasis.
      ,
      • Hancock B.W.
      • Wheatley K.
      • Harris S.
      • Ives N.
      • Harrison G.
      • Horsman J.M.
      • et al.
      Adjuvant interferon in high-risk melanoma: the AIM HIGH Study–United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon Alfa-2a in high-risk resected malignant melanoma.
      ,
      • Cascinelli N.
      • Belli F.
      • MacKie R.M.
      • Santinami M.
      • Bufalino R.
      • Morabito A.
      Effect of long-term adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: a randomised trial.
      ,
      • Cameron D.A.
      • Cornbleet M.C.
      • Mackie R.M.
      • Hunter J.A.
      • Gore M.
      • Hancock B.
      • et al.
      Adjuvant interferon alpha 2b in high risk melanoma - the Scottish study.
      ,
      • Kirkwood J.M.
      • Ibrahim J.G.
      • Sondak V.K.
      • Richards J.
      • Flaherty L.E.
      • Ernstoff M.S.
      • et al.
      High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190.
      ,
      • Grob J.J.
      • Dreno B.
      • de la Salmoniere P.
      • Delaunay M.
      • Cupissol D.
      • Guillot B.
      • et al.
      Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. French Cooperative Group on Melanoma.
      ,
      • Hansson J.
      • Aamdal S.
      • Bastholt L.
      • Brandberg Y.
      • Hernberg M.
      • Nilsson B.
      • et al.
      Two different durations of adjuvant therapy with intermediate-dose interferon alfa-2b in patients with high-risk melanoma (Nordic IFN trial): a randomised phase 3 trial.
      ,
      • Eggermont A.M.
      • Suciu S.
      • MacKie R.
      • Ruka W.
      • Testori A.
      • Kruit W.
      • et al.
      Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial.
      ,
      • Kirkwood J.M.
      • Strawderman M.H.
      • Ernstoff M.S.
      • Smith T.J.
      • Borden E.C.
      • Blum R.H.
      Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684.
      ,
      • Creagan E.T.
      • Dalton R.J.
      • Ahmann D.L.
      • Jung S.H.
      • Morton R.F.
      • Langdon Jr., R.M.
      • et al.
      Randomized, surgical adjuvant clinical trial of recombinant interferon alfa-2a in selected patients with malignant melanoma.
      ,
      • Eggermont A.M.
      • Suciu S.
      • Santinami M.
      • Testori A.
      • Kruit W.H.
      • Marsden J.
      • et al.
      Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial.
      ]. Based on the superior data for adjuvant therapy with PD-1 or BRAF/MEK inhibitors (see below), interferon-α should not be used anymore as a first-line option for adjuvant therapy in this patients’ group.

      3.3 Adjuvant immunotherapy with CTLA-4 or PD-1 antibodies in stage III and resected stage IV disease

      Based on its successful use in unresectable metastatic melanoma, PD-1-based immunotherapy was evaluated in the adjuvant treatment of completely resected high-risk primary or locoregional or distant metastatic patients. The following adjuvant immunotherapy trials were conducted (see also Table 1):
      Table 1Key parameters of adjuvant trials with immune checkpoint inhibitors or BRAF/MEK inhibitors that led to approvals.
      TrialTreatment

      arm
      Comparator armPatient

      population
      Patients after complete resection of metastases, all trials used AJCC 7th edition.
      HR for RFS/DFSHR for OSGrade 3–4 AEs in %
      Any AEs regardless of treatment relation.
      Reference
      EORTC

      18,071
      Approved only by the FDA.


      CheckMate 029
      Ipilimumab 10 mg/kgPlaceboIIIA (>1 mm)/B/C0.760.7254[
      • Eggermont A.M.
      • Chiarion-Sileni V.
      • Grob J.J.
      • Dummer R.
      • Wolchok J.D.
      • Schmidt H.
      • et al.
      Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial.
      ,
      • Eggermont A.M.
      • Chiarion-Sileni V.
      • Grob J.J.
      • Dummer R.
      • Wolchok J.D.
      • Schmidt H.
      • et al.
      Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy.
      ]
      CheckMate 238Nivolumab 3 mg/kgIpilimumab 10 mg/kgIIIB/C-IV0.720.8625.4[
      • Weber J.
      • Mandala M.
      • Del Vecchio M.
      • Gogas H.J.
      • Arance A.M.
      • Cowey C.L.
      • et al.
      Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma.
      ]
      EORTC 1325 KEYNOTE 054Pembrolizumab 200 mgPlaceboIIIA (>1 mm)/B/C0.57NA31.6[
      • Eggermont A.M.
      • Blank C.U.
      • Mandalà M.
      • Long G.V.
      • Atkinson V.
      • Dalle S.
      • et al.
      Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: new recurrence-free survival results from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial at three-year median follow-up.
      ]
      COMBI ADDabrafenib 150 mg BID & Trametinib 2 mg ODPlaceboIIIA (>1 mm)/B/C0.510.5741[
      • Long G.V.
      • Hauschild A.
      • Santinami M.
      • Atkinson V.
      • Mandala M.
      • Chiarion-Sileni V.
      • et al.
      Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma.
      ,
      • Hauschild A.
      • Dummer R.
      • Schadendorf D.
      • Santinami M.
      • Atkinson V.
      • Mandala M.
      • et al.
      Longer follow-up confirms relapse-free survival benefit with adjuvant dabrafenib plus trametinib in patients with resected BRAF V600-mutant stage III melanoma.
      ]
      £ result not statistically significant.
      a Patients after complete resection of metastases, all trials used AJCC 7th edition.
      b Any AEs regardless of treatment relation.
      c Approved only by the FDA.
      Ipilimumab: EORTC 18071/CheckMate 029 [
      • Eggermont A.M.
      • Chiarion-Sileni V.
      • Grob J.J.
      • Dummer R.
      • Wolchok J.D.
      • Schmidt H.
      • et al.
      Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial.
      ] compared the CTLA-4 blocking antibody ipilimumab 10 mg/kg given every three weeks for the first 12 weeks followed by an infusion every 12 weeks for up to three years vs. placebo in patients with stage IIIA (>1 mm)/B/C (AJCC 7th edition) [
      • Balch C.M.
      • Gershenwald J.E.
      • Soong S.-J.
      • Thompson J.F.
      • Atkins M.B.
      • Byrd D.R.
      • et al.
      Final version of 2009 AJCC melanoma staging and classification.
      ]. The final data of this trial have been published. With a median OS follow-up of 6.9 years, the RFS (HR 0.75, 95% confidence interval 0.63–0.88; P < 0.001), DMFS (HR 0.76, 0.64–0.90; P = 0.002), and OS (HR 0.73, 0.60–0.89; P = 0.002) benefit observed in the ipilimumab group was durable with an 8.7% absolute difference at seven years for OS [
      • Eggermont A.M.M.
      • Chiarion-Sileni V.
      • Grob J.J.
      • Dummer R.
      • Wolchok J.D.
      • Schmidt H.
      • et al.
      Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial.
      ]. Adjuvant ipilimumab 10 mg/kg was associated with immune-related adverse events (irAEs) in 94% of the patients, and 5 patients died. Concerns about toxicity resulted in limited uptake of this treatment, which was approved by the US-Food and Drug Administration (FDA) and not by European Medicines Agency (EMA).
      Nivolumab: Based on the results of EORTC 18071 trial, adjuvant therapy with nivolumab 3 mg/kg every two weeks for one year was compared to ipilimumab 10 mg/kg in the CheckMate 238 trial [
      • Weber J.
      • Mandala M.
      • Del Vecchio M.
      • Gogas H.J.
      • Arance A.M.
      • Cowey C.L.
      • et al.
      Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma.
      ] in patients with completely resected stage IIIB/C-IV (AJCC 7th edition) [
      • Balch C.M.
      • Gershenwald J.E.
      • Soong S.-J.
      • Thompson J.F.
      • Atkins M.B.
      • Byrd D.R.
      • et al.
      Final version of 2009 AJCC melanoma staging and classification.
      ]. Recently presented five-year results confirm that nivolumab was superior to ipilimumab with a HR of RFS of 0.72 (95% CI; 0.60–0.85) and DMFS HR 0.79 (95% CI: 0.63–0.99) [
      • Ascierto P.A.
      • Del Vecchio M.
      • Mandalá M.
      • Gogas H.
      • Arance A.M.
      • Dalle S.
      • et al.
      Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial.
      ]. OS results showed a non-significant benefit for nivolumab HR 0.86 (95% CI: 0.66–1.12). OS will likely have been impacted by second-line therapies, and it is important to remember that ipilimumab was an active comparator. In addition, this study included patients with resected stage IV disease. As for the safety, grade 3 or 4 adverse events (AE) were reported in 14.4% of the patients in the nivolumab arm compared to 45.9% of those in the ipilimumab group. Serious adverse events (SAE) of any grade were reported in 17.5% of the patients treated with nivolumab group and in 40.4% of patients receiving ipilimumab.
      Pembrolizumab: Pembrolizumab 200 mg every three weeks for one year was tested against placebo in EORTC1325/KEYNOTE 054 trial [
      • Eggermont A.M.M.
      • Blank C.U.
      • Mandala M.
      • Long G.V.
      • Atkinson V.
      • Dalle S.
      • et al.
      Adjuvant pembrolizumab versus placebo in resected stage III melanoma.
      ] in patients with stage IIIA (>1 mm)/B/C (AJCC 7th edition) [
      • Balch C.M.
      • Gershenwald J.E.
      • Soong S.-J.
      • Thompson J.F.
      • Atkins M.B.
      • Byrd D.R.
      • et al.
      Final version of 2009 AJCC melanoma staging and classification.
      ]. With a median follow-up of 3.5 years, RFS was significantly improved with a HR of 0.59, and an RFS rate difference at 36 months of 20% [
      • Eggermont A.M.
      • Blank C.U.
      • Mandalà M.
      • Long G.V.
      • Atkinson V.
      • Dalle S.
      • et al.
      Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: new recurrence-free survival results from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial at three-year median follow-up.
      ]. Distant metastases survival was also improved with a HR of 0.60 and differed by 16.7% at 36 months [
      • Eggermont CUB A.M.M.
      • Mandala M.
      • Long G.V.
      • Victoria Atkinson V.
      • Dalle S.
      • Haydon A.M.
      • et al.
      LBA46 - pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: final results regarding distant metastasis-free survival from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial.
      ]. This trial did have a crossover design allowing patients who progressed in the placebo arm to receive pembrolizumab either as adjuvant therapy following a second round of surgery or in the unresectable metastatic setting. Of 298 patients who relapsed in the placebo arm, 155 received pembrolizumab within the study protocol, 50 with resected stage III disease, and 105 with unresectable stage III/IV disease. The overall response rate (ORR) in inoperable stage IV was 38.8% and 32% of these patients were free from progression at 36 months of follow-up with no significant difference between resected and unresectable metastatic patients, just showing an expected PFS rate to anti-PD-1 in those who never received it [
      • Eggermont A.M.
      • Meshcheryakov A.
      • Atkinson V.
      • Blank C.U.
      • Mandalà M.
      • Long G.V.
      • et al.
      Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase 3 trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma.
      ]. The real measure of this crossover would be a comparison of the OS in those who were treated early in adjuvant compared to those treated later at relapse. Regarding safety, AEs of any grade were reported in 77.8% of the patients receiving pembrolizumab and in 66.1% of the patient's receiving placebo. Grade 3, 4, or 5 AE occurred in 14.7% of the patients in the pembrolizumab arm and in 3.4% in the placebo arm, with one death in the pembrolizumab arm due to myositis.
      Ipilimumab and Nivolumab: CheckMate 915 trial tested a combination of nivolumab at 240 mg every two weeks and ipilimumab at 1 mg/kg every six weeks for one year against nivolumab 480 mg every four weeks in 1844 patients with completely resected stage IIIB, C, and IV melanoma. This study failed to demonstrate a significant difference in its dual endpoints of RFS in the ITT population and in patients with a tumor PD-L1 < 1%, respectively [
      • Long G.V.S.D.
      • Del Vecchio M.
      • et al.
      Adjuvant therapy with nivolumab combined with ipilimumab vs nivolumab alone in patients with resected stage IIIB-D/IV melanoma (CheckMate 915).
      ]. The combination therapy was associated with more toxicity than nivolumab alone. The rates of grade 3 or 4 AE were 33% with the combination vs. 13% with nivolumab; 19% of the patients in the combination arm discontinued therapy due to AE compared to 6% in the nivolumab arm. Four treatment-related deaths were reported with nivolumab plus ipilimumab and none with nivolumab alone.
      In the phase II study ImmuNED, 167 patients with stage IV melanoma without evidence of disease following surgery or radiotherapy were randomized to receive one year of either ipilimumab 3 mg/kg plus nivolumab 1 mg/kg for four doses every three weeks followed by nivolumab 3 mg/kg every two weeks; nivolumab 3 mg/kg every two weeks; or placebo. Although the median time on treatment was only 6.5 weeks in the ipilimumab and nivolumab arm, with treatment discontinuation being mostly due to high-grade toxicity, RFS after 24 months was 70% for nivolumab plus ipilimumab, compared to 42% for nivolumab and 14% for placebo, resulting in a HR of 0.23 for nivolumab plus ipilimumab over placebo [
      • Zimmer L.
      • Livingstone E.
      • Hassel J.C.
      • Fluck M.
      • Eigentler T.
      • Loquai C.
      • et al.
      Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial.
      ]. In the nivolumab plus ipilimumab arm, 71% of patients experienced treatment-related grade 3–4 AEs compared to 27% in the nivolumab arm; 62% of the patients discontinued treatment due to AE in the combination arm, compared to 13% in the nivolumab arm and there were no treatment-related deaths. Based on these results, adjuvant nivolumab plus ipilimumab can be offered to selected high-risk patients with stage IV NED melanoma following complete resection or radiotherapy, although toxicity is a major consideration.

      3.4 Adjuvant-targeted therapy with BRAF/MEK inhibitors

      Two large-sized, prospectively randomized trials on either the BRAF inhibitor vemurafenib alone (BRIM8) or the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib (COMBI-AD) have been performed in patients with completely resected BRAF V600 mutated melanoma with locoregionally metastases (see also Table 1).
      Vemurafenib: BRIM8 [
      • Maio M.
      • Lewis K.
      • Demidov L.
      • Mandala M.
      • Bondarenko I.
      • Ascierto P.A.
      • et al.
      Adjuvant vemurafenib in resected, BRAF(V600) mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.
      ] was a trial designed before combined treatment with BRAF and MEK inhibitors became the standard of care for BRAF mutated melanoma. It compared one year of treatment with vemurafenib 960 mg BID vs. placebo in patients with completely resected BRAF V600 mutated melanoma in stages IIC, IIIA/B (cohort I), and IIIC (cohort II, all AJCC 7th edition) [
      • Balch C.M.
      • Gershenwald J.E.
      • Soong S.-J.
      • Thompson J.F.
      • Atkins M.B.
      • Byrd D.R.
      • et al.
      Final version of 2009 AJCC melanoma staging and classification.
      ]. This study did not reach its primary endpoint as defined by the statistical plan, although it seemed to show improvement for cohort I.
      Dabrafenib plus trametinib: The COMBI-AD trial [
      • Long G.V.
      • Hauschild A.
      • Santinami M.
      • Atkinson V.
      • Mandala M.
      • Chiarion-Sileni V.
      • et al.
      Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma.
      ] compared one year of the combination of 150 mg dabrafenib BID with 2 mg trametinib OD (D + T) against a matched placebo in patients with stage IIIA (>1 mm)/B/C melanoma with a BRAF-V600  E/K mutation. It demonstrated a highly significant benefit in RFS with a HR of 0.51 at five-year and a RFS rate difference of 16% [
      • Hauschild A.
      • Dummer R.
      • Santinami M.
      • Atkinson V.
      • Mandalà M.
      • Kirkwood J.M.
      • et al.
      Long-term benefit of adjuvant dabrafenib + trametinib (D+T) in patients (pts) with resected stage III BRAF V600–mutant melanoma: Five-year analysis of COMBI-AD.
      ]. An early assessment of OS differences at a median follow-up of 2.8 years did demonstrate an improvement in OS for D + T with a HR of 0.57 and a 13% difference in OS rates at three years, considered not significant. This is so far the only adjuvant study with published data on the improvement of OS.
      The D + T combination was associated with pyrexia grade 1–2 in 97% with chills in 37% and grade 3–4 pyrexia in 5%. Grade 3–4 events occurred in 41% of the patients, i.e., hypertension (6%), fatigue (4%), and hepatitis (4%). Drug-related AEs lead to drug discontinuation in 26% of patients. There were no drug-related deaths. The high rate of pyrexia associated with D + T can be reduced by using the management algorithm investigated in the COMBI-Aplus trial. In this trial, D + T was interrupted promptly at the onset of pyrexia (temperature ≥38 °C), and if suspected recurrent pyrexia, D + T could be interrupted in the presence of pyrexia syndrome (i.e., chills, rigors, night sweats, or influenza-like symptoms without temperature ≥38 °C), at investigators’ discretion. The trial met its primary endpoint of reducing grade 3/4 pyrexia, pyrexia-related hospitalization, and treatment discontinuation, apparently without compromising therapy efficacy [
      • Atkinson V.
      • Robert C.
      • Grob J.-J.
      • Gogas H.
      • Dutriaux C.
      • Demidov L.V.
      • et al.
      Improved pyrexia-related outcomes associated with an adapted pyrexia adverse event (AE) management algorithm in patients (pts) treated with adjuvant dabrafenib + trametinib (dab + tram): primary results of COMBI-APlus.
      ].

      3.5 Current approval status

      The clinical trials mentioned above recruited only high-risk patients in stage III, meaning that patients with stage IIIA melanoma could only be included if the metastasis in the SLNB had more than 1 mm. However, adjuvant therapies are approved in all stage III sub-stages.

      3.6 Adjuvant therapy in stage II disease

      Pembrolizumab 200 mg for one year was compared against placebo in more than 900 patients with stage IIB and IIC melanoma in KEYNOTE 716 trial [
      • Luke PR J.J.
      • Queirolo P.
      • Del Vecchio M.
      • Mackiewicz J.
      • Chiarion Sileni V.
      • de la Cruz Merino L.
      • et al.
      LBA3 PR - pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: efficacy and safety results from the KEYNOTE-716 double-blind phase III trial.
      ]. With a median follow-up of 20.5 months, RFS did show a significant improvement with an HR of 0.61 and 86 vs. 77% of patients being free of relapse in the pembrolizumab and placebo arms at 18 months, respectively. Subgroup analyses so far show the highest benefit with an HR of 0.4 is in patients with T3b melanoma. In patients with stage IIC melanoma, an HR of 0.82 was reported. These early data resulted in the approval of adjuvant pembrolizumab n stage II by the FDA, and EMA approval is expected in the near future. Regarding safety, grade ≥3 drug-related AEs occurred in 16.1% of the patients receiving pembrolizumab compared to 4.3% receiving placebo. Treatment discontinuation associated with AE was seen in 15.3% and 2.5% of the patients, respectively. Immune-mediated AEs, mostly grade 1 and 2, occurred in 36.2% of the patients in the pembrolizumab arm compared to 8.4% in the placebo arm. The most commonly reported immune-mediated AE were hypothyroidism (15.7% vs. 3.5%) and hyperthyroidism (10.4% vs. 0.6%).
      A phase III study evaluating the role of 12 months of nivolumab in stage IIB and IIC vs. placebo (CheckMate 76 K, NCT04099251) has completed accrual, and another one that will test the use of BRAF/MEK inhibitors (COLUMBUS-AD-EORTC 1902) is shortly to open.

      3.7 Future directions

      Presently, there are two main directions. One is trying to increase the efficiency and toxicity/efficacy ratio of adjuvant therapies. Current adjuvant studies in completely resected stage III disease test combinations of nivolumab and the LAG3-antibody relatlimab (Relativity 098, NCT05002569) or nivolumab and the pegylated Il-2 molecule bempegaldesleukin (Pivot 12, NCT04410445) vs. anti-PD-1 monotherapy.
      Tabled 1Recommendation 21
      Adjuvant therapy in stage III/IVEvidence-based recommendation
      Level of recommendation AAdjuvant therapy (anti-PD-1 or targeted therapy) shall be offered to all patients in resected stages IIIA – IIID.

      Adjuvant anti-PD-1 therapy shall be offered to patients in resected stages IIIA - IIID irrespective of the mutational status.

      Adjuvant BRAF/MEK inhibitor therapy shall be offered to patients with BRAFV600  E/K mutation in resected stages IIIA – IIID.

      For fully resected stage IV melanoma patients, nivolumab can be offered regardless of mutation status.
      Level of evidence: 1 bDe novo literature research [
      • Weber J.
      • Mandala M.
      • Del Vecchio M.
      • Gogas H.J.
      • Arance A.M.
      • Cowey C.L.
      • et al.
      Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma.
      ,
      • Long G.V.
      • Hauschild A.
      • Santinami M.
      • Atkinson V.
      • Mandala M.
      • Chiarion-Sileni V.
      • et al.
      Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma.
      ,
      • Eggermont A.M.M.
      • Blank C.U.
      • Mandala M.
      • Long G.V.
      • Atkinson V.
      • Dalle S.
      • et al.
      Adjuvant pembrolizumab versus placebo in resected stage III melanoma.
      ]
      Consensus rate: 100%
      Tabled 1Recommendation 22
      Adjuvant therapy in stage III/IVEvidence-based recommendation
      Level of recommendation BFor stage IIIA with nodal metastasis of less than 1 mm in diameter, the uncertainty of the individual risk/benefit ratio should be carefully discussed with the patients.
      Level of evidence: 1 bDe novo literature research [
      • Weber J.
      • Mandala M.
      • Del Vecchio M.
      • Gogas H.J.
      • Arance A.M.
      • Cowey C.L.
      • et al.
      Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma.
      ,
      • Long G.V.
      • Hauschild A.
      • Santinami M.
      • Atkinson V.
      • Mandala M.
      • Chiarion-Sileni V.
      • et al.
      Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma.
      ,
      • Eggermont A.M.M.
      • Blank C.U.
      • Mandala M.
      • Long G.V.
      • Atkinson V.
      • Dalle S.
      • et al.
      Adjuvant pembrolizumab versus placebo in resected stage III melanoma.
      ]
      Consensus rate: 100%

      4. Neoadjuvant therapy

      Patients with resectable metastases, particularly clinical stage III melanoma (lymph node macro-metastases and/or skin metastasis) can be candidates for receiving a medical treatment before surgery. They might benefit from a neoadjuvant approach in different ways. The goal of neoadjuvant treatment could be firstly to limit the aggressiveness of the surgery if lesions are shrinking by the given treatment. Secondly, a personalization of adjuvant treatment management based on the assessment of the neoadjuvant therapy response might be feasible. Thirdly and ideally, a neoadjuvant treatment could lead to a complete response confirmed by histopathology and therefore major surgery might not be mandatory at all. Besides these potential benefits for the patient, a neoadjuvant treatment is the perfect setting for testing new drugs with the ability of investigating tissue biomarkers at baseline, and after investigational treatments when tumor is resected.
      Since melanoma is a disease with frequent skin and lymph node metastases, it is a prototype for a rational drug development based on neoadjuvant treatment results.
      A pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC) [
      • Menzies A.M.
      • Amaria R.N.
      • Rozeman E.A.
      • Huang A.C.
      • Tetzlaff M.T.
      • van de Wiel B.A.
      • et al.
      Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC).
      ] evaluated six available clinical trials on either anti-PD-1-based immunotherapies (PD-1-antibodies alone or ipilimumab plus nivolumab) and BRAF/MEK inhibitors. A total of 192 patients were included, of whom 141 received immunotherapies. The vast majority of patients (n = 104) were treated with the combination of ipilimumab (1 mg/kg) and nivolumab (3 mg/kg). The approved dose of 1 mg/kg nivolumab plus 3 mg/kg of ipilimumab was previously evaluated in the OpACIN-neo trial [
      • Rozeman E.A.
      • Menzies A.M.
      • van Akkooi A.C.J.
      • Adhikari C.
      • Bierman C.
      • van de Wiel B.A.
      • et al.
      Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial.
      ]. However, this dose showed to have a higher toxicity compared to the reduced dose of ipilimumab, without added efficacy. Therefore, the lower dose of ipilimumab was chosen for future trials. In the pooled analysis, a pathological complete response (pCR) occurred in 40% of all patients: 47% with BRAF/MEK inhibitors and 33% with immunotherapies. However, the combined immune checkpoint inhibition demonstrated a response rate of 43% in contrast to only 20% response rate in the monotherapy of anti-PD-1-antibodies. The pCR rate correlated with the improved RFS (pCR two-year: 89% vs. no pCR 50%, p < 0.001) and OS (pCR two-year OS 95% vs. no pCR 83%, p = 0.027). Very few relapses have been observed in patients with pCR, near pCR, or partial pathologically confirmed responses with immunotherapies. The two-year RFS rate for those patients was 96%. In contrast, the two-year RFS for the targeted agents was only 79% and the OS 91% [
      • Amaria R.N.
      • Postow M.A.
      • Tetzlaff M.T.
      • Ross M.I.
      • Glitza I.C.
      • McQuade J.L.
      • et al.
      Neoadjuvant and adjuvant nivolumab (nivo) with anti-LAG3 antibody relatlimab (rela) for patients (pts) with resectable clinical stage III melanoma.
      ]. A small pilot study on the LAG-3 antibody relatlimab in combination with nivolumab for patients with AJCC stage IIIB/IIIC and D and stage IV M1a (fully resected) used only two infusions four weeks apart. The pathologically confirmed complete response rate after eight weeks in 30 melanoma patients was 52%, another 7% had an almost pCR, and 7% a pPR. However, in this particular clinical trial, all patients received a postoperative adjuvant treatment for ten months with relatlimab and nivolumab additionally. Therefore, the long-term trial results need to be considered as a combination of neoadjuvant plus adjuvant treatment. After 16 months of follow-up, 93% of the patients remained disease-free and 95% of the patients were still alive. If there was a pCR or near pCR, the RFS rate was 100%. The neoadjuvant proportion of the treatment was excellently tolerated with no grade 3/4 toxicities after eight weeks. However, in the adjuvant phase of the trial, 26% grade 3/4 toxicities were reported. There were no new safety signals.
      To summarize, a number of small neoadjuvant trials have consistently shown that the neoadjuvant approach is working. Additionally, it was demonstrated that immunotherapy works better than targeted therapy, which gives high response rates, but with a lower durability. Furthermore, it was observed that combination of nivolumab plus ipilimumab is better than monotherapy with anti-PD-1 single agent, and that initial pathological response is highly predictive of RFS.

      4.1 The future of neoadjuvant therapy

      There are a number of other neoadjuvant trials underway. One direction is to use intralesional immune drugs since they are particularly adapted to the management of accessible tumors. This is the case of T-VEC or L910-IL2; Daromun. Another direction is to improve efficacy and toxicity/efficacy ratio of current neoadjuvant therapy, using combinations of anti-PD-1 and anti-LAG 3, for instance. A final direction is to collect information to design integrated strategies to best combine the neoadjuvant, adjuvant, and surgical approaches of the regional disease. In this regard, several trials are ongoing or planned comparing the efficacy of neoadjuvant therapy to adjuvant therapy and the combination of the two, or assessing the possibility to condition the surgery or the adjuvant treatment to the initial response to neoadjuvant treatment.
      Neoadjuvant treatments are not yet a standard of care because there is a lack of prospective randomized clinical trials to demonstrate a superiority of neoadjuvant approaches over conventional surgery plus postoperative adjuvant treatment. However, with a careful discussion in tumor boards, some patients may already benefit of a treatment that is no more than a medical treatment of a regional disease. Currently, there are two neoadjuvant trials ongoing. The phase III Nadina trial (NCT04949113) is comparing routine TLND followed by routine anti-PD-1 adjuvant therapy with two courses of neoadjuvant combination of nivolumab plus ipilimumab, followed by surgery. Another ongoing trial is the phase II SWOG 1801 study, examining routine TLND followed by adjuvant pembrolizumab (maximum of 18 courses) to neoadjuvant pembrolizumab (three courses), followed by TLND and subsequent adjuvant pembrolizumab (15 courses).

      5. Systemic therapy for metastatic disease

      In the last decade, the increased knowledge about signaling pathways associated with tumor development and progression, and the molecular mechanisms of signaling and controlling of the immune system transformed the survival outcomes of melanoma patients [
      • Chapman P.B.
      • Hauschild A.
      • Robert C.
      • Haanen J.B.
      • Ascierto P.
      • Larkin J.
      • et al.
      Improved survival with vemurafenib in melanoma with BRAF V600E mutation.
      ,
      • Hodi F.S.
      • O'Day S.J.
      • McDermott D.F.
      • Weber R.W.
      • Sosman J.A.
      • Haanen J.B.
      • et al.
      Improved survival with ipilimumab in patients with metastatic melanoma.
      ]. Indeed, these advances were responsible for increasing the RFS, DMFS, PFS, and OS in advanced melanoma patients in the last decade [
      • Schadendorf D.
      • van Akkooi A.C.J.
      • Berking C.
      • Griewank K.G.
      • Gutzmer R.
      • Hauschild A.
      • et al.
      ]. Despite all these advances, many stage IV patients do not benefit from these systemic therapies and died from the disease [
      • Amaral T.
      • Seeber O.
      • Mersi E.
      • Sanchez S.
      • Thomas I.
      • Meiwes A.
      • et al.
      Primary resistance to PD-1-based immunotherapy-A study in 319 patients with stage IV melanoma.
      ]. Inclusion in clinical trials is an important therapeutic option and should be offered to all eligible patients.

      5.1 Immune checkpoint inhibitors

      5.1.1 Monotherapy with anti-CTLA-4 and anti-PD-1

      Blockade of immune checkpoint mechanisms with antibodies to CTLA-4 and PD-1 expressed by lymphocytes abrogates down-regulation of immune responses and leads to continued activation of lymphocytes, enabling killing of tumor cells. This immunostimulation is non-specific and can lead to immunologically mediated toxicity. The anti-CTLA-4 antibody ipilimumab was the first immunotherapy that showed an OS benefit in two controlled trials in metastatic melanoma [
      • Hodi F.S.
      • O'Day S.J.
      • McDermott D.F.
      • Weber R.W.
      • Sosman J.A.
      • Haanen J.B.
      • et al.
      Improved survival with ipilimumab in patients with metastatic melanoma.
      ,
      • Morton D.L.M.N.
      • Thompson J.F.
      • et al.
      An international, randomized, phase III trial of bacillus Calmette-Guerin (BCG) plus allogeneic melanoma vaccine (MCV) or placebo after complete resection of melanoma metastatic to regional or distant sites.
      ,
      • Ko J.M.
      • Fisher D.E.
      A new era: melanoma genetics and therapeutics.
      ,
      • Sosman J.A.
      • Kim K.B.
      • Schuchter L.
      • Gonzalez R.
      • Pavlick A.C.
      • Weber J.S.
      • et al.
      Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib.
      ,
      • Greger J.G.
      • Eastman S.D.
      • Zhang V.
      • Bleam M.R.
      • Hughes A.M.
      • Smitheman K.N.
      • et al.
      Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations.
      ,
      • Falchook G.S.
      • Long G.V.
      • Kurzrock R.
      • Kim K.B.
      • Arkenau T.H.
      • Brown M.P.
      • et al.
      Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial.
      ,
      • Long G.V.
      • Trefzer U.
      • Davies M.A.
      • Kefford R.F.
      • Ascierto P.A.
      • Chapman P.B.
      • et al.
      Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial.
      ,
      • Robert C.
      • Thomas L.
      • Bondarenko I.
      • O'Day S.
      • Weber J.
      • Garbe C.
      • et al.
      Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.
      ]. Ipilimumab is approved for the treatment of stage IV melanoma both by the FDA and EMA. It is presently administered as four intravenous infusions at a dose of 3 mg/kg/infusion separated by three weeks. Serious immune-related AE, including skin rashes, colitis, thyroiditis, hepatitis, hypophysitis, and others can develop in some patients and require interdisciplinary management. Early recognition of these side effects is essential and requires specific training of the treating physicians [
      • Champiat S.
      • Lambotte O.
      • Barreau E.
      • Belkhir R.
      • Berdelou A.
      • Carbonnel F.
      • et al.
      Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper.
      ,
      • Haanen J.B.A.G.
      • Carbonnel F.
      • Robert C.
      • Kerr K.M.
      • Peters S.
      • Larkin J.
      • et al.
      Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ].
      The response rate to ipilimumab is only about 15%, but remarkable durable remissions were observed in stage IV patients previously treated with other drugs [
      • Schadendorf D.
      • Hodi F.S.
      • Robert C.
      • Weber J.S.
      • Margolin K.
      • Hamid O.
      • et al.
      Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma.
      ]. Patients with stable disease or initial disease progression can also benefit from prolonged survival. Meanwhile, the introduction of PD-1 antibodies changed the role of ipilimumab, which is no longer considered as the treatment of choice for first-line therapy. Currently, ipilimumab is used in combination with PD-1 antibodies or as second-line therapy.
      The anti-PD-1 antibodies nivolumab and pembrolizumab are approved by both FDA and EMA for the treatment of unresectable melanoma. Nivolumab was shown to improve PFS and OS as compared to dacarbazine (CheckMate-066 trial [
      • Robert C.
      • Long G.V.
      • Brady B.
      • Dutriaux C.
      • Maio M.
      • Mortier L.
      • et al.
      Nivolumab in previously untreated melanoma without BRAF mutation.
      ]) and as compared to ipilimumab (CheckMate-067 trial [
      • Hodi F.S.
      • Chiarion-Sileni V.
      • Gonzalez R.
      • Grob J.J.
      • Rutkowski P.
      • Cowey C.L.
      • et al.
      Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial.
      ]). Pembrolizumab showed improved PFS and OS in comparison with ipilimumab (KEYNOTE-006 trial [
      • Pires da Silva I.
      • Ahmed T.
      • Reijers I.L.M.
      • Weppler A.M.
      • Betof Warner A.
      • Patrinely J.R.
      • et al.
      Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study.
      ]). Objective response rates of 35%–42% were achieved with PD-1 blockade. Long-term survival data after five years are available and show a survival rate of 34% for any-line treatment (KEYNOTE-001 trial) and 43% for treatment-naïve patients (KEYNOTE-006) [
      • Hamid O.
      • Robert C.
      • Daud A.
      • Hodi F.S.
      • Hwu W.J.
      • Kefford R.
      • et al.
      Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.
      ,
      • Pires da Silva I.
      • Ahmed T.
      • Reijers I.L.M.
      • Weppler A.M.
      • Betof Warner A.
      • Patrinely J.R.
      • et al.
      Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study.
      ] During the Society for Melanoma Research (SMR) 2021 Congress, an update of the KEYNOTE-066 trial with seven-year follow-up showed that the median OS for pembrolizumab and ipilimumab was 32.7 and 15.9 months (HR = 0.70; 95% CI, 0.58–0.83) and the seven-year OS rates were 37.8% and 25.3%, respectively. This exploratory analysis showed that pembrolizumab was associated with improved clinical outcomes regardless of BRAF status, prior BRAF/MEK inhibitors therapy, high LDH level, larger tumor size, or presence of brain metastases.
      PD-1 blockade is considered an effective option for the first-line treatment of patients with both BRAF wild-type and BRAF mutated tumors. The dose of nivolumab and pembrolizumab depends on which type of administration schema is used (Table 2). Both a body surface-based dose or a flat dose can be offered. The difference between these options is the frequency of the therapy, and patients’ preferences and potential previous toxicities should be taken into consideration when discussing which schedule to choose [
      • Long G.V.
      • Tykodi S.S.
      • Schneider J.G.
      • Garbe C.
      • Gravis G.
      • Rashford M.
      • et al.
      Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer.
      ,
      • Lala M.
      • Li M.
      • Sinha V.
      • de Alwis D.
      • Chartash E.
      • Jain L.
      A six-weekly (Q6W) dosing schedule for pembrolizumab based on an exposure-response (E-R) evaluation using modeling and simulation.
      ,
      • Freshwater T.
      • Kondic A.
      • Ahamadi M.
      • Li C.H.
      • de Greef R.
      • de Alwis D.
      • et al.
      Evaluation of dosing strategy for pembrolizumab for oncology indications.
      ,
      • Lala M.
      • Li T.R.
      • de Alwis D.P.
      • Sinha V.
      • Mayawala K.
      • Yamamoto N.
      • et al.
      A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation.
      ].
      Table 2Checkpoint blockade therapies for advanced cutaneous melanoma described in prospective randomized trials.
      SubstanceDoseResponse rateOverall survival
      Ipilimumab [
      • Hodi F.S.
      • O'Day S.J.
      • McDermott D.F.
      • Weber R.W.
      • Sosman J.A.
      • Haanen J.B.
      • et al.
      Improved survival with ipilimumab in patients with metastatic melanoma.
      ,
      • Robert C.
      • Thomas L.
      • Bondarenko I.
      • O'Day S.
      • Weber J.
      • Garbe C.
      • et al.
      Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.
      ,
      • Schadendorf D.
      • Hodi F.S.
      • Robert C.
      • Weber J.S.
      • Margolin K.
      • Hamid O.
      • et al.
      Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma.
      ]
      3 mg/kg i.v. every three weeks for four cycles12–19%3 y OS 22%
      Nivolumab [
      • Robert C.
      • Long G.V.
      • Brady B.
      • Dutriaux C.
      • Maio M.
      • Mortier L.
      • et al.
      Nivolumab in previously untreated melanoma without BRAF mutation.
      ,
      • Topalian S.L.
      • Hodi F.S.
      • Brahmer J.R.
      • Gettinger S.N.
      • Smith D.C.
      • McDermott D.F.
      • et al.
      Safety, activity, and immune correlates of anti–PD-1 antibody in cancer.
      ]
      3 mg/kg i.v. every two weeks until tumor progression40%–44%
      Nivolumab [
      • Long G.V.
      • Tykodi S.S.
      • Schneider J.G.
      • Garbe C.
      • Gravis G.
      • Rashford M.
      • et al.
      Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer.
      ]
      480 mg i.v. every four weeks (flat dose) until tumor progression
      Pembrolizumab [
      • Robert C.
      • Schachter J.
      • Long G.V.
      • Arance A.
      • Grob J.J.
      • Mortier L.
      • et al.
      Pembrolizumab versus ipilimumab in advanced melanoma.
      ] + update KEYNOTE 006 SMR 21 (ref)
      2 mg/kg i.v. every three weeks until tumor progression33%7 y OS 37.8%
      Pembrolizumab [
      • Lala M.
      • Li M.
      • Sinha V.
      • de Alwis D.
      • Chartash E.
      • Jain L.
      A six-weekly (Q6W) dosing schedule for pembrolizumab based on an exposure-response (E-R) evaluation using modeling and simulation.
      ,
      • Freshwater T.
      • Kondic A.
      • Ahamadi M.
      • Li C.H.
      • de Greef R.
      • de Alwis D.
      • et al.
      Evaluation of dosing strategy for pembrolizumab for oncology indications.
      ,
      • Lala M.
      • Li T.R.
      • de Alwis D.P.
      • Sinha V.
      • Mayawala K.
      • Yamamoto N.
      • et al.
      A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation.
      ]
      400 mg i.v. every six weeks (flat dose) until tumor progression

      200 mg i.v. every three weeks (flat dose) until tumor progression
      Nivolumab + Ipilimumab [
      • Hodi F.S.
      • Chiarion-Sileni V.
      • Gonzalez R.
      • Grob J.J.
      • Rutkowski P.
      • Cowey C.L.
      • et al.
      Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial.
      ,
      • Larkin J.
      • Hodi F.S.
      • Wolchok J.D.
      Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.
      ]
      Ipilimumab 3 mg/kg i.v. plus nivolumab 1 mg/kg i.v. every three weeks for four cycles, continuation with 3 mg/kg nivolumab every two weeks until tumor progression49%6.5 y OS 49%
      Nivolumab + Ipilimumab [
      • Lebbé C.
      • Meyer N.
      • Mortier L.
      • Marquez-Rodas I.
      • Robert C.
      • Rutkowski P.
      • et al.
      Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: results from the phase IIIb/IV CheckMate 511 trial.
      ,
      • Lebbe C.
      • Meyer N.
      • Mortier L.
      • Marquez-Rodas I.
      • Robert C.
      • Rutkowski P.
      • et al.
      Two dosing regimens of nivolumab (NIVO) plus ipilimumab (IPI) for advanced (adv) melanoma: three-year results of CheckMate 511.
      ]
      Ipilimumab 1 mg/kg i.v. plus nivolumab 3 mg/kg i.v. every three weeks for four cycles, continuation with 3 mg/kg nivolumab every two weeks until tumor progression59%3 y OS 59%
      Pembrolizumab + ipilimumab (KEYNOTE 029) (ref)Pembrolizumab 2 mg/kg every three weeks for 24 months plus four doses ipilimumab 1 mg/kg every three weeks (part 1 B)65.8%5 y OS 68.3%
      Pembrolizumab 200 mg every three weeks for 24 months plus four doses ipilimumab 50 mg every six weeks (part 1C arm A)69.9%3 y OS74.3%
      Pembrolizumab 200 mg every three weeks for 24 months plus four doses ipilimumab 100 mg every 12 weeks (part 1C arm B)76.7%3 y OS 70.4%

      5.1.2 Anti-PD-1 plus anti-CTLA-4

      The combination of nivolumab with ipilimumab has shown to be superior, in terms of PFS, to ipilimumab and to nivolumab as single drugs (CheckMate-067 trial [
      • Hodi F.S.
      • Chiarion-Sileni V.
      • Gonzalez R.
      • Grob J.J.
      • Rutkowski P.
      • Cowey C.L.
      • et al.
      Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial.
      ]) and is therefore approved by FDA and EMA. OS data showed a trend, but no significance in comparison with nivolumab monotherapy with the combination only. The long-term survival data after 4, 5, and 6.5 years indicate the excellent therapeutic potential with a durable, sustained survival benefit and a hope for cure, both with nivolumab alone and the combination approach [
      • Hodi F.S.
      • Chiarion-Sileni V.
      • Gonzalez R.
      • Grob J.J.
      • Rutkowski P.
      • Cowey C.L.
      • et al.
      Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial.
      ,
      • Larkin J.
      • Chiarion-Sileni V.
      • Gonzalez R.
      • Grob J.-J.
      • Rutkowski P.
      • Lao C.D.
      • et al.
      Five-year survival with combined nivolumab and ipilimumab in advanced melanoma.
      ,
      • Wolchok J.D.
      • Chiarion-Sileni V.
      • Gonzalez R.
      • Grob J.-J.
      • Rutkowski P.
      • Lao C.D.
      • et al.
      CheckMate 067: 6.5-year outcomes in patients (pts) with advanced melanoma.
      ]. Because there is substantially more toxicity, including irreversible AEs, with the nivolumab plus ipilimumab combination this treatment needs to be supervised by experienced physicians, who are familiar with irAE management procedures.
      CheckMate 511 evaluated the difference in toxicity between ipilimumab 3 mg/kg plus nivolumab 1 mg/kg vs. ipilimumab 1 mg/kg plus nivolumab of 3 mg/kg for four cycles followed by nivolumab 480 mg every 4weeks [
      • Lebbé C.
      • Meyer N.
      • Mortier L.
      • Marquez-Rodas I.
      • Robert C.
      • Rutkowski P.
      • et al.
      Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: results from the phase IIIb/IV CheckMate 511 trial.
      ,
      • Lebbé C.
      • Meyer N.
      • Mortier L.
      • Marquez-Rodas I.
      • Robert C.
      • Rutkowski P.
      • et al.
      Initial results from a phase IIIb/IV study evaluating two dosing regimens of nivolumab (NIVO) in combination with ipilimumab (IPI) in patients with advanced melanoma (CheckMate 511).
      ]. The grade 3/4 toxicity was reduced by half, while the efficacy was largely the same in both regimens. The updated data with a median follow-up of more than 40 months show that ipilimumab 1 mg/kg plus nivolumab 3 mg/kg continue to demonstrate an improved safety profile compared with ipilimumab 3 mg/kg plus nivolumab 1 mg/kg. In the descriptive analyses, both groups demonstrated high and similar 3-year OS rates [
      • Lebbe C.
      • Meyer N.
      • Mortier L.
      • Marquez-Rodas I.
      • Robert C.
      • Rutkowski P.
      • et al.
      Two dosing regimens of nivolumab (NIVO) plus ipilimumab (IPI) for advanced (adv) melanoma: three-year results of CheckMate 511.
      ]. Based on these data, many centers European centers have adopted this practice.
      Finally, the KEYNOTE-029 trial investigated the combination of the standard dose of pembrolizumab with an alternate dose of ipilimumab in patients with advanced melanoma [
      • Long G.V.
      • Robert C.
      • Butler M.O.
      • Couture F.
      • Carlino M.S.
      • Day S.
      • et al.
      Standard-dose pembrolizumab plus alternate-dose ipilimumab in advanced melanoma: KEYNOTE-029 cohort 1C, a phase 2 randomized study of two dosing schedules.
      ]. In part 1 B, patients with or without previous systemic therapies received pembrolizumab 3 mg/kg every three weeks for 24 months and four doses of ipilimumab 1 mg/kg every three weeks. In part 1C, therapy naïve patients were randomized to receive pembrolizumab 200 mg every three weeks for 24 months and four doses of ipilimumab 50 mg every six weeks (arm A) or pembrolizumab 200 mg every three weeks for 24 months and four doses of ipilimumab 100 mg every 12 weeks (arm B). The last update of this trial showed that the five-year OS rate was 68.3% for part 1 B, and the duration of response for more than 48 months was 86.2%. For part C, the three-year OS was 74.3% in arm A and 70.4% in arm B, and the duration of response for more than 36 months was 82.3% and 78.7%, respectively. In terms of safety, combination therapy was well tolerated, but ipilimumab 50 mg every six weeks led to fewer grade 3–5 treatment-related AE than the regimen of ipilimumab 100 mg every 12 weeks. In part 1C, one patient in arm A died of treatment-related autoimmune myocarditis.
      Presently, there are no predictive biomarkers for PD-1-based immunotherapy. The assessment of PD-L1 expression as a predictive factor was investigated in the CheckMate 067 trial [
      • Wolchok J.D.
      • Chiarion-Sileni V.
      • Gonzalez R.
      • Rutkowski P.
      • Grob J.-J.
      • Cowey C.L.
      • et al.
      Overall survival with combined nivolumab and ipilimumab in advanced melanoma.
      ]. Currently, available data did not show significant differences in OS according to PD-L1 expression. Therefore, PD-L1 expression determination should not be mandatory and should not be considered for therapeutic decisions in stage IV melanoma.

      5.2 Targeted therapy

      In melanoma, different activating mutations have been described, mainly resulting in an increased signaling of the MAP kinase and AKT pathways [
      • Ko J.M.
      • Fisher D.E.
      A new era: melanoma genetics and therapeutics.
      ]. About 45% of patients with cutaneous melanoma carry an activating BRAF V600 mutation, for which several highly selective inhibitors have been developed. Vemurafenib and dabrafenib were shown to achieve a high rapid tumor response rate (roughly 50%) in patients carrying the BRAFV600E mutation and a substantial prolongation of PFS and OS in comparison with dacarbazine (DTIC) [
      • Chapman P.B.
      • Hauschild A.
      • Robert C.
      • Haanen J.B.
      • Ascierto P.
      • Larkin J.
      • et al.
      Improved survival with vemurafenib in melanoma with BRAF V600E mutation.
      ,
      • Hodi F.S.
      • O'Day S.J.
      • McDermott D.F.
      • Weber R.W.
      • Sosman J.A.
      • Haanen J.B.
      • et al.
      Improved survival with ipilimumab in patients with metastatic melanoma.
      ,
      • Ko J.M.
      • Fisher D.E.
      A new era: melanoma genetics and therapeutics.
      ,
      • Sosman J.A.
      • Kim K.B.
      • Schuchter L.
      • Gonzalez R.
      • Pavlick A.C.
      • Weber J.S.
      • et al.
      Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib.
      ]. Vemurafenib and dabrafenib are approved for melanoma therapy in the USA and the EU. Systemic (arthralgia and fatigue) and cutaneous AEs have been reported, including photosensitivity (only vemurafenib), development of epithelial tumors, and in rare cases new primary melanomas. Development of secondary resistance to BRAF inhibitors with varying time courses is a frequent event. MEK inhibitors supplement the inhibition of the MAP kinase pathway. Combinations of BRAF and MEK inhibitors like vemurafenib/cobimetinib (coBRIM trial [
      • Ascierto P.A.
      • McArthur G.A.
      • Dreno B.
      • Atkinson V.
      • Liszkay G.
      • Di Giacomo A.M.
      • et al.
      Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial.
      ]), dabrafenib/trametinib (COMBI-d, COMBI-v [
      • Robert C.
      • Grob J.J.
      • Stroyakovskiy D.
      • Karaszewska B.
      • Hauschild A.
      • Levchenko E.
      • et al.
      Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma.
      ,
      • Grob J.J.
      • Amonkar M.M.
      • Karaszewska B.
      • Schachter J.
      • Dummer R.
      • Mackiewicz A.
      • et al.
      Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial.
      ]), and encorafenib/binimetinib (COLUMBUS [
      • Dummer R.
      • Ascierto P.A.
      • Gogas H.J.
      • Arance A.
      • Mandala M.
      • Liszkay G.
      • et al.
      Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial.
      ,
      • Ascierto P.A.
      • Dummer R.
      • Gogas H.J.
      • Flaherty K.T.
      • Arance A.
      • Mandala M.
      • et al.
      Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma.
      ]) were able to show a significantly increased objective response rate, PFS, and OS in four independent phase III trials (Table 3). A pooled analysis of COMBI-d/v reported that the five-year OS rate was 34% for patients treated with dabrafenib plus trametinib. In patients with normal LDH levels at baseline, this increased to 41%. The median OS for the combination was 25.1 months in the COMBI-d study and 26.1 months in the COMBI-v study, and the median PFS was 11.1 and 11.4 months, respectively [
      • Robert C.
      • Grob J.J.
      • Stroyakovskiy D.
      • Karaszewska B.
      • Hauschild A.
      • Levchenko E.
      • et al.
      Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma.
      ]. Currently, the five-year OS data are also available for the co-BRIM and COLUMBUS study.
      Table 3Targeted therapy for advanced cutaneous melanoma described in prospective randomized trials or phase II studies, if phase III trials were not available.
      SubstanceDoseResponse rateOverall survival
      BRAF mutation
      Dabrafenib + Trametinib

      [
      • Robert C.
      • Karaszewska B.
      • Schachter J.
      • Rutkowski P.
      • Mackiewicz A.
      • Stroiakovski D.
      • et al.
      Improved overall survival in melanoma with combined dabrafenib and trametinib.
      ,
      • Long G.V.
      • Stroyakovsky D.L.
      • Gogas H.
      • Levchenko E.
      • de Braud F.
      • Larkin J.M.G.
      • et al.
      COMBI-d: a randomized, double-blinded, Phase III study comparing the combination of dabrafenib and trametinib to dabrafenib and trametinib placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAFV600E/K mutation-positive cutaneous melanoma.
      ]
      2 × 150 mg p.o. daily

      1 × 2 mg p.o. daily
      64%–67%5 y OS 34%
      Vemurafenib + Cobimetinib [
      • Ascierto P.A.
      • McArthur G.A.
      • Dreno B.
      • Atkinson V.
      • Liszkay G.
      • Di Giacomo A.M.
      • et al.
      Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial.
      ,
      • Larkin J.
      • Ascierto P.A.
      • Dreno B.
      • Atkinson V.
      • Liszkay G.
      • Maio M.
      • et al.
      Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.
      ,
      • Ribas A.
      • Gonzalez R.
      • Pavlick A.
      • Hamid O.
      • Gajewski T.F.
      • Daud A.
      • et al.
      Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study.
      ]
      2 × 960 mg p.o. daily

      1 × 60 mg p.o, daily for 21 days, followed by 7 days off treatment
      54–68%5 y OS 30.8%
      Encorafenib + Binimetinib [
      • Dummer R.
      • Ascierto P.A.
      • Gogas H.J.
      • Arance A.
      • Mandala M.
      • Liszkay G.
      • et al.
      Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial.
      ,
      • Ascierto P.A.
      • Dummer R.
      • Gogas H.J.
      • Flaherty K.T.
      • Arance A.
      • Mandala M.
      • et al.
      Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma.
      ,
      • Dummer R.
      • Ascierto P.A.
      • Gogas H.
      • Arance A.M.
      • Mandalà M.
      • Liszkay G.
      • et al.
      Overall survival in COLUMBUS: a phase 3 trial of encorafenib (ENCO) plus binimetinib (BINI) vs vemurafenib (VEM) or enco in BRAF-mutant melanoma.
      ]
      1 × 450 mg p.o. daily

      2 × 45 mg p.o. daily
      68–76%5 y OS 34.7%
      cKIT mutation
      Imatinib mesylate [
      • Guo J.
      • Si L.
      • Kong Y.
      • Flaherty K.T.
      • Xu X.
      • Zhu Y.
      • et al.
      Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification.
      ]
      1 × 400 mg p.o. daily until tumor progression23%
      NRAS mutation
      Binimetinib

      [
      • Dummer R.
      • Schadendorf D.
      • Ascierto P.A.
      • Arance A.
      • Dutriaux C.
      • Di Giacomo A.M.
      • et al.
      Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial.
      ,
      • Dummer R.
      • Arenberger P.
      • Ascierto P.A.
      • De Groot J.W.
      • Hallmeyer S.
      • Lotem M.
      • et al.
      1130TiP- NEMO: a phase 3 trial OF binimetinib (MEK162) versus dacarbazine IN patients with advanced NRAS-mutant melanoma who are untreated or have progressed after any number of immunotherapy regimens.
      ]
      2 × 45 mg (3 × 15 mg tablets) p.o. daily until tumor progression15%
      In the co-BRIM study, and after a median follow-up of 21.2 months for the cobimetinib plus vemurafenib arm and 16.6 months for the vemurafenib arm, the median OS was 22.5 months and 17.4 months, respectively (95% CI: 20.3–28.8 and 15.0–19.8). The 5-year OS rates were 31% for the combination therapy and 26% for the monotherapy. As for the median PFS, it was 12.6 months for patients receiving cobimetinib plus vemurafenib and 7.2 months for patients receiving vemurafenib (95% CI: 9.5–14.8 and 5.6–7.5). The five-year PFS rates were 14% and 10%, respectively. Also in this study, the OS and PFS were longer in patients with normal baseline LDH levels and low tumor burden, but also in those with complete response [
      • Ascierto P.A.
      • Dréno B.
      • Larkin J.
      • Ribas A.
      • Liszkay G.
      • Maio M.
      • et al.
      5-Year outcomes with cobimetinib plus vemurafenib in BRAF (V600) mutation-positive advanced melanoma: extended follow-up of the coBRIM study.
      ].
      In the COLUMBUS study and for patients receiving encorafenib plus binimetinib, the median OS and five-year OS rate were 33.6 months and 34.7%, respectively (95%CI: 24.4–39.2 months and 28.0–41.5%). The five-year PFS rate was 22.9% with a median duration of response of 18.6 months. For patients with normal baseline LDH levels, the five-year OS rate was 45.1% (95%CI: 36.5–53.2). Patients receiving encorafenib 300 mg QD and vemurafenib monotherapy had worse survival outcomes and shorter median duration of response [
      • Dummer R.
      • Flaherty K.
      • Robert C.
      • Arance A.M.
      • Groot JWd
      • Garbe C.
      • et al.
      Five-year overall survival (OS) in COLUMBUS: a randomized phase 3 trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients (pts) with BRAF V600-mutant melanoma.
      ].
      A small proportion of melanomas arising in sun-protected sites have mutations in cKIT and they have been treated with the cKIT inhibitor imatinib-mesylate. Responses have been described in case reports and a phase II trial showed an objective response rate of 23% in patients with cKIT mutated melanoma (Table 3) [
      • Guo J.
      • Si L.
      • Kong Y.
      • Flaherty K.T.
      • Xu X.
      • Zhu Y.
      • et al.
      Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification.
      ]. There is significant variability in response rate and response duration. This is probably due to the significant number of different c-Kit mutations and the lack of consistency of response even when the same mutation is present.
      An NRAS mutation is detected in 15–20% of cutaneous melanomas. Presently, there are no effective NRAS-inhibiting molecules available. Trials have been performed investigating MEK inhibitors like binimetinib (NEMO trial [
      • Dummer R.
      • Schadendorf D.
      • Ascierto P.A.
      • Arance A.
      • Dutriaux C.
      • Di Giacomo A.M.
      • et al.
      Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial.
      ]) and pimasertib (NCT01693068) in this setting. A low response rate has been observed with no significant impact on OS. Furthermore, the MEK inhibitor binimetinib appeared to be more toxic than a single-agent treatment with conventional DTIC chemotherapy [
      • Dummer R.
      • Schadendorf D.
      • Ascierto P.A.
      • Arance A.
      • Dutriaux C.
      • Di Giacomo A.M.
      • et al.
      Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial.
      ].

      5.3 Therapy sequence in BRAF mutated melanoma

      Patients with BRAF mutated tumors may be offered therapy with PD-1-based immunotherapy or BRAF/MEK inhibitors. An indirect comparison of 26 trials representative of these two treatment strategies in advanced metastatic melanoma was published by Ugurel et al in 2020 [
      • Ugurel S.
      • Röhmel J.
      • Ascierto P.A.
      • Becker J.C.
      • Flaherty K.T.
      • Grob J.J.
      • et al.
      Survival of patients with advanced metastatic melanoma: the impact of MAP kinase pathway inhibition and immune checkpoint inhibition - update 2019.
      ]. In first-line setting, the averaged three-year OS proportions were 58.4% for CTLA-4 plus anti-PD-1, 49.9% for anti-PD-1, and 41.3% for BRAF/MEK. For second line or later, combined BRAF/MEK was superior to PD-1 monotherapy in the first three years; averaged three-year OS proportions were 42.4% for BRAF/MEK, and 40.1% for PD-1 inhibitors.
      In order to prospectively answer the question, the phase II SECOMBIT trial, investigated three different therapeutic approaches in this subgroup of patients, using combined targeted therapy with encorafenib plus binimetinib and nivolumab plus ipilimumab. In arm A, patients received encorafenib plus binimetinib until progression followed by combined immunotherapy; in arm B, patients received combined immunotherapy first until progressive disease, followed by combined targeted therapy; in arm C, patients received encorafenib plus binimetinib for eight weeks, followed by combined immunotherapy until progression, followed by combined targeted therapy. The last update with a median follow-up of 32.2 months was presented in the ESMO21 congress. The mOS was not reached in either arm. The three-year OS rate was 54%, 62%, and 60% in arms A, B, and C, respectively, and the three-year PFS rate was 41%, 53%, and 54% in arms A, B, and C, respectively [
      • Ascierto P.A.
      • Mandala M.
      • Ferrucci P.F.
      • Rutkowski P.
      • Guidoboni M.
      • Arance Fernandez A.M.
      • et al.
      LBA40 - SECOMBIT: the best sequential approach with combo immunotherapy ipilimumab (I)/nivolumab (N) and combo target therapy encorafenib (E)/binimetinib (B) in patients with BRAF mutated metastatic melanoma: a phase II randomized study.
      ].
      The phase III DREAMSeq trial also investigated the best sequence in patients with BRAFV600 mutated melanoma [
      • Atkins M.B.
      • Lee S.J.
      • Chmielowski B.
      • Ribas A.
      • Tarhini A.A.
      • Truong T.-G.
      • et al.
      DREAMseq (doublet, randomized evaluation in advanced melanoma sequencing): a phase III trial—ECOG-ACRIN EA6134.
      ]. Therapy naïve stage IV melanoma patients with BRAFV600 mutation were randomized 1:1 to receive either nivolumab plus ipilimumab (arm A) or dabrafenib plus trametinib (arm B) until disease progression. In this case, patients were then enrolled into the second phase of the study to receive the alternate therapy – combined targeted therapy (arm C) or combined immunotherapy (arm D).
      Long-term OS was higher in patients receiving combined immunotherapy (arm A) followed by targeted therapy (arm C) than in the reverse sequence. The two-year OS rate for patients starting in arm A was 72% and 52% for those starting with arm B. Increased OS was seen after ten months, indicating the importance of switching to targeted therapy salvage in the small percentage of patients with rapid progression on first-line immunotherapy.

      5.4 Talimogene laherperepvec

      T-VEC is an oncolytic viral therapy approved for the local treatment of unresectable metastatic stage IIIB/C–IVM1a melanoma.
      The MASTERKEY-265 is a phase III randomized trial that investigated the treatment with pembrolizumab with or without T-VEC in unresectable, treatment naïve stage IIIb/IVM1c melanoma patients. Patients with BRAF mutated melanoma previously treated with one BRAF/MEK combination were also included. Patients were randomized 1:1 to receive T-VEC plus pembrolizumab or placebo plus pembrolizumab, and the primary endpoint was PFS by blinded independent central review or OS. The final results were presented showing that the mPFS for T-VEC plus pembrolizumab and pembrolizumab alone was 14.3 months and 8.5 months, respectively (95%CI: 10.25–22.11 and 5.72–13.54; HR 0.86 (95% CI 0.71, 1.04), P = 0.13). The mOS was not reached in the combination arm and was 49.2 months in the pembrolizumab arm (40.57-NR; HR 0.96 (95% CI 0.76, 1.22), P = 0.74). No new safety issues were reported. In conclusion, the addition of T-VEC to pembrolizumab did not improve PFS or OS compared to pembrolizumab alone [
      • Gogas H.J.
      • Ribas A.
      • Chesney J.
      • Long G.V.
      • Kirkwood J.M.
      • Dummer R.
      • et al.
      1037O - MASTERKEY-265: a phase III, randomized, placebo (Pbo)-controlled study of talimogene laherparepvec (T) plus pembrolizumab (P) for unresectable stage IIIB–IVM1c melanoma (MEL).
      ].
      Currently, it is unclear what is the place for the combined therapy of T-VEC and anti-PD-1. However, based on the data OPTiM trial, T-VEC can continue to be offered to patients with unresectable stage IIIB-IVM1c melanoma [
      • Andtbacka R.H.I.
      • Collichio F.
      • Harrington K.J.
      • Middleton M.R.
      • Downey G.
      • Ӧhrling K.
      • et al.
      Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma.
      ].

      5.4.1 Anti-LAG3

      The RELATIVTY-047 trial is a phase III trial that investigates the first-line relatlimab plus nivolumab vs. nivolumab alone in patients with advanced melanoma [
      • Lipson E.J.
      • Tawbi H.A.-H.
      • Schadendorf D.
      • Ascierto P.A.
      • Matamala L.
      • Gutiérrez E.C.
      • et al.
      Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-047 (CA224-047).
      ]. Lymphocyte-activation gene 3 (LAG 3) is an immune checkpoint that inhibits T-cell activity and is upregulated in several tumor types, including melanoma. Relatlimab is a human anti-LAG-3 that restores the effector function of exhausted T-cells. In this trial, patients were randomized to receive a fixed-dose combination of relatlimab 160 mg plus nivolumab 480 mg every four weeks (RELA + NIVO FDC) or nivolumab monotherapy, until progression or unacceptable toxicity. The primary endpoint was PFS by blinded independent central review, and the secondary endpoints were OS and ORR. The first results showed that the median PFS was 10.1 months in the RELA + NIVO FDC group (95% CI: 6.4–15.7) and 4.6 months in the monotherapy group (95% CI: 3.4–5.6; HR 0.75; 95% CI, 0.6–0.9; p = 0.0055). The incidence of grade 3 or 4 treatment-related AE was higher in the combination arm (18.9% vs. 9.7%).
      An exploratory analysis was later presented showing the potential benefit in terms of subgroups and beyond initial treatment [
      • Hodi HAT F.S.
      • Lipson E.J.
      • Schadendorf D.
      • Ascierto P.A.
      • Matamala L.
      • Gutiérrez E.C.
      • et al.
      1036O - relatlimab (RELA) + nivolumab (NIVO) vs. NIVO in previously untreated metastatic or unresectable melanoma: additional efficacy in RELATIVITY-047.
      ]. Data on PFS 2 – time from randomization to progression after the next line of systemic therapy, per investigator assessment, or death – were also presented. The median PFS2 was not reached for RELA + NIVO FDC (95% CI 21.8–NA) and was 20 months in the nivolumab arm (95%CI: 15.4–25.1); HR 0.77 (95% CI 0.61–0.97). Finally, patients treated with RELA + NIVO FDC had a longer treatment-free interval compared to those receiving nivolumab monotherapy, i.e., 3.98 months vs. 1.45 months (95%CI: 2.10–7.43 and 1.25–171, respectively; HR 0.63; 95%CI 0.48–0.83).
      With these data, two questions arise:
      • (1)
        How can we select patients to receive RELA + NIVO FDC, as the benefit for RELA + NIVO FDC was seen regardless of LAG-3 expression.
      • (2)
        Where should we place this combination when comparing with the results of CheckMate-067, CheckMate-511, and KEYNOTE-029 trials? Here, more mature data are needed, especially OS data, before a recommendation can be given.
      • (3)
        Is nivolumab monotherapy still standard of care? Also, when comparing (indirect comparison) the median PFS data from the nivolumab arm in the RELATIVITY-047 trial and the CheckMate-067, the results are numerically different, with patients in the nivolumab arm of the CheckMate 067 doing better than those treated in the RELATIVITY-047 trial (mPFS was 6.9 months and 4.6 months (95% CI 5.1–9.7 and 3.4–5.6, respectively).

      5.5 Chemotherapy

      Before targeted and immunotherapies became available, chemotherapy was the only systemic treatment that could be offered to stage IV melanoma patients. Presently, chemotherapy may only be considered as last-line treatment in patients with resistance to immunotherapies and – where applicable – targeted therapies and/or if participation in a clinical trial is not available [
      • Goldinger S.M.
      • Buder-Bakhaya K.
      • Lo S.N.
      • Forschner A.
      • McKean M.
      • Zimmer L.
      • et al.
      Chemotherapy after immune checkpoint inhibitor failure in metastatic melanoma: a retrospective multicentre analysis.
      ]. However, single-agent and combination chemotherapy may still play a role in countries where the new and more effective drugs are still not available and/or reimbursed. Finally, chemotherapy can also be considered in particular situations of patients without BRAF mutation and who developed severe toxicity to immune checkpoint inhibitors.
      Tabled 1Recommendation 23
      Immunotherapy in stage IVEvidence-based recommendation
      Level of recommendation AIn stage IV patients, immunotherapy with checkpoint inhibitors shall be offered as first-line, irrespective of BRAF status. The options include anti-PD-1 monotherapy and combination of anti-PD-1 plus anti-CTLA-4 (in different doses and schedules).

      PD-L1 expression determination should not be mandatory and should not be considered for therapeutic decisions in stage IV melanoma.
      Level of evidence: 1aDe novo literature research [
      • Robert C.
      • Long G.V.
      • Brady B.
      • Dutriaux C.
      • Maio M.
      • Mortier L.
      • et al.
      Nivolumab in previously untreated melanoma without BRAF mutation.
      ,
      • Lala M.
      • Li T.R.
      • de Alwis D.P.
      • Sinha V.
      • Mayawala K.
      • Yamamoto N.
      • et al.
      A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation.
      ,
      • Larkin J.
      • Chiarion-Sileni V.
      • Gonzalez R.
      • Grob J.-J.
      • Rutkowski P.
      • Lao C.D.
      • et al.
      Five-year survival with combined nivolumab and ipilimumab in advanced melanoma.
      ,
      • Wolchok J.D.
      • Chiarion-Sileni V.
      • Gonzalez R.
      • Grob J.-J.
      • Rutkowski P.
      • Lao C.D.
      • et al.
      CheckMate 067: 6.5-year outcomes in patients (pts) with advanced melanoma.
      ,
      • Lebbé C.
      • Meyer N.
      • Mortier L.
      • Marquez-Rodas I.
      • Robert C.
      • Rutkowski P.
      • et al.
      Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: results from the phase IIIb/IV CheckMate 511 trial.
      ,
      • Lebbe C.
      • Meyer N.
      • Mortier L.
      • Marquez-Rodas I.
      • Robert C.
      • Rutkowski P.
      • et al.
      Two dosing regimens of nivolumab (NIVO) plus ipilimumab (IPI) for advanced (adv) melanoma: three-year results of CheckMate 511.
      ,
      • Topalian S.L.
      • Hodi F.S.
      • Brahmer J.R.
      • Gettinger S.N.
      • Smith D.C.
      • McDermott D.F.
      • et al.
      Safety, activity, and immune correlates of anti–PD-1 antibody in cancer.
      ,
      • Robert C.
      • Schachter J.
      • Long G.V.
      • Arance A.
      • Grob J.J.
      • Mortier L.
      • et al.
      Pembrolizumab versus ipilimumab in advanced melanoma.
      ,
      • Larkin J.
      • Hodi F.S.
      • Wolchok J.D.
      Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.
      ]
      Consensus rate: 100%
      Tabled 1Recommendation 24
      Oncolytic viral therapy in advanced melanomaEvidence-based recommendation
      Level of recommendation B:In unresectable stage IIIB/C-IVa melanoma patients, therapy with T-VEC can be recommended.
      Level of evidence: 1 bDe novo literature research [
      • Gogas H.J.
      • Ribas A.
      • Chesney J.
      • Long G.V.
      • Kirkwood J.M.
      • Dummer R.
      • et al.
      1037O - MASTERKEY-265: a phase III, randomized, placebo (Pbo)-controlled study of talimogene laherparepvec (T) plus pembrolizumab (P) for unresectable stage IIIB–IVM1c melanoma (MEL).
      ,
      • Andtbacka R.H.I.
      • Collichio F.
      • Harrington K.J.
      • Middleton M.R.
      • Downey G.
      • Ӧhrling K.
      • et al.
      Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma.
      ]:
      Consensus rate: 85%
      Tabled 1Recommendation 25
      Targeted therapy in stage IVEvidence-based recommendation
      Level of recommendation BIn particular scenarios∗ for patients with stage IV melanoma and a BRAF-V600  E/K mutation, first-line therapy with BRAF/MEK inhibitors should be offered as an alternative to immunotherapy.
      Level of evidence: 1 bDe novo literature research [
      • Ascierto P.A.
      • McArthur G.A.
      • Dreno B.
      • Atkinson V.
      • Liszkay G.
      • Di Giacomo A.M.
      • et al.
      Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial.
      ,
      • Grob J.J.
      • Amonkar M.M.
      • Karaszewska B.
      • Schachter J.
      • Dummer R.
      • Mackiewicz A.
      • et al.
      Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial.
      ,
      • Dummer R.
      • Ascierto P.A.
      • Gogas H.J.
      • Arance A.
      • Mandala M.
      • Liszkay G.
      • et al.
      Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial.
      ,
      • Ascierto P.A.
      • Dummer R.
      • Gogas H.J.
      • Flaherty K.T.
      • Arance A.
      • Mandala M.
      • et al.
      Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma.
      ,
      • Ascierto P.A.
      • Dréno B.
      • Larkin J.
      • Ribas A.
      • Liszkay G.
      • Maio M.
      • et al.
      5-Year outcomes with cobimetinib plus vemurafenib in BRAF (V600) mutation-positive advanced melanoma: extended follow-up of the coBRIM study.
      ,
      • Dummer R.
      • Flaherty K.
      • Robert C.
      • Arance A.M.
      • Groot JWd
      • Garbe C.
      • et al.
      Five-year overall survival (OS) in COLUMBUS: a randomized phase 3 trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients (pts) with BRAF V600-mutant melanoma.
      ,
      • Pires da Silva I.
      • Ahmed T.
      • Reijers I.L.M.
      • Weppler A.M.
      • Betof Warner A.
      • Patrinely J.R.
      • et al.
      Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study.
      ]
      Consensus rate: 100%
      ∗Poor performance status, high LDH, high tumor burden, aggressive course of the disease, symptomatic brain metastases, and patient's preference.
      Tabled 1Recommendation 26
      Targeted therapy in stage IVEvidence-based recommendation
      Level of recommendation AIn patients with resistance to immunotherapy and harboring a BRAF-V600  E/K mutation, BRAF/MEK inhibitors shall be offered in second line.
      Level of evidence: 1 bDe novo literature research [
      • Ascierto P.A.
      • McArthur G.A.
      • Dreno B.
      • Atkinson V.
      • Liszkay G.
      • Di Giacomo A.M.
      • et al.
      Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial.
      ,
      • Grob J.J.
      • Amonkar M.M.
      • Karaszewska B.
      • Schachter J.
      • Dummer R.
      • Mackiewicz A.
      • et al.
      Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial.
      ,
      • Dummer R.
      • Ascierto P.A.
      • Gogas H.J.
      • Arance A.
      • Mandala M.
      • Liszkay G.
      • et al.
      Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial.
      ,
      • Ascierto P.A.
      • Dummer R.
      • Gogas H.J.
      • Flaherty K.T.
      • Arance A.
      • Mandala M.
      • et al.
      Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma.
      ,
      • Ascierto P.A.
      • Dréno B.
      • Larkin J.
      • Ribas A.
      • Liszkay G.
      • Maio M.
      • et al.
      5-Year outcomes with cobimetinib plus vemurafenib in BRAF (V600) mutation-positive advanced melanoma: extended follow-up of the coBRIM study.
      ,
      • Dummer R.
      • Flaherty K.
      • Robert C.
      • Arance A.M.
      • Groot JWd
      • Garbe C.
      • et al.
      Five-year overall survival (OS) in COLUMBUS: a randomized phase 3 trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients (pts) with BRAF V600-mutant melanoma.
      ,
      • Pires da Silva I.
      • Ahmed T.
      • Reijers I.L.M.
      • Weppler A.M.
      • Betof Warner A.
      • Patrinely J.R.
      • et al.
      Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study.
      ]
      Consensus rate: 100%
      Tabled 1Recommendation 27
      Chemotherapy in stage IVConsensus-based recommendation
      GCPChemotherapy can be considered in patients with good PS only when there is resistance to immunotherapy and targeted therapies. The alternative is palliative best supportive care.
      Consensus rate: 100%
      Table 4Examples of monochemotherapy and polychemotherapy for advanced cutaneous melanoma described in prospective randomized trials or phase II studies, if phase III trials were not available.
      MedicationDoseResponse rate
      Dacarbazine [
      • Middleton M.R.
      • Grob J.J.
      • Aaronson N.
      • Fierlbeck G.
      • Tilgen W.
      • Seiter S.
      • et al.
      Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma.
      ,
      • Ringborg U.
      • Rudenstam C.M.
      • Hansson J.
      • Hafstrom L.
      • Stenstam B.
      • Strander H.
      Dacarbazine versus dacarbazine-vindesine in disseminated malignant melanoma: a randomized phase II study.
      ,
      • Chiarion Sileni V.
      • Nortilli R.
      • Aversa S.M.
      • Paccagnella A.
      • Medici M.
      • Corti L.
      • et al.
      Phase II randomized study of dacarbazine, carmustine, cisplatin and tamoxifen versus dacarbazine alone in advanced melanoma patients.
      ,
      • Young A.M.
      • Marsden J.
      • Goodman A.
      • Burton A.
      • Dunn J.A.
      Prospective randomized comparison of dacarbazine (DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in metastatic melanoma.
      ]
      250 mg/m2 i.v. daily for five days every three–four weeks

      800–1200 mg/m2 i.v. daily on one day every three–four weeks
      12.1–17.6%

      5.3–23%
      Temozolomide [
      • Middleton M.R.
      • Grob J.J.
      • Aaronson N.
      • Fierlbeck G.
      • Tilgen W.
      • Seiter S.
      • et al.
      Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma.
      ,
      • Bleehen N.M.
      • Newlands E.S.
      • Lee S.M.
      • Thatcher N.
      • Selby P.
      • Calvert A.H.
      • et al.
      Cancer Research Campaign phase II trial of temozolomide in metastatic melanoma.
      ]
      150–200 mg/m2 p.o. daily for five days every four weeks13.5–21%
      Fotemustine [
      • Jacquillat C.
      • Khayat D.
      • Banzet P.
      • Weil M.
      • Avril M.F.
      • Fumoleau P.
      • et al.
      Chemotherapy by fotemustine in cerebral metastases of disseminated malignant melanoma.
      ,
      • Mornex F.
      • Thomas L.
      • Mohr P.
      • Hauschild A.
      • Delaunay M.M.
      • Lesimple T.
      • et al.
      A prospective randomized multicentre phase III trial of fotemustine plus whole brain irradiation versus fotemustine alone in cerebral metastases of malignant melanoma.
      ]
      100 mg/m2 i.v. on days 1, 8, and 15; then four weeks pause and then repeat single dose every three weeks7.4–24.2%
      CarboTaxol [
      • Rao R.D.
      • Holtan S.G.
      • Ingle J.N.
      • Croghan G.A.
      • Kottschade L.A.
      • Creagan E.T.
      • et al.
      Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma.
      ]
      Carboplatin AUC6 i.v. day 1, after four cycles reduce to AUC4

      Paclitaxel 225 mg/m2 i.v. day 1 every three weeks, after four cycles reduce to 175 mg/m2
      (12.1%

      second line)
      DVC [
      • Verschraegen C.F.
      • Kleeberg U.R.
      • Mulder J.
      • Rumke P.
      • Truchetet F.
      • Czarnetzki B.
      • et al.
      Combination of cisplatin, vindesine, and dacarbazine in advanced malignant melanoma. A phase II study of the EORTC malignant melanoma cooperative group.
      ]
      DTIC 450 mg/m2 i.v. days 1 + 8

      Vindesine 3 mgm2 i.v. days 1 + 8

      Cisplatin 50 mgm2 i.v. days 1 + 8 every three–four weeks
      24%

      5.6 Brief conclusions on stage IV treatment

      Presently, insufficient data are available to establish a comprehensive treatment algorithm for stage IV melanoma. The basic structure of decisions in the therapy of non-resectable melanoma is shown in Fig. 1. That being said some general principles can be applied:
      • The treatment of metastatic melanoma patients should be discussed in interdisciplinary tumor boards with representation from multiple oncology sub-specialties.
      • Mutation testing of tumor tissue (at least a search for BRAF mutations) is a prerequisite for treatment decisions and should be performed preferentially in metastatic tumor tissue from AJCC stage IIIB onward.
      • Further targeted panel sequencing should be offered when available.
      • PD-1 blockade either as monotherapy or in combination with CTLA-4 blockade should be considered for first-line treatment for all patients with unresectable metastatic melanoma and independent from tumor BRAF status. For selected patients, targeted therapy may be a more appropriate first-line if BRAF mutation is present.
      • The combination of BRAF/MEK inhibitors is the standard of care for patients receiving targeted therapies. Monotherapy with BRAF inhibitors alone is not recommended unless MEK inhibitors are contraindicated.
      • Chemotherapy may be considered in patients with a good performance status, who are resistant to targeted therapies and immune checkpoint modulators, or in those with BRAF wild-type tumors who developed severe toxicity to immunotherapy.
      • C-KIT inhibitors may play a minor role in the second-line treatment of CKIT-mutant melanomas if PD-1-antibodies with or without ipilimumab have been used already.
      Fig. 1
      Fig. 1Proposed algorithm for the treatment of stage IV melanoma; in the first-line setting, the treatment priority should be read from left to right.

      5.7 Brain metastasis

      Until 2010, systemic therapy in melanoma brain metastasis was limited to using chemotherapeutic agents (mainly fotemustine) after the failure of local therapies. However, melanoma treatment of brain metastases has seen a recent surge in novel therapeutics, including anti-PD-1 immunotherapy and targeted therapy effective in treating CNS metastases.
      The current standard of care for asymptomatic brain metastases is a systemic therapy. However, ongoing trials might change the landscape of therapeutic options for these patients in the near future.

      5.7.1 Immunotherapy

      In the first trial of immunotherapy for patients with brain metastases, the CTLA-A4 antibody ipilimumab was tested in an open-label phase II study in patients with asymptomatic and symptomatic brain metastases [
      • Margolin K.
      • Ernstoff M.S.
      • Hamid O.
      • Lawrence D.
      • McDermott D.
      • Puzanov I.
      • et al.
      Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial.
      ]. While an intracranial response rate of 16% and long-term benefit were seen in asymptomatic patients, the response rate deteriorated to 5% in symptomatic patients.
      Immunotherapy with PD-1 blocking antibodies or in combination with CTLA-4 blocking monoclonal antibodies has been tested in two recent prospective trials – the CheckMate 204 trial and the ABC trial. The CheckMate 204 study investigated combined immunotherapy with nivolumab and ipilimumab in patients with asymptomatic (cohort A) and symptomatic (cohort B) melanoma brain metastases [
      • Tawbi H.A.
      • Forsyth P.A.
      • Algazi A.
      • Hamid O.
      • Hodi F.S.
      • Moschos S.J.
      • et al.
      Combined nivolumab and ipilimumab in melanoma metastatic to the brain.
      ]. The last updated results from this trial were presented during the ESMO21 congress. In cohort A, the 36 months intracranial PFS rate was 52% (95%CI: 41%–65%), and the OS rate was 72% (95%CI: 62%–80%). In cohort B, the 36 months intracranial PFS rate was 28% (95CI: 10%–50%), and the OS rate was 37% (95%CI: 14%–60%) [
      • Margolin HAT K.A.
      • Forsyth P.A.
      • Hodi F.S.
      • Algazi A.
      • Hamid O.
      • Lao C.D.
      • et al.
      1039MO - CheckMate 204: 3-year outcomes of treatment with combination nivolumab (NIVO) plus ipilimumab (IPI) for patients (pts) with active melanoma brain metastases (MBM).
      ].
      The Australian ABC trial reported similarly outstanding results for combined nivolumab and ipilimumab in asymptomatic patients not requiring steroids [
      • Long G.V.
      • Atkinson V.
      • Lo S.
      • Sandhu S.
      • Guminski A.D.
      • Brown M.P.
      • et al.
      Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study.
      ]. This study investigated immunotherapy in three different cohorts of patients. Patients with asymptomatic brain metastases with no prior local brain therapy were randomized to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, Q3W for four cycles followed by nivolumab 3 mg/kg Q2W (cohort A), or nivolumab 3 mg/kg Q2W (cohort B). Patients with brain metastases who failed local therapy had neurological symptoms and/or with the leptomeningeal disease were treated with nivolumab 3 mg/kg Q2W (cohort C). The last updated data presented during the ASCO21 congress showed that in cohort A, the five-year intracranial PFS rate was 46%, and the five-year OS rate was 51%. For treatment naïve patients, the five-year intracranial PFS rate was 52% with a five-year OS rate of 55% [
      • Long G.V.
      • Atkinson V.
      • Lo S.
      • Guminski A.D.
      • Sandhu S.K.
      • Brown M.P.
      • et al.
      Five-year overall survival from the anti-PD1 brain collaboration (ABC Study): randomized phase 2 study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets).
      ].

      5.7.2 Targeted therapy

      Tabled 1Recommendation 28
      Systemic therapy for brain metastasesConsensus-based recommendation
      Level of recommendation A:In eligible patients with brain metastases, combined immunotherapy shall be offered as first-line therapy.
      Level of evidence: 1 bDe novo literature research [
      • Margolin HAT K.A.
      • Forsyth P.A.
      • Hodi F.S.
      • Algazi A.
      • Hamid O.
      • Lao C.D.
      • et al.
      1039MO - CheckMate 204: 3-year outcomes of treatment with combination nivolumab (NIVO) plus ipilimumab (IPI) for patients (pts) with active melanoma brain metastases (MBM).
      ,
      • Long G.V.
      • Atkinson V.
      • Lo S.
      • Guminski A.D.
      • Sandhu S.K.
      • Brown M.P.
      • et al.
      Five-year overall survival from the anti-PD1 brain collaboration (ABC Study): randomized phase 2 study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets).
      ]:
      Consensus rate: 100%
      Tabled 1Recommendation 29
      Systemic therapy for brain metastasesConsensus-based recommendation
      Level of recommendation C:Targeted therapy can be an alternative in patients with BRAFV600  E/K mutation, especially in symptomatic brain disease.
      Level of evidence: 1 bDe novo literature research [
      • Margolin HAT K.A.
      • Forsyth P.A.
      • Hodi F.S.
      • Algazi A.
      • Hamid O.
      • Lao C.D.
      • et al.
      1039MO - CheckMate 204: 3-year outcomes of treatment with combination nivolumab (NIVO) plus ipilimumab (IPI) for patients (pts) with active melanoma brain metastases (MBM).
      ,
      • Long G.V.
      • Atkinson V.
      • Lo S.
      • Guminski A.D.
      • Sandhu S.K.
      • Brown M.P.
      • et al.
      Five-year overall survival from the anti-PD1 brain collaboration (ABC Study): randomized phase 2 study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets).
      ]:
      Consensus rate: 100%

      5.7.3 Local therapy

      Tabled 1Recommendation 30
      Surgery and radiotherapy for brain metastasesEvidence-based recommendation
      Level of recommendation BEligible patients with brain metastases should be treated with stereotactic radiotherapy. Surgery can be an option when stereotactic radiotherapy is not possible.
      Guideline adaptation [
      • Onkologie L.
      Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): Diagnostik, Therapie und Nachsorge des Melanoms, Langversion 3.1.
      ,
      • Pflugfelder A.
      • Kochs C.
      • Blum A.
      • Capellaro M.
      • Czeschik C.
      • Dettenborn T.
      • et al.
      Malignant melanoma S3-guideline “diagnosis, therapy and follow-up of melanoma”.
      ]
      Consensus rate: 100%
      Tabled 1Recommendation 31
      Whole brain radiotherapy (WBRT)Evidence-based recommendation
      Level of recommendation CWhole brain radiotherapy can no longer be recommended for the treatment of melanoma brain metastases.
      Guideline adaptation [
      • Onkologie L.
      Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): Diagnostik, Therapie und Nachsorge des Melanoms, Langversion 3.1.
      ,
      • Pflugfelder A.
      • Kochs C.
      • Blum A.
      • Capellaro M.
      • Czeschik C.
      • Dettenborn T.
      • et al.
      Malignant melanoma S3-guideline “diagnosis, therapy and follow-up of melanoma”.
      ]
      Consensus rate: 100%

      5.7.4 Combined approaches

      The combination of SRS with systemic therapies (BRAF/MEK inhibition and PD-1-based immunotherapy) has been reported in numerous retrospective studies with improved intracranial control, as well as encouraging PFS and OS data [
      • Amaral T.
      • Kiecker F.
      • Schaefer S.
      • Stege H.
      • Kaehler K.
      • Terheyden P.
      • et al.
      Combined immunotherapy with nivolumab and ipilimumab with and without local therapy in patients with melanoma brain metastasis: a DeCOG∗ study in 380 patients.
      ]. Currently, definitive results from prospective trials investigating the combination of checkpoint inhibitors or BRAF/MEK inhibitors and radiotherapy/surgery are still missing, and the best sequence remains to be determined [
      • Galli G.
      • Cavalieri S.
      • Di Guardo L.
      • Cimminiello C.
      • Nichetti F.
      • Corti F.
      • et al.
      Combination of immunotherapy and brain radiotherapy in metastatic melanoma: a retrospective analysis.
      ,
      • Gonzalez M.
      • Hong A.M.
      • Carlino M.S.
      • Atkinson V.
      • Wang W.
      • Lo S.
      • et al.
      A phase II, open label, randomized controlled trial of nivolumab plus ipilimumab with stereotactic radiotherapy versus ipilimumab plus nivolumab alone in patients with melanoma brain metastases (ABC-X Trial).
      ,
      • Marquez-Rodas I.
      • Arance A.
      • Berciano Guerrero M.A.
      • Díaz Beveridge R.
      • Alamo M.D.C.
      • Garcia Castaño A.
      • et al.
      1038MO - intracranial activity of encorafenib and binimetinib followed by radiotherapy in patients with BRAF mutated melanoma and brain metastasis: preliminary results of the GEM1802/EBRAIN-MEL phase II clinical trial.
      ].

      5.8 Progression after PD-1-based immunotherapy

      Patients with BRAF wild-type melanoma, who do not respond to PD-1-based immunotherapy, particularly to combined anti-PD-1 and anti-CTLA-4, have very limited therapeutic options available. Recently, data evaluating second-line therapies in this setting have been presented. Yet, it is our opinion that inclusion in a clinical trial is still the best option available for this collective of patients.

      5.8.1 PD-1 rechallenge

      Patients treated with anti-PD-1 monotherapy can derive benefit from a second course of anti-PD-1, particularly when they benefited from the first-line therapy, i.e., when response at the time of discontinuation was at least SD. Data from the KEYNOTE 066 trial showed that for patients receiving second-line pembrolizumab, the mOS was 23.5 (16.8–34.2), and the five-year OS rate was 32.3 (25.5–39.3). [
      • Robert C.
      • Ribas A.
      • Schachter J.
      • Arance A.
      • Grob J.-J.
      • Mortier L.
      • et al.
      Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study.
      ] Also, in the CheckMate 067 trial, 152 patients included in the nivolumab arm received subsequently systemic therapy with another immunotherapy (n = 105), namely anti-PD-1 (n = 49) [
      • Larkin J.
      • Chiarion-Sileni V.
      • Gonzalez R.
      • Grob J.-J.
      • Rutkowski P.
      • Lao C.D.
      • et al.
      Five-year survival with combined nivolumab and ipilimumab in advanced melanoma.
      ].

      5.8.2 Ipilimumab and ipilimumab plus anti-PD-1

      Ipilimumab alone or in combination with nivolumab can also be a therapeutic option for patients progressing to PD-1-based immunotherapy. In the KEYNOTE 066 trial, the mOS for second-line ipilimumab was 13.6 months (10.7–22.0), and the five-year OS rate was 27.3% (18.3–37.0).
      In the CheckMate 067 trial, 91 patients in the nivolumab arm received subsequent systemic therapy with ipilimumab, but the survival benefit associated with this second line was not reported. Finally, in a multicenter retrospective analysis, it was shown that after progression under PD-1 therapy combined nivolumab plus ipilimumab resulted in a higher response rate and longer PFS and OS compared to ipilimumab monotherapy, with similar toxicity [
      • Pires da Silva I.
      • Ahmed T.
      • Reijers I.L.M.
      • Weppler A.M.
      • Betof Warner A.
      • Patrinely J.R.
      • et al.
      Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study.
      ]. Therefore, when possible, the combination therapy should be preferred.

      5.8.3 Adoptive T-cell transfer

      Adoptive T-cell transfer (ATT) of tumor-infiltrating lymphocytes represents a potential alternative therapy for resistance to immune checkpoint inhibition, which is currently under development. Ex vivo-expanded tumor-infiltrating lymphocytes (TILs) are administered to lymphodepleted melanoma patients along with high-dose IL-2. High rates of clinical response and long-term survival have been reported for this therapy [
      • Rosenberg S.A.
      • Restifo N.P.
      Adoptive cell transfer as personalized immunotherapy for human cancer.
      ]. Currently, there are no approved TIL-ATT regimens. The process of producing TILs is technically challenging, and concomitant administration of IL-2 is associated with significant toxicity.
      An open-label phase II study was conducted to determine the efficacy and safety of a TIL-ATT (lifileucel) in 66 patients with unresectable metastatic melanoma and progression on anti-PD-1 therapy or BRAF/MEK inhibition [
      • Chesney J.A.
      • Larkin J.M.
      • Kirkwood J.M.
      • Weber J.S.
      • Khushalani N.I.
      • Lewis K.
      • et al.
      Abstract CT008: lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced (unresectable or metastatic) melanoma: durable duration of response at 28 month follow up.
      ]. The study regimen began with a one-week nonmyeloablative lymphodepletion with 60 mg/kg cyclophosphamide and 25 mg/m2 fludarabine, followed by a single infusion of lifileucel. Patients then received up to six doses of interleukin (IL)-2. The median follow-up time was 28.1 months. There was an objective response rate of 36.4%, with a complete response rate of 4.5%. Forty-four percent of patients had stable disease after treatment, for an overall disease control rate of 80.3%. An application for approval has been submitted to the FDA.

      5.8.4 Lenvatinib

      Tabled 1Recommendation 32
      Progression after PD-1-based immunotherapyConsensus-based recommendation
      Level of recommendation B:In patients with resistance to PD-1 monotherapy, combined immunotherapy with anti-PD-1 and anti-CTLA-4 or CTLA-4 monotherapy should be offered.

      In BRAFV600 mutated patients, targeted therapy shall be offered.

      For patients with BRAF wild-type tumors and resistance to combined anti-PD-1 and anti-CTLA-4 immunotherapy, inclusion in a clinical trial is the best therapeutic option.
      Level of evidence: 2De novo literature research [
      • Chesney J.A.
      • Larkin J.M.
      • Kirkwood J.M.
      • Weber J.S.
      • Khushalani N.I.
      • Lewis K.
      • et al.
      Abstract CT008: lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced (unresectable or metastatic) melanoma: durable duration of response at 28 month follow up.
      ,
      • Arance A.M.
      • Cruz-Merino Ldl
      • Petrella T.M.
      • Jamal R.
      • Ny L.
      • Carneiro A.
      • et al.
      Lenvatinib (len) plus pembrolizumab (pembro) for patients (pts) with advanced melanoma and confirmed progression on a PD-1 or PD-L1 inhibitor: updated findings of LEAP-004.
      ]:
      Consensus rate: 100%

      5.9 Acral melanoma

      Acral melanoma is a unique subtype of melanoma occurring on the palms, soles, and nails. Its development is independent of UV exposure, and its frequency is similar in all ethnic populations. The tumor mutation burden (TMB) of acral melanoma is comparatively low and is about one power of ten lower than that of cutaneous melanoma. In a comparative study of metastatic tissue, the TMB was 9.5 mut/mB for cutaneous melanoma and 1.5 mut/mB for acral melanoma [
      • Hilke F.J.
      • Sinnberg T.
      • Gschwind A.
      • Niessner H.
      • Demidov G.
      • Amaral T.
      • et al.
      Distinct mutation patterns reveal melanoma subtypes and influence immunotherapy response in advanced melanoma patients.
      ]. Cutaneous melanoma is induced by UV radiation and therefore carries a high number of mutations leading to an excellent response to immunotherapies. In contrast, the response of acral melanoma to immunotherapy is significantly lower. A meta-analysis of studies on the treatment of metastatic acral melanoma with checkpoint inhibitors showed an objective response rate of 20%, which is significantly higher than with chemotherapy. In acral melanoma, treatment with anti-PD-1 (n = 330) was associated with significantly better OS at 12 months (53%) than patients treated with anti-CTLA-4 therapies (n = 94) (34% survival at 12 months, P < 0.001) [
      • Cho K.K.
      • Cust A.E.
      • Foo Y.M.
      • Long G.V.
      • Menzies A.M.
      • Eslick G.D.
      Metastatic acral melanoma treatment outcomes: a systematic review and meta-analysis.
      ]. The combination therapy of anti-CTLA-4 and anti-PD-1 immunotherapy showed increased efficacy with an objective response rate of 43% as compared to single-agent therapy [
      • Zheng Q.
      • Li J.
      • Zhang H.
      • Wang Y.
      • Zhang S.
      Immune checkpoint inhibitors in advanced acral melanoma: a systematic review.
      ]. Up to 20% of acral melanomas carry a BRAF V600 mutation [
      • Gaiser M.R.
      • Skorokhod A.
      • Gransheier D.
      • Weide B.
      • Koch W.
      • Schif B.
      • et al.
      Variables that influence BRAF mutation probability: a next-generation sequencing, non-interventional investigation of BRAFV600 mutation status in melanoma.
      ]. Therefore, in metastatic acral melanomas, mutation diagnosis should always be performed and the possibility of therapy with BRAF/MEK inhibitors should be considered as in other subtypes of melanoma. cKIT mutations occur in 5–10% of acral melanomas. Treatment with imatinib of advanced melanomas with c-KIT alterations shown some efficacy in terms of ORR – treatment with imatinib had an ORR of 23.3% and with nilotinib an ORR of 26.2% in phase II trials [
      • Teixido C.
      • Castillo P.
      • Martinez-Vila C.
      • Arance A.
      • Alos L.
      Molecular markers and targets in melanoma.
      ]. Treatment of metastatic acral melanoma follows the same recommendations as for other metastatic cutaneous melanomas. In the first line, immunotherapy with PD-1 inhibitors or combined immunotherapy with PD-1 and CTLA-4 inhibitors should be offered. In the second line, BRAF/MEK inhibitors as well as cKIT inhibitors should be used if the corresponding mutations are present.

      5.10 Mucosal melanoma

      The following information is an abbreviated discussion on the therapeutic options for metastatic mucosal melanoma and do not replace detailed guidelines [
      • Nenclares P.
      • Ap Dafydd D.
      • Bagwan I.
      • Begg D.
      • Kerawala C.
      • King E.
      • et al.
      Head and neck mucosal melanoma: the United Kingdom national guidelines.
      ,
      • Smith H.G.
      • Bagwan I.
      • Board R.E.
      • Capper S.
      • Coupland S.E.
      • Glen J.
      • et al.
      Ano-uro-genital mucosal melanoma UK national guidelines.
      ].
      Tabled 1Recommendation 33
      Systemic therapy for mucosal melanomaConsensus-based recommendation
      Level of recommendation B:Patients with metastatic mucosal melanoma should be offered combined immunotherapy with anti-PD-1 and anti-CTLA-4
      Level of evidence: 1 bDe novo literature research [
      • Shoushtari A.N.
      • Wagstaff J.
      • Ascierto P.A.
      • Butler M.O.
      • Lao C.D.
      • Marquez-Rodas I.
      • et al.
      CheckMate 067: long-term outcomes in patients with mucosal melanoma.