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Melanoma: HELP
Articles by Caroline Robert
Based on 135 articles published since 2008
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Between 2008 and 2019, Caroline Robert wrote the following 135 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6
1 Editorial MAP-kinase pathway up or down? Just look at the skin of your patients! 2014

Robert, Caroline / Thomas, Marina / Mateus, Christina. ·aDermatology Service, Gustave Roussy bINSERM U981, Paris Sud University, Villejuif, France. ·Melanoma Res · Pubmed #25185691.

ABSTRACT: -- No abstract --

2 Review Is earlier better for melanoma checkpoint blockade? 2018

Robert, Caroline. ·Paris-Sud University, Kremlin-Bicêtre, France. caroline.robert@gustaveroussy.fr. · Oncology Department and INSERM U981, Villejuf, France. caroline.robert@gustaveroussy.fr. ·Nat Med · Pubmed #30401867.

ABSTRACT: A neoadjuvant approach relying on the administration of combined anti-CTLA-4-anti-PD-1 treatment before lymph node surgery is evaluated in two phase 1 trials. Encouraging clinical, pathological and immunological responses to neoadjuvant therapy were observed, suggesting that this concept warrants further exploration; however, any future approach must address the unacceptably high toxicity of the regimens evaluated in these trials.

3 Review New Era in the Management of Melanoma Brain Metastases. 2018

Tawbi, Hussein A / Boutros, Celine / Kok, David / Robert, Caroline / McArthur, Grant. ·From The University of Texas MD Anderson Cancer Center, Houston, TX; Institut Gustave Roussy, Paris, France; Peter MacCallum Cancer Centre, Melbourne, Australia. ·Am Soc Clin Oncol Educ Book · Pubmed #30231345.

ABSTRACT: The remarkable advances in the systemic therapy of metastatic melanoma have now extended the 1-year overall survival rate from 25% to nearing 85%. Systemic treatment in the form of BRAF-targeted therapy and immunotherapy is slowly but surely proving its efficacy in the treatment of metatstatic brain metastases (MBM). Single-agent BRAF inhibitors provide an intracranial response rate of 25% to 40%, whereas the combination of BRAFi/MEKi leads to responses in up to 58%. However, the durability of responses induced by BRAFi/MEKi seems to be even shorter than in extracranial disease. On the other hand, single-agent ipilimumab provides comparable clinical benefit in MBMs as it does in extracranial metastases. Single-agent PD-1 anitbodies induce response rates of approximately 20%, and those responses appear durable. Similarly the combination of CTLA-4+ PD-1 antibodies induces durable responses at an impressive rate of 55% and is safe to administer. Although the local treatment approaches with radiation and surgery remain important and are critically needed in the management of MBM, systemic therapy offers a new dimension that can augment the impact of those therapies and come at a potentially lower cost of neurocognitive impairment. Considerations for combining those modalities are direly needed, in addition to considering novel systemic combinations that target mechanisms specific to MBM. In this report, we will discuss the underlying biology of melanoma brain metastases, the clinical outcomes from recent clinical trials of targeted and immunotherapy, and their impact on clinical practice in the context of existing local therapeutic modalities.

4 Review Survival of patients with advanced metastatic melanoma: the impact of novel therapies-update 2017. 2017

Ugurel, Selma / Röhmel, Joachim / Ascierto, Paolo A / Flaherty, Keith T / Grob, Jean Jacques / Hauschild, Axel / Larkin, James / Long, Georgina V / Lorigan, Paul / McArthur, Grant A / Ribas, Antoni / Robert, Caroline / Schadendorf, Dirk / Garbe, Claus. ·Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. Electronic address: selma.ugurel@uk-essen.de. · Bremen, Germany. · Melanoma, Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", Naples, Italy. · Massachusetts General Hospital, Boston, MA, USA. · Department of Dermatology, Timone Hospital and Aix-Marseille University, Marseille, France. · Department of Dermatology, University Hospital of Schleswig-Holstein, Kiel, Germany. · Royal Marsden Hospital NHS Foundation Trust, London, UK. · Melanoma Institute Australia, The University of Sydney, and Royal North Shore Hospital, Sydney, NSW, Australia. · University of Manchester, The Christie NHS Foundation Trust, Manchester, UK. · Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia and University of Melbourne, Parkville, VIC, Australia. · University of California, Los Angeles, CA, USA. · Gustave Roussy Cancer Campus, Villejuif Grand-Paris, France. · Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. · Center for Dermatooncology, Department of Dermatology, University of Tuebingen, Tuebingen, Germany. ·Eur J Cancer · Pubmed #28756137.

ABSTRACT: The treatment of metastatic melanoma is still undergoing a process of major change. The two most important novel therapeutic strategies, selective kinase inhibitors and immune checkpoint blockers, both significantly prolong survival times of patients with advanced metastatic disease. Different agents, dose regimens and combinations have been tested against each other vigorously within these two groups. However, results from prospective head-to-head comparative studies of both strategies are still lacking. We performed an exploratory analysis of survival data from selected clinical trials representative for the new treatment strategies in advanced metastatic melanoma. Eighty-three Kaplan-Meier survival curves from 25 trials were digitised and grouped by therapeutic strategy and treatment line. For each of these groups, mean survival curves were generated for progression-free (PFS) and overall survival (OS) by weighted averaging. Survival curves grouped together by therapeutic strategy revealed a high concordance, particularly in the first-line setting. For kinase inhibitors, the most favourable PFS and OS in all therapy lines were observed for combined BRAF plus MEK inhibition. For immune checkpoint inhibitors, combined PD-1 plus CTLA-4 inhibition demonstrated the best survival outcome in all categories except for OS in first-line therapy. For the latter, combined PD-1 plus CTLA-4 inhibition showed similar outcomes as single-agent PD-1 inhibition. Comparison of kinase inhibitors and checkpoint blockers revealed a superiority of combined BRAF plus MEK inhibition within the first 6 months, later changing to a superiority of PD-1 blockers alone or in combination with CTLA-4 blockers. These results need confirmation by prospective clinical trials.

5 Review Systemic Therapy Options for Patients With Unresectable Melanoma. 2017

Yushak, Melinda / Chapman, Paul / Robert, Caroline / Kudchadkar, Ragini. ·From the Winship Cancer Institute of Emory University, Atlanta, GA; Memorial Sloan Kettering Cancer Center, New York, NY; Institute Gustave Roussy, Villejuif, France. ·Am Soc Clin Oncol Educ Book · Pubmed #28561662.

ABSTRACT: There has been a therapeutic revolution in the treatment of metastatic melanoma over the past decade. Patients presenting with inoperable disease have several therapeutic options, which can include both targeted and immune therapy. Immune checkpoint inhibitors have demonstrated an improvement in overall survival and led to some durable responses. However, toxicity, especially in combination regimens, can be severe. Adverse events should be anticipated, diagnosed as early as possible, monitored, and managed. Combination BRAF and MEK inhibition has also been shown to improve overall survival in patients with V600E-mutated melanoma. Responses to therapy are often rapid, and treatment is not associated with immune-related adverse events. Current trials are under way to determine which option is optimal as frontline therapy for patients with V600E melanoma. In patients with progressive disease despite standard therapies, clinical trials are recommended. There are several promising agents in development.

6 Review [Not Available]. 2016

Mateus, Christine / Libenciuc, Cristina / Robert, Caroline. ·Service de dermatologie, Gustave Roussy, Université Paris-Saclay, Département de Médecine Oncologique, Villejuif, F-94805, France. Electronic address: christine.mateus@gustaveroussy.fr. · Service de dermatologie, Gustave Roussy, Université Paris-Saclay, Département de Médecine Oncologique, Villejuif, F-94805, France. ·Bull Cancer · Pubmed #27494973.

ABSTRACT: ANTI-PD1 ROLE IN TREATMENT OF CUTANEOUS MELANOMA: The treatment of metastatic melanoma dramatically changed over the last years. Two therapeutic revolutions emerged in parallel, targeted anti-BRAF and anti-MEK therapies, for patients BRAFV600 mutated and immunotherapy with immune checkpoint blockers using anti-CTLA-4 then anti-PD1 monoclonal antibodies. Indeed, melanoma immunotherapy was a golden objective for many years but in spite of important efforts using cytokines (interferon, interleukin) and different vaccine approaches no objective improvement of patients 'prognosis was obtained. Ipilimumab, authorized in 2011, was the first drug which showed a benefit of overall survival in patients with metastatic melanoma in spite a low response rate (10-15) and the occurrence of about 25% of serious toxicity. Anti-PD1 appear as a new generation of immune checkpoint blockade with response rates between 30 to 40% of the patients, a proven overall survival benefit as compared with chemotherapy or ipilimumab and less toxicity than ipilimumab. Two molecules, pembrolizumab and nivolumab were recently approved in monotherapy, for metastatic melanoma. Several questions remain unresolved: the respective indications of anti-PD1 and targeted therapies in first line therapy in patients with BRAF mutant melanoma, the benefit of combining immunotherapy with radiotherapy or with targeted therapies, the optimal treatment duration, and the benefit of the anti-PD1 in the adjuvant setting. The combination of ipilimumab and nivolumab, recently approved by the FDA but not yet in Europ, shows an improvement of the objective response rates (50-57%) and progression free survival compared with nivolumab but is associated with an higer incidence of serious adverse events (more than 50%).

7 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.

8 Review Survival of patients with advanced metastatic melanoma: The impact of novel therapies. 2016

Ugurel, Selma / Röhmel, Joachim / Ascierto, Paolo A / Flaherty, Keith T / Grob, Jean Jacques / Hauschild, Axel / Larkin, James / Long, Georgina V / Lorigan, Paul / McArthur, Grant A / Ribas, Antoni / Robert, Caroline / Schadendorf, Dirk / Garbe, Claus. ·Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. Electronic address: selma.ugurel@uk-essen.de. · 28355 Bremen, Germany. · Melanoma, Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples, Italy. · Massachusetts General Hospital, Boston, MA, USA. · Dermatology Department, Timone Hospital and Aix-Marseille University, Marseille, France. · University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany. · Royal Marsden Hospital NHS Foundation Trust, London, UK. · Melanoma Institute Australia and The University of Sydney, Sydney, NSW, Australia. · University of Manchester, The Christie NHS Foundation Trust, Manchester, UK. · Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; University of Melbourne, Parkville, VIC, Australia. · University of California, Los Angeles, CA, USA. · Gustave Roussy Cancer Campus, Villejuif Grand-Paris, France. · Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. · Center for Dermatooncology, Department of Dermatology, University Tuebingen, 72074 Tuebingen, Germany. ·Eur J Cancer · Pubmed #26707829.

ABSTRACT: The survival of advanced metastatic melanoma has been greatly improved within the past few years. New therapeutic strategies like kinase inhibitors for BRAF-mutant melanoma and immune checkpoint blockers proved to prolong survival times within clinical trials, and many of them have already entered routine clinical use. However, these different treatment modalities have not yet been tested against each other, which complicate therapy decisions. We performed an explorative analysis of survival data from recent clinical trials. Thirty-five Kaplan-Meier survival curves from 17 trials were digitised, re-grouped by matching inclusion criteria and treatment line, and averaged by therapy strategy. Notably, the survival curves grouped by therapy strategy revealed a very high concordance, even if different agents were used. The greatest survival improvement was observed with the combination of BRAF plus MEK inhibitors as well as with Programmed-death-1 (PD1) blockers with or without cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockers, respectively, with these two treatment strategies showing similar survival outcomes. For first-line therapy, averaged survival proportions of patients alive at 12 months were 74.5% with BRAF plus MEK inhibitor treatment versus 71.9% with PD-1 blockade. This explorative comparison shows the kinase inhibitors as similarly effective as immune checkpoint blockers with regard to survival. However, to confirm these first trends for implementation into an individualised treatment of melanoma patients, data from prospective clinical trials comparing the different treatment strategies head-to-head have to be awaited.

9 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.

10 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.

11 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.

12 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.

13 Review [Immunotherapies and melanoma]. 2014

Routier, Émilie / Robert, Caroline / Mateus, Christina. ·Gustave-Roussy, Service de dermatologie, 114, rue Édouard-Vaillant, 94805 Villejuif cedex, France. Electronic address: emilie.routier@gustaveroussy.fr. · Gustave-Roussy, Service de dermatologie, 114, rue Édouard-Vaillant, 94805 Villejuif cedex, France. ·Bull Cancer · Pubmed #25776763.

ABSTRACT: Metastatic melanoma treatment has been radically modified over the last four years with the emergence of new and effective therapeutic strategies targeted anti-BRAF therapies as well as immunotherapy. Following this latter immunotherapy strategy, anti-CTLA4 antibody ipilimumab demonstrated a benefit in terms of overall survival in patients with metastatic melanoma and is now challenged by other checkpoint inhibitors, antibodies directed against PD-1 and PD-L1 that have extremely promising benefit/risk ratio. Adverse events as well as evaluation criteria are different from the ones associated with classical chemotherapy or targeted therapies. The challenge for the next years will be to optimize these new strategies, by possibly using these new drugs sequentially or in combination for a higher clinical benefit for our patients.

14 Review [Detection of residual microscopic disease in melanoma: interest of the sentinel lymph node procedure?]. 2014

Mateus, Christine / Thomas, Marina / Robert, Caroline. ·Université Paris-Sud, Service de dermatologie, Gustave-Roussy, 114, rue Édouard-Vaillant, 94805 Villejuif cedex, France. ·Bull Cancer · Pubmed #24793626.

ABSTRACT: The prognosis of metastatic melanoma, despite many important and recent progresses, remains poor. The detection of microscopic disease must be a key point in fundamental and clinical research. Current recommendations, with clinical and radiological monitoring, only permit to detect macroscopic relapses. No seric tumor marker is presently sufficiently reproducible and determinant to be used in clinical practice to precociously diagnose a relapse. The sentinel lymph node procedure is currently the only technique largely used to determine microscopic metastasis. This technique allows defining a group of patients with poor prognosis but its therapeutic impact remains discussed. Completion lymph node dissection of the area after positive sentinel lymph node is currently performed but its real benefit to improve overall survival must be proved. Interferon is now the only treatment approved in adjuvant setting, but its interest remains discussed. Therapeutic trials are ongoing to really identify patients who could benefit from adjuvant treatment with interferon. Other trials probably more attractive (anti-CTLA4, BRAF and MEK inhibitors), with molecules recently approved in metastatic phase are also ongoing.

15 Review [Management of patients with melanoma]. 2014

Robert, Caroline / Cavalcanti, Andrea / Kolb, Frédéric / Sarfati, Benjamin / Moya-Plana, Antoine / Tomasic, Gorana / Mateus, Christina. · ·Rev Prat · Pubmed #24649552.

ABSTRACT: Management of patients with metastatic melanoma has been revolutionized over the last few years with targeted anti-BRAF therapies for BRAF-mutant melanomas (in about 50% of the cases) and immunotherapy with anti-CTLA-4. Several new drugs are now authorized and available. Because of their new mechanisms of action, they also have new adverse events and guidelines concerning their safety are of critical importance. New innovative strategies using combination of targeted therapies and immunotherapies with anti-PD-1 are in accelerated development. The quality of patient-physician relationship is central to this promising but complex new paradigm of treatment.

16 Review [How to announce the diagnosis for melanoma?]. 2014

Charles, Cécile / Rouby, Pascal / Robert, Caroline. · ·Rev Prat · Pubmed #24649547.

ABSTRACT: Announcing a diagnosis of cutaneaous melanoma is a complex moment of medical activity and has some specificities due to the disease, but also to its management. After defining these aspects, the article deals with the principals steps and elements, including communicative ones, of this form of announcement. Its aim is above all practice: it is proposing some guidelines drawn from official recommendations and recent works on the physician-patient relationship in oncology, aiming at helping health professionals in this field.

17 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.

18 Review CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. 2013

Ott, Patrick A / Hodi, F Stephen / Robert, Caroline. ·Authors' Affiliations: Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; and Institut Gustave Roussy, Villejuif-Paris Sud, Paris, France. ·Clin Cancer Res · Pubmed #24089443.

ABSTRACT: Immune checkpoint blockade with monoclonal antibodies directed at the inhibitory immune receptors CTLA-4, PD-1, and PD-L1 has emerged as a successful treatment approach for patients with advanced melanoma. Ipilimumab is the first agent associated with a documented improved overall survival benefit in this patient population. A striking attribute of CTLA-4 blockade is the durability of objective responses, leading to speculation of a possible cure for some patients. Many tumor responses achieved with PD-1 and PD-L1 inhibition were durable in the phase I trials and were seen in a higher proportion of patients with melanoma than typically observed with ipilimumab. Biomarker development to identify the subset of patients with melanoma who will achieve durable clinical benefit with checkpoint blockade is critical; tumor PD-L1 expression has been promising in early studies. The contrast between unprecedented response rates but limited durability of responses achieved with BRAF and MEK inhibition in BRAF(V600)-mutated melanoma and the impressive durability but relatively low rate of response achieved with immune checkpoint blockade is striking. Preclinical data on potential synergies between CTLA-4/PD-1/PD-L1 inhibition and MAPK-targeted therapy is emerging, and combined immune checkpoint blockade and MAPK inhibition are being explored in clinical trials. Other promising approaches to increase the number of patients with melanoma who benefit from durable responses with immune checkpoint blockade include concurrent or sequenced CTLA-4 and PD-1/PD-L1 inhibition and combination with other immunotherapeutic strategies. Clin Cancer Res; 19(19); 5300-9. ©2013 AACR.

19 Review Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. 2013

Wolchok, Jedd D / Hodi, F Stephen / Weber, Jeffrey S / Allison, James P / Urba, Walter J / Robert, Caroline / O'Day, Steven J / Hoos, Axel / Humphrey, Rachel / Berman, David M / Lonberg, Nils / Korman, Alan J. ·Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. wolchokj@mskcc.org ·Ann N Y Acad Sci · Pubmed #23772560.

ABSTRACT: The immunotherapeutic agent ipilimumab has helped address a significant unmet need in the treatment of advanced melanoma. Ipilimumab is a fully human monoclonal antibody that targets cytotoxic T-lymphocyte antigen-4 (CTLA-4), thereby augmenting antitumor immune responses. After decades in which a number of clinical trials were conducted, ipilimumab was the first therapy to improve overall survival in a randomized, controlled phase III trial of patients with advanced melanoma. These results led to the regulatory approval of ipilimumab at 3 mg/kg for the treatment of unresectable or metastatic melanoma. More than 17,000 patients worldwide have received ipilimumab, either as a commercial drug at 3 mg/kg or in clinical trials and expanded access programs at different doses. Consistent with its proposed mechanism of action, the most common toxicities associated with ipilimumab therapy are inflammatory in nature. These immune-related adverse events were mostly reversible when effective treatment guidelines were followed. Importantly, long-term follow-up of patients who received ipilimumab in a phase III trial showed that 24% survived at least two years, and in phase II studies, a proportion of patients survived at least five years. Evaluation of ipilimumab is ongoing in the adjuvant setting for melanoma, and for advanced disease in nonsmall cell lung, small cell lung, prostate, ovarian, and gastric cancers.

20 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.

21 Review [Major therapeutic advances in the treatment of metastatic melanoma]. 2012

Mateus, Christine / Robert, Caroline. ·Institut Gustave-Roussy, service de dermatologie, 39, rue Camille-Desmoulins, 94805 Villejuif, France. christine.mateus@igr.fr ·Bull Cancer · Pubmed #22652330.

ABSTRACT: The treatment of metastatic melanoma is presently in complete revolution. Two molecules have recently been authorized for this indication. These treatments have a very different mechanism of action compared to previous chemotherapies. Vemurafenib is a targeted therapy, which blocks BRAF selectively. This molecule induces objective responses in more than 50 % of the patients with V600E mutated melanoma and a benefit in terms of overall survival. However, many patients relapse after about 6 to 8 months of treatment. Many mechanisms are evoked to explain these secondary resistances to therapy. Ipilimumab is an immunotherapy that blocks CTLA4, a physiological brake of lymphocyte activation. With ipilimumab, the objective responses are less frequent than with vemurafenib but are more prolonged over time. Two phases III have demonstrated that ipilimumab treatment is effective on the overall survival of patients with metastatic melanoma. New combination therapies and additional targeted and immunotherapy agents are exciting perspectives that make us more optimistic for the future of metastatic melanoma treatment.

22 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.

23 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.

24 Review [New treatments for metastatic melanoma: a first hope]. 2011

Robert, Caroline / Mateus, Christina. ·Caroline Service de dermatologie, Institut Gustave-Roussy, 94805 Villejuif. caroline.robert@igr.fr ·Rev Prat · Pubmed #22338196.

ABSTRACT: -- No abstract --

25 Review [Anti-CTLA-4 monoclonal antibody: a major step in the treatment of metastatic melanoma]. 2011

Robert, Caroline / Mateus, Christine. ·Institut Gustave Roussy, Villejuif, France. caroline.robert@igr.fr ·Med Sci (Paris) · Pubmed #22027422.

ABSTRACT: The anti-CTLA-4 Mab ipilimumab is an efficient treatment of metastatic melanoma as a single agent and combined with dacarbazine chemotherapy. The benefit is observed in 10 to 20 % of the patients but it is the only drug to demonstrate an increase in overall survival of patients with metastatic melanoma. The pattern of response is new with delayed and prolonged responses over time. New evaluation criteria have been proposed to evaluate the efficacy of this new therapy. The safety profile is new also with frequent and potentially severe side effects related to the activation of the immune system. The challenges are now to identify biomarkers able to predict ipilimumab benefit and to know how to use ipilimumab in combination with new targeted therapies of melanoma in order to optimize the treatment efficacy.

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