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Melanoma: HELP
Articles by Dr. Alexander Eggermont
Based on 176 articles published since 2008
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Between 2008 and 2019, A. Eggermont wrote the following 176 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7 · 8
1 Guideline Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline--Update 2012. 2012

Garbe, Claus / Peris, Ketty / Hauschild, Axel / Saiag, Philippe / Middleton, Mark / Spatz, Alan / Grob, Jean-Jacques / Malvehy, Josep / Newton-Bishop, Julia / Stratigos, Alexander / Pehamberger, Hubert / Eggermont, Alexander M / Anonymous220737 / Anonymous230737 / Anonymous240737. ·University Department of Dermatology, Tuebingen, Germany. claus.garbe@med.uni-tuebingen.de ·Eur J Cancer · Pubmed #22981501.

ABSTRACT: Cutaneous melanoma (CM) is potentially the most dangerous form of skin tumour and causes 90% of skin cancer mortality. A unique collaboration of multi-disciplinary 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 CM diagnosis and treatment, based on systematic literature reviews and the experts' experience. Diagnosis is made clinically and staging is based upon the AJCC system. CMs are excised with one to two centimetre safety margins. Sentinel lymph node dissection (SLND) is routinely offered as a staging procedure in patients with tumours more than 1mm in thickness, although there is as yet no clear survival benefit for this approach. Interferon-α treatment may be offered to patients with stage II and III melanoma as an adjuvant therapy, as this treatment increases at least the disease-free survival (DFS) and less clear the overall survival (OS) time. The treatment is however associated with significant toxicity. In distant metastasis, all options of surgical therapy have to be considered thoroughly. In the absence of surgical options, systemic treatment is indicated. BRAF inhibitors like vemurafenib for BRAF mutated patients as well as the CTLA-4 antibody ipilimumab offer new therapeutic opportunities apart from conventional chemotherapy. Therapeutic decisions in stage IV patients should be primarily made by an interdisciplinary oncology team ('tumour board').

2 Guideline Diagnosis and treatment of melanoma: European consensus-based interdisciplinary guideline. 2010

Garbe, Claus / Peris, Ketty / Hauschild, Axel / Saiag, Philippe / Middleton, Mark / Spatz, Alain / Grob, Jean-Jacques / Malvehy, Josep / Newton-Bishop, Julia / Stratigos, Alexander / Pehamberger, Hubert / Eggermont, Alexander. ·Center for Dermatooncology, Department of Dermatology, 72076 Tübingen, Germany. claus.garbe@med.uni-tuebingen.de ·Eur J Cancer · Pubmed #19959353.

ABSTRACT: Cutaneous melanoma (CM) is potentially the most dangerous form of skin tumour and causes 90% of skin cancer mortality. A unique collaboration of multi-disciplinary experts from the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organization of Research and Treatment of Cancer was formed to make recommendations on CM diagnosis and treatment, based on systematic literature reviews and the experts' experience. Diagnosis is made clinically and staging is based upon the AJCC system. CMs are excised with one to two centimetre safety margins. Sentinel lymph node dissection is routinely offered as a staging procedure in patients with tumours more than 1mm in thickness, although there is as yet no resultant survival benefit. Interferon-alpha treatment can be offered to patients with more than 1.5mm in thickness and stage II to III melanoma as an adjuvant therapy, as this treatment increases the relapse-free survival. The lack of a clear survival benefit and the presence of toxicity however limit its use in practice. In distant metastasis, all options of surgical therapy have to be considered thoroughly. In the absence of surgical options, systemic medical treatment is indicated, but with, to date, low response rates. Therapeutic decisions should be made by the melanoma team and the informed patient after full discussion of the options.

3 Guideline EANM-EORTC general recommendations for sentinel node diagnostics in melanoma. 2009

Chakera, Annette H / Hesse, Birger / Burak, Zeynep / Ballinger, James R / Britten, Allan / Caracò, Corrado / Cochran, Alistair J / Cook, Martin G / Drzewiecki, Krzysztof T / Essner, Richard / Even-Sapir, Einat / Eggermont, Alexander M M / Stopar, Tanja Gmeiner / Ingvar, Christian / Mihm, Martin C / McCarthy, Stanley W / Mozzillo, Nicola / Nieweg, Omgo E / Scolyer, Richard A / Starz, Hans / Thompson, John F / Trifirò, Giuseppe / Viale, Giuseppe / Vidal-Sicart, Sergi / Uren, Roger / Waddington, Wendy / Chiti, Arturo / Spatz, Alain / Testori, Alessandro / Anonymous1200637. ·Department of Plastic Surgery and Burns Unit, Rigshospitalet, Copenhagen, Denmark. annette.hougaard.chakera@live.dk ·Eur J Nucl Med Mol Imaging · Pubmed #19714329.

ABSTRACT: The accurate diagnosis of a sentinel node in melanoma includes a sequence of procedures from different medical specialities (nuclear medicine, surgery, oncology, and pathology). The items covered are presented in 11 sections and a reference list: (1) definition of a sentinel node, (2) clinical indications, (3) radiopharmaceuticals and activity injected, (4) dosimetry, (5) injection technique, (6) image acquisition and interpretation, (7) report and display, (8) use of dye, (9) gamma probe detection, (10) surgical techniques in sentinel node biopsy, and (11) pathological evaluation of melanoma-draining sentinel lymph nodes. If specific recommendations given cannot be based on evidence from original, scientific studies, referral is given to "general consensus" and similar expressions. The recommendations are designed to assist in the practice of referral to, performance, interpretation and reporting of all steps of the sentinel node procedure in the hope of setting state-of-the-art standards for good-quality evaluation of possible spread to the lymphatic system in intermediate-to-high risk melanoma without clinical signs of dissemination.

4 Editorial When to perform surgery in stage IV melanoma patients? 2008

de Wilt, Johannes H W / Eggermont, Alexander M M. · ·Onkologie · Pubmed #18497510.

ABSTRACT: -- No abstract --

5 Review Combination Immunotherapy Development in Melanoma. 2018

Eggermont, Alexander M M / Crittenden, Marka / Wargo, Jennifer. ·From the Gustave Roussy Cancer Institute and University Paris-Saclay, Villejuif, France; Earle A. Chiles Research Institute, Portland, OR; The University of Texas MD Anderson Cancer Center, Houston, TX. ·Am Soc Clin Oncol Educ Book · Pubmed #30231333.

ABSTRACT: Melanoma has been the most important cancer to drive immunotherapy development of solid tumors. Since 2010, immunotherapy has been revolutionized by the concept of breaking tolerance. It represents a major paradigm shift and marks the beginning of a new era. The impact of the first immune checkpoint inhibitors, anti-CTLA-4 and anti-PD-1/anti-PD-L1, is unprecedented. In 7 years, it transformed advanced-stage melanoma into a curable disease in over 50% of patients. Another major step has been the development of the combination of BRAF inhibitors plus MEK inhibitors in the treatment of BRAF-mutant melanomas. For the treatment of advanced disease, approvals were obtained for the immune checkpoint inhibitors ipilimumab (2011), nivolumab (2014), pembrolizumab (2014), the combination ipilimumab plus nivolumab (2015), and the oncolytic virus vaccine laherparepvec (2015). The combination dabrafenib plus trametinib for BRAF-mutant melanoma was approved in 2014, with similar success for other BRAF plus MEK inhibitor combinations. Because of its unique therapeutic index (high efficacy and low toxicity) anti-PD-1 agents (nivolumab and pembrolizumab) have now been placed at the center of practically all combination therapy development strategies in melanoma. Anti-PD-1 agents are the central molecule for combinations with a great variety of other immunotherapeutics such as immune checkpoint inhibitors, agonists, IDO inhibitors, macrophage polarizing agents, monoclonal antibodies, vaccines, targeted agents, chemotherapeutics, radiation therapy, and even microbiome modulators.

6 Review Relapse-Free Survival as a Surrogate for Overall Survival in the Evaluation of Stage II-III Melanoma Adjuvant Therapy. 2018

Suciu, Stefan / Eggermont, Alexander M M / Lorigan, Paul / Kirkwood, John M / Markovic, Svetomir N / Garbe, Claus / Cameron, David / Kotapati, Srividya / Chen, Tai-Tsang / Wheatley, Keith / Ives, Natalie / de Schaetzen, Gaetan / Efendi, Achmad / Buyse, Marc. ·European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium; Gustave Roussy Cancer Campus Grand Paris, Villejuif, France; The Christie NHS Foundation Trust, Manchester, UK; University of Pittsburgh Cancer Institute and School of Medicine, Pittsburgh, PA; Mayo Clinic Rochester, Rochester, MN; University of Tubingen, Tubingen, Germany; University of Edinburgh, Western General Hospital, Edinburgh, UK; Bristol-Myers Squibb, Wallingford, CT; Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK; Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK; Universitas Brawijaya, Malang, Indonesia; IDDI, Louvain-la-Neuve, Belgium. ·J Natl Cancer Inst · Pubmed #28922786.

ABSTRACT: Background: We assessed whether relapse-free survival (RFS; time until recurrence/death) is a valid surrogate for overall survival (OS) among resected stage II-III melanoma patients through a meta-analysis of randomized controlled trials. Methods: Individual patient data (IPD) on RFS and OS were collected from 5826 patients enrolled in 11 randomized adjuvant trials comparing interferon (IFN) to observation. In addition, IPD from two studies comparing IFN and vaccination in 989 patients were included. A two-level modeling approach was used for assessing Spearman's patient-level correlation (rho) of RFS and OS and the trial-level coefficient of determination (R²) of the treatment effects on RFS and on OS. The results were validated externally in 13 adjuvant studies without available IPD. We then tested the results on the European Organisation for Research and Treatment of Cancer (EORTC) 18071 double-blind trial comparing ipilimumab 10 mg/kg with placebo, which showed a statistically significant impact of the checkpoint inhibitor on RFS and OS. All statistical tests were two-sided. Results: With a median follow-up of seven years, 12 of 13 trials showed a consistency between the IFN vs No IFN differences regarding RFS (hazard ratio [HR]RFS = 0.88) and OS (HROS = 0.91), but the small trial, Eastern Cooperative Oncology Group 2696, was an outlier (HRRFS = 0.72 vs HROS = 1.11). Therefore, even if rho was high, R² was low and could not reliably be estimated. Based on the 12 trials, rho remained high (0.89), and the hazard ratios for RFS and OS were strongly correlated (R² = 0.91). The surrogate threshold effect for RFS was estimated to be 0.77. For the EORTC 18071 trial, the hazard ratio for RFS was 0.75, predicting an effect of ipilimumab on OS. This was subsequently confirmed (HROS = 0.72, 95.1% confidence interval = 0.58 to 0.88, P = .001). Conclusions: In high-risk stage II-III melanoma, RFS appeared to be a valid surrogate end point for OS for adjuvant randomized studies assessing interferon or a checkpoint inhibitor. In future similar adjuvant studies, a hazard ratio for RFS of 0.77 or less would predict a treatment impact on OS.

7 Review Adjuvant interferon-α for the treatment of high-risk melanoma: An individual patient data meta-analysis. 2017

Ives, Natalie J / Suciu, Stefan / Eggermont, Alexander M M / Kirkwood, John / Lorigan, Paul / Markovic, Svetomir N / Garbe, Claus / Wheatley, Keith / Anonymous3260912. ·Birmingham Clinical Trials Unit, College of Medical and Dental Sciences, Public Health Building, University of Birmingham, Birmingham, B15 2TT, UK. · EORTC Headquarters, Avenue Emmanuel Mounier 83/11, 1200 Brussels, Belgium. · Gustave Roussy Cancer Campus Grand Paris, 114 Rue Edouard Vaillant, 94800, Villejuif, France. · University of Pittsburgh Cancer Institute and School of Medicine, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA. · The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester, M20 4BX, UK. · Mayo Clinic Rochester, 200 First St. SW, Rochester, MN, 55905, USA. · University of Tubingen, Liebermeisterstraße 25, 72076, Tübingen, Germany. · Cancer Research UK Clinical Trials Unit, College of Medical and Dental Sciences, Robert Aitken Institute, University of Birmingham, Birmingham, B15 2TT, UK. Electronic address: k.wheatley@bham.ac.uk. ·Eur J Cancer · Pubmed #28692949.

ABSTRACT: BACKGROUND: Many randomised trials assessing interferon-α (IFN-α) as adjuvant therapy for high-risk malignant melanoma have been undertaken. To better assess the role of IFN-α, an individual patient data (IPD) meta-analysis of these trials was undertaken. METHODS: IPD was sought from all randomised trials of adjuvant IFN-α versus no IFN-α for high-risk melanoma. Primary outcomes were event-free survival (EFS) and overall survival (OS). Standard methods for quantitative IPD meta-analysis were used. Subgroup analyses by dose, duration of treatment and various patient and disease-specific parameters were performed. FINDINGS: Fifteen trials were included in the analysis (eleven with IPD). EFS was significantly improved with IFN-α (hazard ratio [HR] = 0.86, CI 0.81-0.91; P < 0.00001), as was OS (HR = 0.90, CI 0.85-0.97; P = 0.003). The absolute differences in EFS at 5 and 10 years were 3.5% and 2.7%, and for OS were 3.0% and 2.8% respectively in favour of IFN-α. There was no evidence that the benefit of IFN-α differed depending on dose or duration of treatment, or by age, gender, site of primary tumour, disease stage, Breslow thickness, or presence of clinical nodes. Only for ulceration was there evidence of an interaction (test for heterogeneity: P = 0.04 for EFS; P = 0.002 for OS); only patients with ulcerated tumours appeared to obtain benefit from IFN-α. CONCLUSION: This meta-analysis provides clear evidence that adjuvant IFN-α significantly reduces the risk of relapse and improves survival and shows no benefit for higher doses compared to lower doses. The increased benefit in patients with ulcerated tumours, and lack of benefit in patients without ulceration, needs further investigation.

8 Review A systematic review examining factors influencing health related quality of life among melanoma cancer survivors. 2016

Hamel, Jean-Francois / Pe, Madeline / Coens, Corneel / Martinelli, Francesca / Eggermont, Alexander M M / Brandberg, Yvonne / Bottomley, Andrew. ·European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium; Biostatistics and Methodology Department, Angers University Hospital, Angers, France. Electronic address: jeanfrancois.hamel@chu-angers.fr. · European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium. · Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. · Oncology and Pathology Department, Karolinska Institutet, Stockholm, Sweden. ·Eur J Cancer · Pubmed #27838512.

ABSTRACT: Eighty percent of melanomas are diagnosed at a localised stage, when they are highly curable. Their survival rate induces long follow-up periods, transforming melanoma into a chronic disease and patients' health-related quality of life (HRQoL). Understanding which patient characteristics are associated with poor HRQoL should allow a more personalised management of their HRQoL. Hence, we propose a systematic review for this purpose. Systematic literature searches were performed in three different electronic databases: PubMed, Web of Science and the Cochrane Library. Only studies published in English after 2005 until June 2016 and exploring HRQoL over a period of at least one year were considered. 10 articles were identified from seven different studies, representing a total of 4246 patients. All were observational: six were cross-sectional and only one was prospective. Several patient characteristics associated with HRQoL were identified. Women tend to have lower psychological HRQoL than men. Age was generally associated with variations in HRQoL levels, but there was no consistency across studies. Positive associations between marital status or social interactions and psychological subscales were highlighted by a few studies. Finally, the stage related severity of prognosis at initial diagnosis was systematically associated with worse HRQoL levels (either psychological, physical or global). Several patient characteristics could be identified in melanoma studies that were associated with HRQoL levels. However, these relations were not consistent across studies. Such findings highlight the current lack of empirical data available. Further evidence is needed on HRQoL factors in melanoma survivors.

9 Review Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. 2016

Boutros, Celine / Tarhini, Ahmad / Routier, Emilie / Lambotte, Olivier / Ladurie, Francois Leroy / Carbonnel, Franck / Izzeddine, Hassane / Marabelle, Aurelien / Champiat, Stephane / Berdelou, Armandine / Lanoy, Emilie / Texier, Matthieu / Libenciuc, Cristina / Eggermont, Alexander M M / Soria, Jean-Charles / Mateus, Christine / Robert, Caroline. ·Dermatology Service, Department of Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. · University of Pittsburgh, 4200 Fifth Avenue, Pittsburgh, Pennsylvania 15260, USA. · AP-HP, Internal Medicine Department, University Hospital of Bicêtre, 78 Rue du General Leclerc, 94270 Le Kremlin-Bicetre, France. · Paris Sud University, 63 Rue Gabriel Peri, 94270 Le Kremlin Bicêtre, France. · INSERM Unit U1184, 63 Rue Gabriel Peri, 94270 Le Kremlin Bicêtre, France. · Thoracic and Vascular Surgery Service, Centre Chirurgical Marie Lannelongue, 133 Avenue de la Resistance, 92350 Le Plessis-Robinson, France. · AP-HP, Department of Gastroenterology, University Hospital of Bicêtre, Paris Sud University, 78 Rue du General Leclerc, 94270 Le Kremlin-Bicetre, France. · Department of Nephrology, Pitié-Salpêtrière Hospital, 47-83 Boulevard de l'hopital, 75013 Paris, France. · Drug Development Department (DITEP), Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. · INSERM Unit U981, 114 Rue Edouard Vaillant, 94805 Villejuif, France. · Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. · Biostatistic and Epidemiology Unit, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. ·Nat Rev Clin Oncol · Pubmed #27141885.

ABSTRACT: Inhibition of immune checkpoints using anti-programmed cell death-1 (PD-1) or anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibodies has revolutionized the management of patients with advanced-stage melanoma and is among the most promising treatment approaches for many other cancers. Use of CTLA-4 and PD-1 inhibitors, either as single agents, or in combination, has been approved by the US FDA for the treatment of metastatic melanoma. Treatment with these novel immunotherapies results in a unique and distinct spectrum of adverse events, which are mostly related to activation of the immune system and are, therefore, an unwanted consequence of their mechanisms of action. Adverse effects of CTLA-4 and/or PD-1 inhibition are most commonly observed in the skin, gastrointestinal tract, liver and endocrine systems and include pruritus, rash, nausea, diarrhoea and thyroid disorders. In this Review, the authors describe the adverse event profile of checkpoint inhibitors targeting CTLA-4 and PD-1, used both as monotherapies and in combination and aim to provide some general guidelines, based upon the mechanisms of action of these therapies and on the management of these immune-related adverse events.

10 Review Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. 2016

Champiat, S / Lambotte, O / Barreau, E / Belkhir, R / Berdelou, A / Carbonnel, F / Cauquil, C / Chanson, P / Collins, M / Durrbach, A / Ederhy, S / Feuillet, S / François, H / Lazarovici, J / Le Pavec, J / De Martin, E / Mateus, C / Michot, J-M / Samuel, D / Soria, J-C / Robert, C / Eggermont, A / Marabelle, A. ·Department of Drug Development (DITEP), Gustave Roussy Inserm U981, Univ. Paris-Sud, Université Paris-Saclay, Villejuif. · Department of Internal Medicine and Clinical Immunology, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Bicêtre, Le Kremlin Bicêtre Université Paris Sud 11, Le Kremlin-Bicêtre CEA, DSV/iMETI, Division of Immuno-Virology, IDMIT, Fontenay-aux-Roses INSERM, U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Le Kremlin-Bicêtre. · Department of Ophthalmology, Hôpital Universitaire Bicêtre, Le Kremlin Bicêtre. · Department of Rheumatology, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, AP-HP, Le Kremlin Bicêtre. · Department of Nuclear Medicine and Endocrine Tumors, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif. · Gastroenterology Unit, Université Paris-Sud, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Sud, Le Kremlin Bicêtre. · Division of Adult Neurology, Hôpital Universitaire Bicêtre, Le Kremlin Bicêtre. · Faculty of Medicine, Université Paris-Saclay, Univ Paris-Sud, Paris-Sud, UMR-S1185, Le Kremlin Bicêtre Unit of Endocrinology and reproductive Health, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital de Bicêtre, Le Kremlin Bicêtre Unit of Gastroenterology, Institut National de la Santé et de la Recherche Médicale U1185 (P.C.), Le Kremlin Bicêtre. · Department of Nephrology and Transplantation, Bicêtre Hospital, Paris Saclay University, INSERM 1197, Le Kremlin Bicêtre. · Department of Cardiology, Saint-Antoine Hospital, Assistance Publique-Hôpitaux de Paris, Pierre et Marie Curie University [UPMC], Paris-Sorbonne, Paris. · Department of Thoracic and cardiovascular, and transplantation cardio-pulmonary, Hôpital Marie-Lannelongue, Le Plessis-Robinson Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre. · Hematology Unit, Department of Medical Oncology, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif. · Department of Thoracic and cardiovascular, and transplantation cardio-pulmonary, Hôpital Marie-Lannelongue, Le Plessis-Robinson Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre UMR_S 999, Univ. Paris-Sud; INSERM; Hôpital Marie Lannelongue, Le Plessis Robinson. · Centre Hépato-Biliaire, AP-HP, Hôpital Universitaire Paul Brousse Inserm U1193. · Dermatology Unit, Department of Medical Oncology, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif. · Department of Drug Development (DITEP), Gustave Roussy. · Inserm U981, Univ. Paris-Sud, Université Paris-Saclay, Villejuif Dermatology Unit, Department of Medical Oncology, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif. · Gustave Roussy Cancer Campus, Villejuif. · Department of Drug Development (DITEP), Gustave Roussy Gustave Roussy Cancer Campus, Villejuif Inserm 1015, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, France aurelien.marabelle@gustaveroussy.fr. ·Ann Oncol · Pubmed #26715621.

ABSTRACT: Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for the treatment of metastatic melanoma and advanced/refractory non small-cell lung cancers. Therefore, their use will not be limited anymore to selected hospitals involved in clinical trials. Indeed, they will be routinely prescribed in many cancer centers across the world. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse events (irAEs). This new family of dysimmune toxicities remains largely unknown to the broad oncology community. Although severe irAEs remain rare (∼10% of cases under monotherapy), they can become life-threatening if not anticipated and managed appropriately. Over the last 5 years, Gustave Roussy has accumulated a significant experience in the prescription of immune checkpoint blockade (ICB) antibodies and the management of their toxicities. Together with the collaboration of Gustave Roussy's network of organ specialists with expertise in irAEs, we propose here some practical guidelines for the oncologist to help in the clinical care of patients under ICB immunotherapy.

11 Review Immune checkpoint inhibitors in melanoma provide the cornerstones for curative therapies. 2015

Eggermont, Alexander M M / Maio, Michele / Robert, Caroline. ·Gustave Roussy Cancer Campus Grand Paris and University Paris-Sud, Paris, France. Electronic address: alexander.eggermont@gustaveroussy.fr. · Medical Oncology and Immunotherapy, University Hospital Siena, Italy. · Gustave Roussy Cancer Campus Grand Paris and University Paris-Sud, Paris, France. ·Semin Oncol · Pubmed #25965361.

ABSTRACT: Immunotherapy has been revolutionalized by the concept of breaking tolerance. It represents a major paradigm shift that marks the beginning of a new era. The impact of the first checkpoint inhibitors, ie, anti-CTLA-4 (cytotoxic T lymphocyte antigen-4) and anti-PD-1/ anti-PD-L1 (programmed death-1 receptor and its ligand, PD-L1) is unprecedented. In only 5 years advanced melanoma has been transformed from an incurable disease into a curable disease, and we are only at the beginning of discovering its transversal impact throughout solid tumor oncology. In advanced melanoma response rates are about 12% for anti-CTLA-4 and about 40% for anti-PD-1, and are remarkably durable, hence their impact on survival. In melanoma anti-CTLA-4 (ipilimumab) was approved in 2011 and anti-PD-1 (pembrolimumab) in 2014. Another anti-PD-1 antibody (nivolumab) has been recently approved based on phase III trial results in metastatic melanoma without BRAF mutation. Ipilimumab already has been evaluated in the adjuvant setting (European Organization for Research and Treatment of Cancer [EORTC] 18071) and shown to significantly improve recurrence-free survival in stage III patients at high risk of relapse. An adjuvant trial to evaluate pembrolizumab in this population (EORTC 1325) was started in early 2015.

12 Review Treatment algorithms in stage IV melanoma. 2015

Espinosa, Enrique / Grob, Jean-Jacques / Dummer, Reinhard / Rutkowski, Piotr / Robert, Caroline / Gogas, Helen / Kefford, Richard / Eggermont, Alexander M M / Martin Algarra, Salvador / Hauschild, Axel / Schadendorf, Dirk. ·1Service of Oncology, Hospital La Paz, Madrid, Spain · 2Department of Dermatology, Hopital Ste Marguerite, Marseille, France · 3Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland · 4Department of Sarcoma and Melanoma, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland · 5Department of Dermatology (CR), and General Director (AE), Institute Gustave Roussy, Villejuif Cedex, France · 6First Department of Medicine, University of Athens Medical School, Athens, Greece · 7Department of Oncology, Westmead Hospital and Melanoma Institute Australia, University of Sydney, Sydney, Australia · 8Service of Oncology, Clinica Universitaria de Navarra, Pamplona, Spain · 9Department of Dermatology, University of Kiel, Kiel, Germany · and 10Department of Dermatology, University Hospital Essen, Essen, Germany. ·Am J Ther · Pubmed #24413374.

ABSTRACT: The molecular classification of melanoma and the advent of new drugs are changing the paradigm of therapy for advanced melanoma. A review of the recent key studies was performed, followed by a discussion in an expert forum. The aim of this review was to generate a therapeutic algorithm for stage IV melanoma. Tumor genotyping for BRAF and/or KIT should be performed before selection of therapy. For most BRAF-mutated melanoma patients and particularly those with a high tumor load, vemurafenib or other BRAF inhibitors such as dabrafenib are the treatment of choice. KIT inhibitors can be effective in KIT-mutant tumors, especially in those patients with mutations at exons 11 and 13. Ipilimumab is a good option for patients with nontargetable or nondetected mutations and those who progress under therapy with vemurafenib or a KIT inhibitor. There is still a role for conventional chemotherapy either as first-line treatment in BRAF wild-type patients or as salvage therapy in second or third line, or after other treatment modalities. Participation in clinical trials is strongly encouraged, either in first or in subsequent lines. New therapeutic options for advanced melanoma are guided by tumor genotyping. The current therapeutic algorithm includes kinase inhibitors, anti-CTLA4 therapy, immunotherapy, and chemotherapy, depending on the tumor genotype and response to previous treatments. Participation in clinical trials should always be encouraged because the treatment goal is long-term survival and potential cure in a subset of patients.

13 Review Side effects and toxicities of targeted therapies in stage IV melanoma. 2015

Ascierto, Paolo A / Bastholt, Lars / Hersey, Peter / Cinat, Gabriela / Eggermont, Alexander M M / Hauschild, Axel / Espinosa, Enrique / Robert, Caroline. ·1Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori-Fondazione G. Pascale, Naples, Italy; 2Odense University Hospital, Odense, Denmark; 3Newcastle University, Newcastle, Australia; 4Instituto de Oncologia Angel Rolfo, Buenos Aires, Argentina; 5Institut Gustave Roussy, Villejuif, France; 6University of Kiel, Kiel, Germany; 7Hospital La Paz, Madrid, Spain; and 8Institut Gustave Roussy, Villejuif, France. ·Am J Ther · Pubmed #24185314.

ABSTRACT: As the incidence of melanoma continues to increase worldwide, the search for new therapies for advanced (stage IV) melanoma brings with it new patterns of toxicity to contend with. This review covers the toxicity profiles of new treatments for advanced melanoma currently in development. Therefore, the latest literature on melanoma treatment was surveyed for data on reported toxicities. The new types of treatments can be roughly divided into targeted tyrosine kinase inhibitors and immunomodulating agents. Each has its own set of toxicities particular to type and to individual drug. Targeted tyrosine kinase inhibitors generally cause fatigue, whereas immunomodulatory agents induce a specific set of adverse events known as immune-related adverse events (irAEs). Despite the incidence of adverse events, these agents hold promise for the treatment of stage IV melanoma. With new treatment opportunities come increased chance of toxic reactions. The key to successful melanoma treatment in the future is likely to be novel combinations of new therapeutic agents.

14 Review Who benefits most from adjuvant interferon treatment for melanoma? 2015

Gogas, Helen / Abali, Huseyin / Ascierto, Paolo A / Demidov, Lev / Pehamberger, Hubert / Robert, Caroline / Schachter, Jacob / Eggermont, Alexander M M / Hauschild, Axel / Espinosa, Enrique. ·1First Department of Medicine, Athens University Medical School, Athens, Greece; 2Division of Medical Oncology, Baskent University School of Medicine, Adana, Turkey; 3Unit of Medical Oncology and Innovative Therapy, Istituto Nazionale Tumori Fondazione "G. Pascale," Naples, Italy; 4Department of Biotherapy, Blokhin Cancer Center, Moscow, Russia; 5Department of Dermatology, Medical University of Vienna, Vienna, Austria; 6Department of Dermatology, Institute Gustave Roussy, Villejuif Cedex, France; 7Department of Oncology, Sheba Medical Center, Tel Hashomer, Israel; 8Department of Dermatologie, University of Kiel, Kiel, Germany; and 9Oncology Service, Hospital La Paz, Madrid, Spain. ·Am J Ther · Pubmed #24176884.

ABSTRACT: Metastatic melanoma has a poor prognosis; the median survival for patients with stage IV melanoma ranges from 8 to 18 months after diagnosis. Interferon-α provides significant improvement in disease-free survival at the cost of poor tolerability. Identifying patients who benefit the most may improve the cost:benefit ratio. In addition, no data exist for the role of adjuvant therapy in noncutaneous melanoma. Molecular profiles may help to identify patients who benefit the most from adjuvant interferon therapy. In this review, the American Joint Commission on Cancer 2009 staging criteria and emerging biomarker data to guide adjuvant treatment decisions will be discussed. Several criteria to guide selection of patients are discussed in detail. These include Breslow thickness, number of positive lymph nodes, whether or not the primary lesion has ulcerated, immunologic markers, and cytokine profiles. Substantial progress has been made in deciding which patients benefit from interferon-α adjuvant therapy. Interferon-α is the only agent currently approved for the adjuvant treatment of this deadly disease, despite its side effect profile. More effective drugs with better tolerability are needed.

15 Review Metastatic melanoma to the liver: a contemporary and comprehensive review of surgical, systemic, and regional therapeutic options. 2014

Agarwala, Sanjiv S / Eggermont, Alexander M M / O'Day, Steven / Zager, Jonathan S. ·Department of Hematology/Oncology, St. Luke's University Health Network, Bethlehem, Pennsylvania. ·Cancer · Pubmed #24301420.

ABSTRACT: Effective management of hepatic metastases from ocular and cutaneous melanoma remains a major therapeutic challenge. Treatment options include hepatic resection, hepatic intra-arterial (HIA) chemotherapy, chemoembolization, and hepatic perfusions. Evaluating the efficacy of these interventions is limited by the retrospective nature of most of the data, although controlled phase 3 studies are starting to emerge. Studies of hepatic resection are strongly suggestive of a survival benefit following surgery in selected patients. Effective systemic agents for metastatic cutaneous melanoma are available and supported by randomized controlled phase 3 trials. In contrast, no active systemic treatment has yet been identified for metastatic ocular melanoma. HIA and intravenous delivery of fotemustine have been compared in a randomized phase 3 trial in patients with unresectable metastases from melanoma, but no differences between the 2 approaches were observed. Hepatic arterial chemoembolization appears only to be moderately effective according to uncontrolled studies; targeting patients with less liver involvement may improve outcomes. A recent phase 3 study showed a significant improvement in hepatic progression-free survival with percutaneous hepatic perfusion compared with best alternative care in patients with metastatic melanoma; however, the overall survival analysis was confounded by crossover of control patients to active treatment. In conclusion, hepatic resection offers the possibility of long-term survival in carefully selected patients with liver-limited metastases from melanoma. In patients with unresectable cutaneous melanoma, effective systemic therapy is the best treatment option. For patients with unresectable ocular melanoma, regional treatments are likely to assume a greater role until effective systemic treatments are identified.

16 Review Cutaneous melanoma. 2014

Eggermont, Alexander M M / Spatz, Alan / Robert, Caroline. ·Melanoma Unit and INSERM U981, Gustave Roussy Cancer Institute, Grand Paris, Villejuif, France; Erasmus University Medical Centre, Rotterdam, Netherlands. Electronic address: alexander.eggermont@igr.fr. · Department of Pathology, McGill University & Lady Davis Institute for Medical Research, Montreal, QC, Canada. · Melanoma Unit and INSERM U981, Gustave Roussy Cancer Institute, Grand Paris, Villejuif, France. ·Lancet · Pubmed #24054424.

ABSTRACT: In the past decade, major advances have been made in the understanding of melanoma. New predisposition genes have been reported and key somatic events, such as BRAF mutation, directly translated into therapeutic management. Surgery for localised melanoma and regional lymph node metastases is the standard of care. Sentinel-node biopsy provides precise staging, but has not been reported to affect survival. The effect of lymph-node dissection on survival is a topic of investigation. Two distinct approaches have emerged to try to extend survival in patients with metastatic melanoma: immunomodulation with anti-CTLA4 monoclonal antibodies, and targeted therapy with BRAF inhibitors or MEK inhibitors for BRAF-mutated melanoma. The combination of BRAF inhibitors and MEK inhibitors might improve progression-free survival further and, possibly, increase overall survival. Response patterns differ substantially-anti-CTLA4 immunotherapy can induce long-term responses, but only in a few patients, whereas targeted drugs induce responses in most patients, but nearly all of them relapse because of pre-existing or acquired resistance. Thus, the long-term prognosis of metastatic melanoma remains poor. Anti-PD1 and anti-PDL1 antibodies have emerged as breakthrough drugs for melanoma that have high response rates and long durability. Biomarkers that have predictive value remain elusive in melanoma, although emerging data for adjuvant therapy indicate that interferon sensitivity is associated with ulceration of the primary melanoma. Intense investigation continues for clinical and biological markers that predict clinical benefit of immunotherapeutic drugs, such as interferon alfa or anti-CTLA4 antibodies, and the mechanisms that lead to resistance of targeted drugs.

17 Review Completion lymph node dissection after a positive sentinel node: no longer a must? 2013

van der Ploeg, Augustinus P T / van Akkooi, Alexander C J / Verhoef, Cornelis / Eggermont, Alexander M M. ·Erasmus University Medical Center, Daniel den Hoed Cancer Center, Rotterdam, the Netherlands. ·Curr Opin Oncol · Pubmed #23328628.

ABSTRACT: PURPOSE OF REVIEW: Sentinel node biopsy (SNB) for primary melanoma is accepted worldwide as a diagnostic procedure. When sentinel node positive, the invasive completion lymph node dissection (CLND) is usually performed. Approximately 20% of CLND patients have nonsentinel node (NSN) metastases. The therapeutic benefit is unknown. This review analyzed the necessity of CLND in sentinel node positive patients. RECENT FINDINGS: Prognosis of sentinel node positive patients is highly heterogeneous. The Rotterdam and Dewar criteria and S-classification are important sentinel node tumor burden criteria to stratify melanoma patients for prognosis and risk of NSN metastases. Patients with less than 0.1 mm metastases seem to have similar prognosis as sentinel node negative patients, especially when located in the subcapsular area. This depends on the use of an extensive sentinel node pathology protocol identifying possibly clinically irrelevant micrometastases. SUMMARY: Consensus on the sentinel node pathology work-up and analysis protocols are crucial for correct risk stratification and for clinical decision-making. Primary and sentinel node tumor burden parameters and patient comorbidities should be taken into consideration when offering CLND to an individual patient. In the future, prospective studies such as the MSLT-II and the EORTC 1208 (Minitub) will provide answers to whether CLND has a therapeutic benefit and to which patients might safely be spared CLND.

18 Review Update on the role of ipilimumab in melanoma and first data on new combination therapies. 2013

Maio, Michele / Di Giacomo, Anna M / Robert, Caroline / Eggermont, Alexander M M. ·Medical Oncology and Immunotherapy, Azienda Ospedaliera Universitaria Senese, Istituto Toscano Tumori, Siena, Italy. mmaio@cro.it ·Curr Opin Oncol · Pubmed #23299197.

ABSTRACT: PURPOSE OF REVIEW: This article provides an update on the therapeutic role of the monoclonal antibody ipilimumab in melanoma. Recent therapeutic combinations, as well as directions for further investigations, will also be discussed. RECENT FINDINGS: By blocking the interaction between CTLA-4 and B7 expressed on activated T lymphocytes and antigen-presenting cells, respectively, ipilimumab inhibits negative signals that physiologically downregulate T-cell activation and exerts its therapeutic activity by upregulating the antitumor activity of T lymphocytes. Ipilimumab has been the first agent to significantly improve the survival of metastatic melanoma patients and to provide long-term benefit to a sizeable proportion of patients treated within phase II/III studies and expanded access programs. On these premises, a number of studies combining ipilimumab with cytotoxic, antiangiogenic, and targeted agents have been most recently conducted. SUMMARY: Ipilimumab is the prototype of a growing family of 'immunomodulating antibodies' and it has demonstrated that immunotherapy will play an increasingly important role in the new treatment approaches for cancer. Combinations of chemotherapy, radiation therapy, and targeted drugs with ipilimumab indicate that additive and synergistic antitumor activity can be achieved. Most importantly, they indicate that involving the immune system is a key strategy to improve the outcome in cancer patients.

19 Review Can immuno-oncology offer a truly pan-tumour approach to therapy? 2012

Eggermont, A M M. ·Cancer Institute Gustave-Roussy, Villejuif/Paris-Sud 94800, France. alexander.eggermont@igr.fr ·Ann Oncol · Pubmed #22918930.

ABSTRACT: Increased understanding of cellular and molecular tumour immunology over the past two decades has enabled the identification of new and innovative ways to manipulate the immune response to cancer, with recent phase III trials in patients with metastatic melanoma and hormone-resistant prostate cancer providing proof-of-principle that immunotherapies can improve survival. Based on these successes, many new immunotherapies are being developed, including vaccines and other agents that prime or boost the immune system, T-cell modulatory agents, agents that enhance innate immunity and agents designed to inhibit immunosuppression within the tumour microenvironment. Current experience suggests that immunotherapies are a promising foundation to build treatment regimens for a variety of tumour types. Because many approaches target the immune system and not the cancer, immunotherapies are being evaluated in almost every tumour type, including those that were not previously considered likely to respond to immune manipulation. Immunotherapies also have potential for durable and adaptable cancer control at different stages of disease, including those with early-stage disease and low tumour burdens. To maximise benefits, however, it is likely that combination regimens with conventional cancer treatments or other immunotherapies will be necessary. In addition, the identification of biomarkers will allow further optimisation from a mechanistic and a patient selection perspective. Further advances in research will necessitate multidisciplinary collaboration among physicians, basic and translational researchers and the pharmaceutical industry to ensure that immuno-oncology becomes a cornerstone element in the development of cancer therapy.

20 Review Management of pegylated interferon alpha toxicity in adjuvant therapy of melanoma. 2012

Daud, Adil / Soon, Christopher / Dummer, Reinhard / Eggermont, Alexander M M / Hwu, Wen-Jen / Grob, Jean Jacques / Garbe, Claus / Hauschild, Axel. ·University of California, San Francisco, Melanoma Program, San Francisco 1600 Divisadero St, Rm A741, Box 1770, San Francisco, CA 94115, USA. adaud@medicine.ucsf.edu ·Expert Opin Biol Ther · Pubmed #22694288.

ABSTRACT: INTRODUCTION: Both native IFNα2b and pegylated IFNα2b (PegIFNα2b) are approved for the adjuvant treatment of high-risk melanoma. AREAS COVERED: This review compares the toxicity profiles of high-dose IFNα2b (HDI) and PegIFNα2b, and provides recommendations on the management of common PegIFNα2b-related toxicities, based on available clinical data and published literature. EXPERT OPINION: The toxicity profile of PegIFNα2b at the approved dose (6 μg/kg/week for 8 weeks then 3 μg/kg/week for up to 5 years) is qualitatively similar to HDI in melanoma. The most common adverse events (AEs) are fatigue, anorexia, hepatotoxicity, flu-like symptoms, injection site reactions and depression. However, fatigue and flu-like symptoms appear less severe with PegIFNα2b, and toxicity seems to occur earlier, whereas with HDI toxicity may increase with time. Most AEs can be managed effectively by dose modification and aggressive symptom control. Dosing to tolerance using a three-step dose reduction schedule to maintain an ECOG performance status of 0 - 1 may enable patients experiencing toxicity to remain on treatment; this can be applied readily in clinical practice. PegIFNα2b is therefore a valuable alternative option for adjuvant treatment in melanoma, with a toxicity profile similar to that of HDI overall but a more convenient administration schedule.

21 Review Is ulceration in cutaneous melanoma just a prognostic and predictive factor or is ulcerated melanoma a distinct biologic entity? 2012

Eggermont, Alexander M M / Spatz, Alan / Lazar, Vladimir / Robert, Caroline. ·Institut de Cancérologie Gustave Roussy, Villejuif, Paris, France. alexander.eggermont@igr.fr ·Curr Opin Oncol · Pubmed #22234255.

ABSTRACT: PURPOSE OF REVIEW: Ulceration of a primary cutaneous melanoma has for many years been recognized as a very important prognostic factor associated with increased risk for recurrence and mortality. Patients with an ulcerated melanoma do much worse than patients with a nonulcerated melanoma with the same breslow thickness. Ulceration may indicate a separate biologic entity. RECENT FINDINGS: Gene profiling studies of fresh frozen melanoma samples indicated that ulcerated melanomas have a very different profile. Analysis of the results of the two largest adjuvant interferon (IFN) trials ever conducted in 2644 patients [European Organization for Research and Treatment of Cancer (EORTC) 18952 and 18991], which used ulceration of the primary as a stratification factor, indicated that ulceration was not only a very strong prognostic factor, but more importantly a significant predictive factor for outcome of adjuvant IFN treatment. Only in patients with an ulcerated primary, was a similar and significant impact on disease-free survival, distant metastasis-free survival and overall survival observed. As a more general finding, in trials independent of ulceration used as a stratification factor, this IFN sensitivity of ulcerated melanomas has been reported in a meta-analysis in more than 3000 patients. It was also identified as a predictive factor of outcome in the Sunbelt adjuvant IFN trial in the USA. SUMMARY: These important findings regarding ulceration need biologic studies to identify the differences between ulcerated and nonulcerated melanoma at the molecular level. Moreover, the importance of ulceration will be assessed prospectively in the EORTC 18081 trial in patients with primary ulcerated melanomas more than 1  mm.

22 Review Melanoma in 2011: a new paradigm tumor for drug development. 2012

Eggermont, Alexander M M / Robert, Caroline. ·Institut de Cancérologie Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, Paris-Sud, France. alexander.eggermont@igr.fr ·Nat Rev Clin Oncol · Pubmed #22231762.

ABSTRACT: Melanoma has emerged as the paradigm tumor for drug development through mutation-targeted therapies (inhibitors targeting BRAF, MEK, and c-KIT) and immunotherapy. Exploring the combinations of both approaches is a challenge that will require scientific rationale and the cooperation of the pharmaceutical industry. But, with these challenges comes another opportunity to change the paradigms in drug development.

23 Review New developments in melanoma: utility of ultrasound imaging (initial staging, follow-up and pre-SLNB). 2011

Ulrich, Jens / van Akkooi, Alexander J C / Eggermont, Alexander M M / Voit, Christiane. ·Department of Dermatology and Skin Cancer Center Harz, Medical Center Quedlinburg, Germany. ·Expert Rev Anticancer Ther · Pubmed #22050018.

ABSTRACT: Melanoma incidence is still increasing, but the mortality rate has remained unchanged. Lymph node metastases are the single most important prognostic factor for stage I/II melanoma patients. Currently, the standard of care with regard to the staging of these patients is the surgical sentinel node procedure. Ultrasound is not routine for the diagnostic work-up of primary melanomas. Some may use ultrasound for the preoperative assessment of the tumor thickness and lymphatic drainage, but this has not found wide application. For the follow-up of melanoma patients, ultrasound has been proven to be superior to physical examination for the detection of lymph node metastases. A meta-analysis has shown that ultrasound is superior to computed tomography (CT) and/or positron emission tomography (PET)-CT for the detection of lymph node metastases, whereas PET-CT was superior for the detection of distant visceral metastases. Ultrasound of regional lymph nodes has been incorporated into many national guidelines across Europe and in Australia for the follow-up of melanoma patients. A new avenue for ultrasound (US)-guided fine-needle aspiration cytology (FNAC) is the pre-sentinel node modality. Like the situation in breast and thyroid cancer, US-FNAC, a minimally invasive procedure, may decrease the need for surgical sentinel node staging. New ultrasound morphology criteria have significantly increased the sensitivity of this technique. Peripheral perfusion is an early sign of metastases (77% sensitivity, 52% positive-predictive value), whereas balloon-shaped lymph node was a late sign of metastases (30% sensitivity, 96% positive-predictive value). Together, these new ultrasound morphology criteria were able to accurately demonstrate metastases in 65% of sentinel node-positive patients. Future perspectives of ultrasound in melanoma include the start of a large multicenter, multicountry validation study - USE-FNAC - by the European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group. In light of new and promising adjuvant therapies, the need for ultrasound staging might increase rapidly.

24 Review Treatment of melanoma metastases in a limb by isolated limb perfusion and isolated limb infusion. 2011

Testori, Alessandro / Verhoef, Cornelis / Kroon, Hidde M / Pennacchioli, E / Faries, Mark B / Eggermont, Alexander M M / Thompson, John F. ·Melanoma and Sarcoma Division, European Institute of Oncology, Milan, Italy. alessandro.testori@ieo.it. ·J Surg Oncol · Pubmed #21858835.

ABSTRACT: In-transit melanoma metastases are often confined to a limb. In this circumstance, treatment by isolated limb perfusion or isolated limb infusion can be a remarkably effective regional treatment option.

25 Review New drugs in melanoma: it's a whole new world. 2011

Eggermont, Alexander M M / Robert, Caroline. ·Institut de Cancérologie Gustave Roussy, Villejuif, Paris-Sud, France. alexander.eggermont@igr.fr ·Eur J Cancer · Pubmed #21802280.

ABSTRACT: Current developments in systemic therapies for melanoma are spectacular. Over the last 40 years no one drug or combination of drugs demonstrated any impact on survival in metastatic melanoma. In contrast, in 2011 a number of new drugs will be approved. In 2011 immunomodulation with ipilimumab, a monoclonal antibody targeting the ligand CTLA-4, has been approved for patients with advanced melanoma in first- and second-line treatment by the Food and Drug Administration (FDA) and in second-line treatment by the European Medicines Agency (EMA). Also in 2011, a significant survival benefit of the combination of ipilimumab with dacarbazine compared with dacarbazine alone for first-line treatment was reported. Other monoclonal antibodies targeting T-cell ligands, such as programmed death-1 (PD-1), also show promise. Various inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) yield high response rates in patients harbouring the BRAF-V600E mutation. A significant impact on both progression-free and overall survival was demonstrated for vemurafenib compared with dacarbazine in a phase-III trial. Approval is expected in 2011. Both drugs had only modest effects of 2-3 months on median survival, so combination therapies must be explored. BRAF inhibitors in combination with mitogen-activated protein kinase (MEK) inhibitors show great potential. Moreover, combinations of immunomodulators and pathway inhibitors are expected to be very active, and phase-III trials are planned. Pegylated interferon-α2b was approved in 2011 on the basis of the results of the European Organisation for Research and Treatment of Cancer (EORTC) 18991 phase-III trial demonstrating a sustained impact on relapse-free survival in patients with lymph-node-positive melanoma. The efficacy of adjuvant therapy with ipilimumab is assessed in the now fully accrued EORTC18071 trial. Adjuvant trials with BRAF and MEK inhibitors are in the planning phase. Never was there a more exciting period in the world of melanoma treatment.

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