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Melanoma: HELP
Articles by Laurent Mortier
Based on 59 articles published since 2008
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Between 2008 and 2019, L. Mortier wrote the following 59 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Editorial [Difficult-to-diagnose melanomas: a key role for the dermatologist]. 2014

Mortier, L. ·Service de dermatologie, hôpital Claude-Huriez, centre hospitalier régional universitaire (CHRU), 1, rue Michel-Polonovski, 59037 Lille cedex, France. Electronic address: laurent.mortier@chru-lille.fr. ·Ann Dermatol Venereol · Pubmed #25442468.

ABSTRACT: -- No abstract --

2 Review Unclassified sclerosing malignant melanomas with AKAP9-BRAF gene fusion: a report of two cases and review of BRAF fusions in melanocytic tumors. 2018

Perron, Emilie / Pissaloux, Daniel / Neub, Angela / Hohl, Daniel / Tartar, Marie Dominique / Mortier, Laurent / Alberti, Laurent / de la Fouchardiere, Arnaud. ·Département de Biopathologie, Centre Leon Bérard, Lyon, France. emilie.perron.1@ulaval.ca. · Département de Biologie médicale, Service d'anatomopathologie, Centre hospitalier universitaire de Québec-Université Laval, 11 Côte du Palais, Québec, QC, G1R 2J6, Canada. emilie.perron.1@ulaval.ca. · Département de Biologie Moléculaire, de Biochimie Médicale et de Pathologie, Faculté de Médecine de l'Université Laval, Québec, Canada. emilie.perron.1@ulaval.ca. · Département de Biopathologie, Centre Leon Bérard, Lyon, France. · Service de Dermatologie et Vénérologie, Centre hospitalier universitaire vaudois (CHUV), Lausanne, Switzerland. · Service de Pathologie, Hôpital Jean Bernard, Valenciennes, France. · Service de Dermatologie, Université de Lille, INSERM U 1189, CHU Lille, F-59000, Lille, France. ·Virchows Arch · Pubmed #29464327.

ABSTRACT: The current classification of melanocytic tumors includes clinical, pathological, and molecular data. A subset of lesions remains difficult to classify according to these complex multilayer schemes. We report two cases of deeply infiltrating melanomas with a sclerosing background. The first case occurred on the back of a middle-aged man appearing clinically as a dermatofibroma. The architectural and cytological aspects resembled those of a desmoplastic melanoma but the strong expression of both melanA and HMB45, two stainings usually reported as negative in this entity, raised the question of an alternate diagnosis. The second case was a large, slowly growing, perivulvar tumor in a middle-aged woman. The morphology was complex with a central junctional spitzoid pattern associating an epidermal hyperplasia with large nests of large spindled melanocytes. The dermal component was made of deeply invasive strands and nests of nevoid unpigmented melanocytes surrounded by fibrosis; a perineural invasion was present at the periphery of the lesion. In both cases, aCGH found, among many other anomalies, a chromosomal breakpoint at the BRAF locus. RNA sequencing identified in both an AKAP9-BRAF gene fusion. A complementary resection was performed and no relapses have been observed in the respectively 15 and 6 months of follow-up. Both of these melanomas remained unclassified. We further review the variety of melanocytic tumors associated with such BRAF fusions.

3 Review [Systemic treatment of melanoma brain metastases]. 2015

Le Rhun, É / Mateus, C / Mortier, L / Dhermain, F / Guillot, B / Grob, J-J / Lebbe, C / Thomas, M / Jouary, T / Leccia, M-T / Robert, C. ·Neuro-oncologie, département de neurochirurgie, hôpital Roger-Salengro, CHRU, rue Émile-Laine, 59037 Lille cedex, France; Oncologie médicale, centre Oscar-Lambret, 3, rue Frédéric-Combemale, BP 307, 59020 Lille cedex, France; Inserm U1192, laboratoire Prism, université Lille 1, bâtiment SN3 1(er) étage, 59655 Villeneuve-d'Ascq cedex, France; Groupe de réflexion sur la prise en charge des métastases cérébrales (GRPCMaC), 13273 Marseille cedex 09, France. Electronic address: emilie.lerhun@chru-lille.fr. · Département de dermatologie, institut de cancérologie Gustave-Roussy, 114, rue Édouard-Vaillant, 94805 Villejuif cedex, France. · Département de dermatologie, centre hospitalier régional et universitaire de Lille, 2, avenue Oscar-Lambret, 59037 Lille cedex, France. · Groupe de réflexion sur la prise en charge des métastases cérébrales (GRPCMaC), 13273 Marseille cedex 09, France; Département de radiothérapie, institut de cancérologie Gustave-Roussy, 114, rue Édouard-Vaillant, 94805 Villejuif cedex, France; Réunion de concertation pluridisciplinaire de neuro-oncologie, institut de cancérologie Gustave-Roussy, 114, rue Édouard-Vaillant, 94805 Villejuif cedex, France. · Département de dermatologie, centre hospitalier universitaire, 80, avenue Augustin-Fliche, 34295 Montpellier cedex 5, France; Université Montpellier 1, 5, boulevard Henri-IV, CS 19044, 34967 Montpellier cedex 2, France. · Département de dermatologie, centre hospitalo-universitaire, AP-HM, 264, rue Saint-Pierre, 13385 Marseille cedex 05, France. · Département de dermatologie, hôpital Saint-Louis, Assistance publique-Hôpitaux de Paris, 1, avenue Claude-Vellefaux, 75010 Paris, France. · Service de dermatologie, pôle d'oncologie-radiothérapie, de dermatologie et des soins palliatifs, groupe hospitalier Saint-André, centre hospitalier universitaire de Bordeaux, 1, rue Jean-Burguet, 33075 Bordeaux, France. · Clinique de dermatologie, d'allergologie et de photobiologie, centre hospitalier Albert-Michallon, boulevard de la Chantourne, BP 217, 38043 Grenoble cedex 9, France; Inserm U832, institut A.-Bonniot, 38043 Grenoble cedex 09, France. ·Cancer Radiother · Pubmed #25656856.

ABSTRACT: Melanomas have a high rate of brain metastases. Both the functional prognosis and the overall survival are poor in these patients. Until now, surgery and radiotherapy represented the two main modalities of treatment. Nevertheless, due to the improvement in the management of the extracerebral melanoma, the systemic treatment may be an option in patients with brain metastases. Immunotherapy with anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) - ipilimumab - or BRAF (serine/threonine-protein kinase B-raf) inhibitors - vemurafenib, dabrafenib - has shown efficacy in the management of brain metastases in a- or pauci-symptomatic patients. Studies are ongoing with anti-PD1 (programmed cell death 1) and combinations of targeted therapies associating anti-RAF (raf proto-oncogene, serine/threonine kinase) and anti-MEK (mitogen-activated protein kinase kinase).

4 Review Metabolic features of melanoma: a gold mine of new therapeutic targets? 2014

Marchetti, Philippe / Guerreschi, Pierre / Kluza, Jérôme / Mortier, Laurent. ·INSERM U 837 Faculte de Medecine, 1, place Verdun F- 59045 Lille Cedex, France. philippe.marchetti@inserm.fr. ·Curr Cancer Drug Targets · Pubmed #24720363.

ABSTRACT: In recent years, our knowledge regarding the metabolism of melanoma has greatly advanced and consequently new therapeutic strategies are being developed. This review is focused on metabolic pathways contributing to melanoma proliferation, the influence of BRAF inhibitors on those metabolic pathways and finally a presentation of potential therapeutic strategies aimed at blocking metabolic signaling pathways and therefore melanoma development.

5 Review [Melanomas that are difficult to diagnose]. 2014

Vercambre-Darras, Sophie / Desmedt, Eve / Maire, Cyril / Mortier, Laurent. · ·Rev Prat · Pubmed #24649550.

ABSTRACT: -- No abstract --

6 Review [New breakthroughs in Oncodermatology]. 2010

Mortier, L. ·Clinique de Dermatologie, CHRU Lille, rue Michel Polonovski, 59037 Lille, France. laurent.mortier@chru-lille.fr ·Ann Dermatol Venereol · Pubmed #21193119.

ABSTRACT: During this year 2010, Oncodermatology was again the object of numerous publications. From the analysis of articles published between October 2009 and October 2010, choices had to be made. Overall, update on skin cancer has been dominated this year by breakthroughs on melanoma, which blows a wind of hope raised by the results of several clinical trials. Among those, it could be shown for the first time that a molecule was able to increase the overall survival of our patients (Ipilimumab). Spectacular results have also been obtained using anti-RAF. It seems that 2010 could be considered as a turning point in the therapeutic management of this cancer. In the field of lymphomas, several systemic treatments showed encouraging results in phase II and phase III trials.

7 Clinical Trial Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. 2017

Weber, Jeffrey / Mandala, Mario / Del Vecchio, Michele / Gogas, Helen J / Arance, Ana M / Cowey, C Lance / Dalle, Stéphane / Schenker, Michael / Chiarion-Sileni, Vanna / Marquez-Rodas, Ivan / Grob, Jean-Jacques / Butler, Marcus O / Middleton, Mark R / Maio, Michele / Atkinson, Victoria / Queirolo, Paola / Gonzalez, Rene / Kudchadkar, Ragini R / Smylie, Michael / Meyer, Nicolas / Mortier, Laurent / Atkins, Michael B / Long, Georgina V / Bhatia, Shailender / Lebbé, Celeste / Rutkowski, Piotr / Yokota, Kenji / Yamazaki, Naoya / Kim, Tae M / de Pril, Veerle / Sabater, Javier / Qureshi, Anila / Larkin, James / Ascierto, Paolo A / Anonymous7111184. ·From New York University Perlmutter Cancer Center, New York (J.W.) · Papa Giovanni XXIII Cancer Center Hospital, Bergamo (M. Mandala), Medical Oncology, National Cancer Institute, Milan (M.D.V.), Oncology Institute of Veneto Istituti di Ricovero e Cura a Carattere Scientifico, Padua (V.C.-S.), Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena (M. Maio), Ospedale Policlinico San Martino, Genoa (P.Q.), and Istituto Nazionale Tumori Fondazione Pascale, Naples (P.A.A.) - all in Italy · National and Kapodistrian University of Athens, Athens (H.J.G.) · Hospital Clinic de Barcelona, Barcelona (A.M.A.), and General University Hospital Gregorio Marañón, Madrid (I.M.-R.) - both in Spain · Texas Oncology-Baylor Cancer Center, Dallas (C.L.C.) · Hospices Civils de Lyon, Pierre Bénite (S.D.), Aix-Marseille University, Hospital de la Timone, Marseille (J.-J.G.), Institut Universitaire du Cancer de Toulouse and Centre Hospitalier Universitaire (CHU), Toulouse (N.M.), Université Lille, INSERM Unité 1189, CHU Lille, Lille (L.M.), and Assistance Publique-Hôpitaux de Paris, Dermatology and Centres d'Investigation Clinique, INSERM Unité 976, Hôpital Saint Louis, Université Paris Diderot, Paris (C.L.) - all in France · Oncology Center Sf. Nectarie, Craiova, Romania (M. Schenker) · Princess Margaret Cancer Centre, University of Toronto, Toronto (M.O.B.), and Cross Cancer Institute, Edmonton, AB (M. Smylie) - both in Canada · the Department of Oncology, University of Oxford, Oxford (M.R.M.), and Royal Marsden NHS Foundation Trust, London (J.L.) - both in the United Kingdom · Gallipoli Medical Research Foundation and University of Queensland, Queensland, VIC (V.A.), and Melanoma Institute Australia, University of Sydney, and Royal North Shore and Mater Hospitals, Sydney (G.V.L.) - all in Australia · University of Colorado, Denver (R.G.) · Winship Cancer Institute, Emory University School of Medicine, Atlanta (R.R.K.) · Georgetown-Lombardi Comprehensive Cancer Center, Washington DC (M.B.A.) · University of Washington, Seattle (S.B.) · Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.) · Nagoya University Graduate School of Medicine, Nagoya (K.Y.), and the National Cancer Center Hospital, Tokyo (N.Y.) - both in Japan · Seoul National University Hospital, Seoul, South Korea (T.M.K.) · and Bristol-Myers Squibb, Princeton, NJ (V.P, J.S., A.Q.). ·N Engl J Med · Pubmed #28891423.

ABSTRACT: BACKGROUND: Nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma. METHODS: In this randomized, double-blind, phase 3 trial, we randomly assigned 906 patients (≥15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence-free survival in the intention-to-treat population. RESULTS: At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment. CONCLUSIONS: Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 238 ClinicalTrials.gov number, NCT02388906 ; Eudra-CT number, 2014-002351-26 .).

8 Clinical Trial Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. 2017

Long, Georgina V / Hauschild, Axel / Santinami, Mario / Atkinson, Victoria / Mandalà, Mario / Chiarion-Sileni, Vanna / Larkin, James / Nyakas, Marta / Dutriaux, Caroline / Haydon, Andrew / Robert, Caroline / Mortier, Laurent / Schachter, Jacob / Schadendorf, Dirk / Lesimple, Thierry / Plummer, Ruth / Ji, Ran / Zhang, Pingkuan / Mookerjee, Bijoyesh / Legos, Jeff / Kefford, Richard / Dummer, Reinhard / Kirkwood, John M. ·From the Melanoma Institute Australia, University of Sydney, Royal North Shore and Mater Hospitals (G.V.L.), and Macquarie University, Melanoma Institute Australia, University of Sydney, and Westmead Hospital (R.K.), Sydney, Princess Alexandra Hospital, Gallipoli Medical Research Foundation, University of Queensland, Brisbane (V.A.), and Alfred Hospital, Melbourne, VIC (A. Haydon) - all in Australia · University Hospital Schleswig-Holstein, Kiel (A. Hauschild), and University Hospital Essen, Essen, and the German Cancer Consortium, Heidelberg (D.S.) - all in Germany · Fondazione Istituto Nazionale Tumori, Milan (M.S.), Papa Giovanni XXIII Cancer Center Hospital, Bergamo (M.M.), and the Melanoma Oncology Unit, Veneto Oncology Institute, Padua (V.C.-S.) - all in Italy · Rikshospitalet-Radiumhospitalet, Oslo (M.N.) · Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux (C.D.), Institute Gustave Roussy, Paris (C.R.), Université de Lille, INSERM Unité 1189, Centre Hospitalier Régional Universitaire de Lille, Lille (L.M.), and the Medical Oncology Department, Centre Eugène Marquis, Rennes (T.L.) - all in France · Ella Institute for Melanoma, Sheba Medical Center, Tel Hashomer, Israel (J.S.) · Royal Marsden NHS Foundation Trust, London (J. Larkin), and Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne (R.P.) - both in the United Kingdom · Novartis Pharmaceuticals, East Hanover, NJ (R.J., P.Z., B.M., J. Legos) · University Hospital Zürich Skin Cancer Center, Zurich, Switzerland (R.D.) · and the Melanoma Program, Hillman UPMC Cancer Center, University of Pittsburgh, Pittsburgh (J.M.K.). ·N Engl J Med · Pubmed #28891408.

ABSTRACT: BACKGROUND: Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety. RESULTS: At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval [CI], 0.39 to 0.58; P<0.001). The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P=0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma. CONCLUSIONS: Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov, NCT01682083 ; EudraCT number, 2012-001266-15 .).

9 Clinical Trial Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). 2017

Schachter, Jacob / Ribas, Antoni / Long, Georgina V / Arance, Ana / Grob, Jean-Jacques / Mortier, Laurent / Daud, Adil / Carlino, Matteo S / McNeil, Catriona / Lotem, Michal / Larkin, James / Lorigan, Paul / Neyns, Bart / Blank, Christian / Petrella, Teresa M / Hamid, Omid / Zhou, Honghong / Ebbinghaus, Scot / Ibrahim, Nageatte / Robert, Caroline. ·Division of Oncology, Ella Lemelbaum Institute for Melanoma, Sheba Medical Center, Tel Hashomer, Israel. Electronic address: jacob.schachter@sheba.health.gov.il. · Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. · Department of Medical Oncology and Translational Research, Melanoma Institute Australia, The University of Sydney, Mater Hospital and Royal North Shore Hospital, Sydney, Australia. · Department of Medical Oncology, Hospital Clinic de Barcelona, Barcelona, Spain. · Department of Dermatology and Skin Cancer, Aix Marseille University, Hôpital de la Timone, Marseille, France. · Department of Dermatology, Université Lille, INSERM U1189, CHU Lille, F-59000, France. · Department of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA. · Department of Medical Oncology, Westmead and Blacktown Hospitals, Melanoma Institute Australia, and The University of Sydney, Sydney, Australia. · Department of Medical Oncology, Chris O'Brien Lifehouse, Royal Prince Alfred Hospital, and Melanoma Institute Australia, Camperdown, Australia. · Department of Melanoma and Cancer Immunotherapy, Sharett Institute of Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel. · Department of Medical Oncology, Royal Marsden Hospital, London, UK. · Department of Medical Oncology University of Manchester and the Christie NHS Foundation Trust, Manchester, UK. · Department of Medical Oncology, Universitair Ziekenhuis Brussel, Brussels, Belgium. · Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands. · Department of Medicine, Division of Medical Oncology/Hematology, Sunnybrook Health Sciences Center, Toronto, ON, Canada. · Department of Hematology/Oncology, The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Department of BARDS, Merck & Co, Kenilworth, NJ, USA. · Department of Clinical Oncology, Merck & Co, Kenilworth, NJ, USA. · Department of Oncology, Gustave Roussy and Paris-Sud University, Villejuif, France. ·Lancet · Pubmed #28822576.

ABSTRACT: BACKGROUND: Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis. METHODS: In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of pembrolizumab, or one regimen of ipilimumab, using a centralised, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3, 2015. This study was registered with ClinicalTrials.gov, number NCT01866319. FINDINGS: Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous pembrolizumab every 2 weeks (n=279), intravenous pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either pembrolizumab group and was 16·0 months with ipilimumab (hazard ratio [HR] 0·68, 95% CI 0·53-0·87 for pembrolizumab every 2 weeks vs ipilimumab; p=0·0009 and 0·68, 0·53-0·86 for pembrolizumab every 3 weeks vs ipilimumab; p=0·0008). 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group. INTERPRETATION: Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between pembrolizumab dosing schedules. These conclusions further support the use of pembrolizumab as a standard of care for advanced melanoma. FUNDING: Merck & Co.

10 Clinical Trial Dabrafenib plus trametinib in patients with BRAF 2017

Davies, Michael A / Saiag, Philippe / Robert, Caroline / Grob, Jean-Jacques / Flaherty, Keith T / Arance, Ana / Chiarion-Sileni, Vanna / Thomas, Luc / Lesimple, Thierry / Mortier, Laurent / Moschos, Stergios J / Hogg, David / Márquez-Rodas, Iván / Del Vecchio, Michele / Lebbé, Céleste / Meyer, Nicolas / Zhang, Ying / Huang, Yingjie / Mookerjee, Bijoyesh / Long, Georgina V. ·Melanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: mdavies@mdanderson.org. · Service de Dermatologie Générale et Oncologique, Hôpital A Paré, Assistance Publique-Hôpitaux de Paris, Boulogne Billancourt, France; EA 4340, Université Versailles Saint-Quentin-en-Yvelines, Boulogne Billancourt, France. · Gustave Roussy, Département de Médecine Oncologique, Service de Dermatologie et Université Paris-Sud, Faculté de Médecine, Villejuif, France. · Service de Dermatologie, Centre Hospitalo-Universitaire Timone, Aix Marseille University, Marseille, France. · Developmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, Boston, MA, USA. · Department of Medical Oncology, Hospital Clinic of Barcelona, Carrer de Villarroel, Barcelona, Spain. · Melanoma and Oesophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Padova, Italy. · Service de Dermatologie, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France. · Oncologie Dermatologique, Centre Eugène Marquis, Rennes, France. · Clinique de Dermatologie, Unité d'Onco-Dermatologie, Le Centre Hospitalier Régional Universitaire de Lille, University Lille 2, Lille, France. · Melanoma Program, Medical Oncology, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA. · Clinical Cancer Research Unit, Princess Margaret Cancer Centre, Toronto, ON, Canada. · Servicio de Oncología Médica; Hospital General Universitario Gregorio Marañon, Madrid, Spain. · Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · APHP Dermatology and CIC Departments, INSERM U976, University Paris Diderot, Hôpital Saint Louis Paris, Paris, France. · Medical Oncology, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France. · Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. · Melanoma Institute Australia, The University of Sydney, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. ·Lancet Oncol · Pubmed #28592387.

ABSTRACT: BACKGROUND: Dabrafenib plus trametinib improves clinical outcomes in BRAF METHODS: This ongoing, multicentre, multicohort, open-label, phase 2 study evaluated oral dabrafenib (150 mg twice per day) plus oral trametinib (2 mg once per day) in four patient cohorts with melanoma brain metastases enrolled from 32 hospitals and institutions in Europe, North America, and Australia: (A) BRAF FINDINGS: Between Feb 28, 2014, and Aug 5, 2016, 125 patients were enrolled in the study: 76 patients in cohort A; 16 patients in cohort B; 16 patients in cohort C; and 17 patients in cohort D. At the data cutoff (Nov 28, 2016) after a median follow-up of 8·5 months (IQR 5·5-14·0), 44 (58%; 95% CI 46-69) of 76 patients in cohort A achieved an intracranial response. Intracranial response by investigator assessment was also achieved in nine (56%; 95% CI 30-80) of 16 patients in cohort B, seven (44%; 20-70) of 16 patients in cohort C, and ten (59%; 33-82) of 17 patients in cohort D. The most common serious adverse events related to study treatment were pyrexia for dabrafenib (eight [6%] of 125 patients) and decreased ejection fraction (five [4%]) for trametinib. The most common grade 3 or worse adverse events, regardless of study drug relationship, were pyrexia (four [3%] of 125) and headache (three [2%]). INTERPRETATION: Dabrafenib plus trametinib was active with a manageable safety profile in this melanoma population that was consistent with previous dabrafenib plus trametinib studies in patients with BRAF FUNDING: Novartis.

11 Clinical Trial Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. 2017

Ascierto, Paolo A / Del Vecchio, Michele / Robert, Caroline / Mackiewicz, Andrzej / Chiarion-Sileni, Vanna / Arance, Ana / Lebbé, Céleste / Bastholt, Lars / Hamid, Omid / Rutkowski, Piotr / McNeil, Catriona / Garbe, Claus / Loquai, Carmen / Dreno, Brigitte / Thomas, Luc / Grob, Jean-Jacques / Liszkay, Gabriella / Nyakas, Marta / Gutzmer, Ralf / Pikiel, Joanna / Grange, Florent / Hoeller, Christoph / Ferraresi, Virginia / Smylie, Michael / Schadendorf, Dirk / Mortier, Laurent / Svane, Inge Marie / Hennicken, Delphine / Qureshi, Anila / Maio, Michele. ·Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. Electronic address: paolo.ascierto@gmail.com. · Medical Oncology, National Cancer Institute, Milan, Italy. · Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. · Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, Poznan Medical University, Poznan, Poland. · IOV-IRCCS, Melanoma Oncology Unit, Padova, Italy. · Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain. · AP-HP Dermatology CIC Departments, Saint-Louis Hospital, INSERM U976, Université Paris Diderot, Paris, France. · Odense University Hospital, Odense, Denmark. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland. · Chris O'Brien Lifehouse and Royal Prince Alfred Hospital, Camperdown, NSW, Australia; Melanoma Institute Australia, Sydney, NSW, Australia. · Eberhard Karls University, Tübingen, Germany. · University Medical Center, Mainz, Germany. · Department of Oncodermatology, INSERM Research Unit 892, Nantes University Hospital, Nantes, France. · Department of Dermatology, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France. · Hospital de la Timone, Marseille, France. · National Institute of Oncology, Budapest, Hungary. · Oslo University Hospital, Oslo, Norway. · Medizinische Hochschule Hannover, Hannover, Germany. · Wojewodzkie Centrum Oncologii, Gdańsk, Poland. · Department of Dermatology, Reims University Hospital, Reims, France. · Medical University of Vienna, Vienna, Austria. · Istituti Fisioterapici Ospitalieri, Rome, Italy. · Cross Cancer Institute, Edmonton, AB, Canada. · University Hospital Essen, Essen, Germany. · Hôspital Claude Huriez, Lille, France. · Herlev Hospital, University of Copenhagen, Herlev, Denmark. · Bristol-Myers Squibb, Princeton, NJ, USA. · University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. ·Lancet Oncol · Pubmed #28359784.

ABSTRACT: BACKGROUND: A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3-4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit-risk profile of ipilimumab 10 mg/kg versus 3 mg/kg. METHODS: This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov, number NCT01515189. FINDINGS: Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6-42·3) for the ipilimumab 10 mg/kg group and 11·2 months (4·9-29·4) for the ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6-17·8) for ipilimumab 10 mg/kg compared with 11·5 months (9·9-13·3) for ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70-0·99; p=0·04). The most common grade 3-4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (<1%) patients died from treatment-related adverse events. INTERPRETATION: In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment. FUNDING: Bristol-Myers Squibb.

12 Clinical Trial Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. 2016

Eggermont, Alexander M M / Chiarion-Sileni, Vanna / Grob, Jean-Jacques / Dummer, Reinhard / Wolchok, Jedd D / Schmidt, Henrik / Hamid, Omid / Robert, Caroline / Ascierto, Paolo A / Richards, Jon M / Lebbé, Céleste / Ferraresi, Virginia / Smylie, Michael / Weber, Jeffrey S / Maio, Michele / Bastholt, Lars / Mortier, Laurent / Thomas, Luc / Tahir, Saad / Hauschild, Axel / Hassel, Jessica C / Hodi, F Stephen / Taitt, Corina / de Pril, Veerle / de Schaetzen, Gaetan / Suciu, Stefan / Testori, Alessandro. ·From Gustave Roussy Cancer Campus Grand Paris, Villejuif (A.M.M.E., C.R.), Aix-Marseille University, Hôpital de La Timone, Marseille (J.-J.G.), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris (C.L.), University Lille, INSERM Unité-1189, Centre Hospitalier Universitaire (CHU) Lille, Service de Dermatologie, Lille (L.M.), and CHU Lyon, Lyon (L.T.) - all in France · the Oncology Institute of Veneto-Istituto di Ricovero e Cura a Carattere Scientifico, Padua (V.C.-S.), Istituto Nazionale Tumori Fondazione G. Pascale, Naples (P.A.A.), Istituti Fisioterapici Ospitalieri, Rome (V.F.), University Hospital of Siena, Istituto Toscano Tumori, Siena (M.M.), and the European Institute of Oncology, Milan (A.T.) - all in Italy · University of Zurich Hospital, Zurich, Switzerland (R.D.) · Memorial Sloan Kettering Cancer Center, New York (J.D.W.) · Aarhus University Hospital, Aarhus (H.S.), and Odense University Hospital, Odense (L.B.) - both in Denmark · the Angeles Clinic and Research Institute, Los Angeles (O.H.) · Oncology Specialists, Park Ridge, IL (J.M.R.) · Cross Cancer Institute, Edmonton, AB, Canada (M.S.) · H. Lee Moffitt Cancer Center, Tampa, FL (J.S.W.) · Broomfield Hospital, Chelmsford, United Kingdom (S.T.) · Universitätsklinikum Schleswig-Holstein, Kiel (A.H.), and University Hospital Heidelberg, Heidelberg (J.C.H.) - both in Germany · Dana-Farber Cancer Institute, Boston (F.S.H.) · Bristol-Myers Squibb, Princeton, NJ (C.T., V.P.) · and the European Organization for Research and Treatment of Cancer, Brussels (G.S., S.S.). ·N Engl J Med · Pubmed #27717298.

ABSTRACT: BACKGROUND: On the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma. METHODS: After patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred. Recurrence-free survival was the primary end point. Secondary end points included overall survival, distant metastasis-free survival, and safety. RESULTS: At a median follow-up of 5.3 years, the 5-year rate of recurrence-free survival was 40.8% in the ipilimumab group, as compared with 30.3% in the placebo group (hazard ratio for recurrence or death, 0.76; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). The rate of overall survival at 5 years was 65.4% in the ipilimumab group, as compared with 54.4% in the placebo group (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P=0.001). The rate of distant metastasis-free survival at 5 years was 48.3% in the ipilimumab group, as compared with 38.9% in the placebo group (hazard ratio for death or distant metastasis, 0.76; 95.8% CI, 0.64 to 0.92; P=0.002). Adverse events of grade 3 or 4 occurred in 54.1% of the patients in the ipilimumab group and in 26.2% of those in the placebo group. Immune-related adverse events of grade 3 or 4 occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. In the ipilimumab group, 5 patients (1.1%) died owing to immune-related adverse events. CONCLUSIONS: As adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis-free survival than placebo. There were more immune-related adverse events with ipilimumab than with placebo. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00636168 , and EudraCT number, 2007-001974-10 .).

13 Clinical Trial First-in-human phase I study of the DNA-repair inhibitor DT01 in combination with radiotherapy in patients with skin metastases from melanoma. 2016

Le Tourneau, C / Dreno, B / Kirova, Y / Grob, J J / Jouary, T / Dutriaux, C / Thomas, L / Lebbé, C / Mortier, L / Saiag, P / Avril, M F / Maubec, E / Joly, P / Bey, P / Cosset, J M / Sun, J S / Asselain, B / Devun, F / Marty, M E / Dutreix, M. ·Department of Medical Oncology, Institut Curie, Paris & Saint-Cloud 75005, France. · EA7285, Versailles-Saint-Quentin-en-Yvelines University, Versailles 78000, France. · CHU de Nantes-Hôtel Dieu, Nantes 44093, France. · Radiotherapy Department, Institut Curie, Paris 75005, France. · La Timone Hospital-APHM, Aix-Marseille University, Marseille 13385, France. · Dermatology department, Saint-André Hospital, CHU de Bordeaux, Bordeaux 33000, France. · Lyon Sud Hospital Center, Lyon 1 University, Pierre Benite 69495, France. · Saint-Louis Hospital, APHP, Paris 75010, France. · Dermatology department, CHRU of Lille, Lille 59037, France. · Ambroise Paré Hospital, Boulogne Billancourt 92104, France. · Cochin hospital, APHP, Paris 75014, France. · Bichat Hospital, Paris 75877, France. · CHU Rouen, Charles-Nicolle, Rouen 76000, France. · Institut Curie, Paris 75005, France. · DNA Therapeutics, Evry 91058, France. · Department of Biostatistics, Institut Curie, Paris 75005, France. · Institut Curie, Orsay 91405, France. · CNRS-UMR3347, INSERM-U1021, Paris-Sud University, Orsay 91405, France. ·Br J Cancer · Pubmed #27140316.

ABSTRACT: BACKGROUND: DT01 is a DNA-repair inhibitor preventing recruitment of DNA-repair enzymes at damage sites. Safety, pharmacokinetics and preliminary efficacy through intratumoural and peritumoural injections of DT01 were evaluated in combination with radiotherapy in a first-in-human phase I trial in patients with unresectable skin metastases from melanoma. METHODS: Twenty-three patients were included and received radiotherapy (30 Gy in 10 sessions) on all selected tumour lesions, comprising of two lesions injected with DT01 three times a week during the 2 weeks of radiotherapy. DT01 dose levels of 16, 32, 48, 64 and 96 mg were used, in a 3+3 dose escalation design, with an expansion cohort at 96 mg. RESULTS: The median follow-up was 180 days. All patients were evaluable for safety and pharmacokinetics. No dose-limiting toxicity was observed and the maximum-tolerated dose was not reached. Most frequent adverse events were reversible grades 1 and 2 injection site reactions. Pharmacokinetic analyses demonstrated a systemic passage of DT01. Twenty-one patients were evaluable for efficacy on 76 lesions. Objective response was observed in 45 lesions (59%), including 23 complete responses (30%). CONCLUSIONS: Intratumoural and peritumoural DT01 in combination with radiotherapy is safe and pharmacokinetic analyses suggest a systemic passage of DT01.

14 Clinical Trial Pembrolizumab versus Ipilimumab in Advanced Melanoma. 2015

Robert, Caroline / Schachter, Jacob / Long, Georgina V / Arance, Ana / Grob, Jean Jacques / Mortier, Laurent / Daud, Adil / Carlino, Matteo S / McNeil, Catriona / Lotem, Michal / Larkin, James / Lorigan, Paul / Neyns, Bart / Blank, Christian U / Hamid, Omid / Mateus, Christine / Shapira-Frommer, Ronnie / Kosh, Michele / Zhou, Honghong / Ibrahim, Nageatte / Ebbinghaus, Scot / Ribas, Antoni / Anonymous4340827. ·The authors' affiliations are listed in the Appendix. ·N Engl J Med · Pubmed #25891173.

ABSTRACT: BACKGROUND: The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma. METHODS: In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival. RESULTS: The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%). CONCLUSIONS: The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.).

15 Clinical Trial Nivolumab in previously untreated melanoma without BRAF mutation. 2015

Robert, Caroline / Long, Georgina V / Brady, Benjamin / Dutriaux, Caroline / Maio, Michele / Mortier, Laurent / Hassel, Jessica C / Rutkowski, Piotr / McNeil, Catriona / Kalinka-Warzocha, Ewa / Savage, Kerry J / Hernberg, Micaela M / Lebbé, Celeste / Charles, Julie / Mihalcioiu, Catalin / Chiarion-Sileni, Vanna / Mauch, Cornelia / Cognetti, Francesco / Arance, Ana / Schmidt, Henrik / Schadendorf, Dirk / Gogas, Helen / Lundgren-Eriksson, Lotta / Horak, Christine / Sharkey, Brian / Waxman, Ian M / Atkinson, Victoria / Ascierto, Paolo A. ·The authors' affiliations are listed in the Appendix. ·N Engl J Med · Pubmed #25399552.

ABSTRACT: BACKGROUND: Nivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma. The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study. METHODS: We randomly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks). The primary end point was overall survival. RESULTS: At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P<0.001). The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P<0.001). The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P<0.001). The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups, including subgroups defined by status regarding the programmed death ligand 1 (PD-L1). Common adverse events associated with nivolumab included fatigue, pruritus, and nausea. Drug-related adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine. CONCLUSIONS: Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation. (Funded by Bristol-Myers Squibb; CheckMate 066 ClinicalTrials.gov number, NCT01721772.).

16 Clinical Trial Improved overall survival in melanoma with combined dabrafenib and trametinib. 2015

Robert, Caroline / Karaszewska, Boguslawa / Schachter, Jacob / Rutkowski, Piotr / Mackiewicz, Andrzej / Stroiakovski, Daniil / Lichinitser, Michael / Dummer, Reinhard / Grange, Florent / Mortier, Laurent / Chiarion-Sileni, Vanna / Drucis, Kamil / Krajsova, Ivana / Hauschild, Axel / Lorigan, Paul / Wolter, Pascal / Long, Georgina V / Flaherty, Keith / Nathan, Paul / Ribas, Antoni / Martin, Anne-Marie / Sun, Peng / Crist, Wendy / Legos, Jeff / Rubin, Stephen D / Little, Shonda M / Schadendorf, Dirk. ·The authors' affiliations are listed in the Appendix. ·N Engl J Med · Pubmed #25399551.

ABSTRACT: BACKGROUND: The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients. METHODS: In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival. RESULTS: At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combination-therapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group. CONCLUSIONS: Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01597908.).

17 Clinical Trial Selection of immunostimulant AS15 for active immunization with MAGE-A3 protein: results of a randomized phase II study of the European Organisation for Research and Treatment of Cancer Melanoma Group in Metastatic Melanoma. 2013

Kruit, Wim H J / Suciu, Stefan / Dreno, Brigitte / Mortier, Laurent / Robert, Caroline / Chiarion-Sileni, Vanna / Maio, Michele / Testori, Alessandro / Dorval, Thierry / Grob, Jean-Jacques / Becker, Juergen C / Spatz, Alan / Eggermont, Alexander M M / Louahed, Jamila / Lehmann, Frédéric F / Brichard, Vincent G / Keilholz, Ulrich. ·Department of Internal Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, the Netherlands. w.kruit@erasmusmc.nl ·J Clin Oncol · Pubmed #23715572.

ABSTRACT: PURPOSE: Active immunization against the tumor-specific MAGE-A3 antigen is followed by a few but impressive and durable clinical responses. This randomized phase II trial evaluated two different immunostimulants combined with the MAGE-A3 protein to investigate whether a more robust and persistent immune response could be associated with increased clinical benefit. PATIENTS AND METHODS: Patients with MAGE-A3-positive stage III or IV M1a melanoma were randomly assigned to receive the MAGE-A3 protein combined either with AS02B or with AS15 immunostimulant. Clinical end points were toxicity and rates of objective clinical responses, progression-free survival (PFS), and overall survival (OS). RESULTS: Seventy-five patients were treated, with 36 eligible patients per arm. Both treatments were well tolerated. In the AS15 arm, four objective responses were observed (three complete responses and one partial response) versus one partial response in the AS02B arm. In the AS15 and AS02B arms, the PFS rates after 6 months were 25% and 14%, respectively; and the median OS times were 33 months and 19.9 months, respectively, with a median observation period of 48 months. Antibodies against MAGE-A3, found in all patients, showed three-fold higher titers in the AS15 arm. The anti-MAGE-A3 cellular response was also more pronounced in the AS15 arm. CONCLUSION: In the MAGE-A3+AS15 arm, clinical activity was higher and the immune response more robust. Therefore, the AS15 immunostimulant was selected for combination with the MAGE-A3 protein in phase III trials.

18 Clinical Trial Final results of phase III SYMMETRY study: randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma. 2013

O'Day, Steven J / Eggermont, Alexander M M / Chiarion-Sileni, Vanna / Kefford, Richard / Grob, Jean Jacques / Mortier, Laurent / Robert, Caroline / Schachter, Jacob / Testori, Alessandro / Mackiewicz, Jacek / Friedlander, Philip / Garbe, Claus / Ugurel, Selma / Collichio, Frances / Guo, Wei / Lufkin, Joelle / Bahcall, Safi / Vukovic, Vojo / Hauschild, Axel. ·Los Angeles Skin Cancer Institute, The Beverly Hills Cancer Center, 8900 Wilshire Blvd, Beverly Hills, CA 90211, USA. stevenjoday@gmail.com ·J Clin Oncol · Pubmed #23401447.

ABSTRACT: PURPOSE: Elesclomol, an investigational first-in-class compound, induces oxidative stress, triggers mitochondrial-induced apoptosis in cancer cells, and shows synergy with taxanes in tumor models. Following completion of a phase II trial of elesclomol in combination with paclitaxel that met its primary end point of progression-free survival (PFS), this randomized, double-blind, controlled phase III study was conducted to confirm the efficacy and tolerability of elesclomol in combination with paclitaxel versus paclitaxel alone in patients with advanced melanoma. PATIENTS AND METHODS: Patients with stage IV chemotherapy-naive melanoma (n = 651) were randomly assigned 1:1 to paclitaxel 80 mg/m(2) either alone or in combination with elesclomol 213 mg/m(2) administered weekly for 3 weeks of a 4-week cycle. Patients were stratified by prior systemic treatment, M1 subclass, and baseline lactate dehydrogenase (LDH) levels. The primary end point was PFS. RESULTS: The study did not achieve its PFS end point (hazard ratio, 0.89; P = .23). The study was stopped when an early overall survival data analysis indicated an imbalance in total deaths favoring paclitaxel, predominantly in patients with high LDH levels. A prospectively defined subgroup analysis revealed a statistically significant improvement in median PFS for the combination in patients with normal baseline LDH. CONCLUSION: The addition of elesclomol to paclitaxel did not significantly improve PFS in unselected patients with advanced melanoma. The association between baseline LDH and clinical outcomes suggests that LDH may be a predictive factor for treatment with this combination, consistent with recent findings on the association between elesclomol anticancer activity and cellular metabolic state.

19 Clinical Trial Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. 2012

Long, Georgina V / Trefzer, Uwe / Davies, Michael A / Kefford, Richard F / Ascierto, Paolo A / Chapman, Paul B / Puzanov, Igor / Hauschild, Axel / Robert, Caroline / Algazi, Alain / Mortier, Laurent / Tawbi, Hussein / Wilhelm, Tabea / Zimmer, Lisa / Switzky, Julie / Swann, Suzanne / Martin, Anne-Marie / Guckert, Mary / Goodman, Vicki / Streit, Michael / Kirkwood, John M / Schadendorf, Dirk. ·Melanoma Institute Australia, Westmead Institute for Cancer Research, and Westmead Hospital, The University of Sydney, Sydney, NSW, Australia. georgina.long@sydney.edu.au ·Lancet Oncol · Pubmed #23051966.

ABSTRACT: BACKGROUND: Brain metastases are common in patients with metastatic melanoma and median overall survival from their diagnosis is typically 17-22 weeks. We assessed dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain. METHODS: We undertook a multicentre, open-label, phase 2 trial in 24 centres in six countries. We enrolled patients with histologically confirmed Val600Glu or Val600Lys BRAF-mutant melanoma and at least one asymptomatic brain metastasis (≥5 mm and ≤40 mm in diameter). Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had adequate organ function. Patients were split into two cohorts: those in cohort A had not received previous local treatment for brain metastases and those in cohort B had progressive brain metastases after previous local treatments. Patients received 150 mg oral dabrafenib twice a day until disease progression, death, or unacceptable adverse events. The primary endpoint was the proportion of patients with Val600Glu BRAF-mutant melanoma who achieved an overall intracranial response, which was defined as a complete response or partial response assessed with a modified form of Response Evaluation Criteria in Solid Tumors (RECIST 1.1). We included patients who received at least one dose of dabrafenib in efficacy and safety analyses. This study is registered with ClinicalTrials.gov, number NCT01266967. FINDINGS: Between Feb 2, 2011, and Aug 5, 2011, we enrolled 172 patients: 89 (52%) in cohort A and 83 (48%) in cohort B. 139 (81%) had Val600Glu BRAF-mutant melanoma. 29 (39·2%, 95% CI 28·0-51·2) of 74 patients with Val600Glu BRAF-mutant melanoma in cohort A achieved an overall intracranial response, as did 20 (30·8%, 19·9-43·4) of 65 in cohort B. One (6·7%, 0·2-31·9) of 15 patients with Val600Lys BRAF-mutant melanoma achieved an overall intracranial response in cohort A, as did four (22·2%, 6·4-47·6) of 18 such patients in cohort B. Treatment-related adverse events of grade 3 or worse occurred in 38 (22%) patients. Eleven (6%) patients developed squamous-cell carcinoma (five [6%] patients in cohort A, of whom one also had keratoacanthoma; six [7%] in cohort B). Four grade 4 treatment-related adverse events occurred in cohort A: one blood amylase increase, one convulsion, one lipase increase, and one neutropenia. Two grade 4 events occurred in cohort B: one agranulocytosis and one intracranial haemorrhage. 51 (30%) patients had a serious adverse event. The three most frequent serious adverse events were pyrexia (ten [6%] patients), intracranial haemorrhage (ten [6%]; one treatment-related), and squamous-cell carcinoma (11 [6%]). INTERPRETATION: Dabrafenib has activity and an acceptable safety profile in patients with Val600Glu BRAF-mutant melanoma and brain metastases irrespective of whether they are untreated or have been previously treated but have progressed. FUNDING: GlaxoSmithKline.

20 Clinical Trial Topical treatment of cutaneous metastases of malignant melanoma using combined imiquimod and 5-fluorouracil. 2012

Florin, Valerie / Desmedt, Eve / Vercambre-Darras, Sophie / Mortier, Laurent. ·Department of Dermatology, Claude-Huriez Hospital, University Hospital of Lille, Lille, France. ·Invest New Drugs · Pubmed #21748297.

ABSTRACT: BACKGROUND: Despite multiple available options, the treatment of cutaneous melanoma metastases is often unsuccessful. Based on the hypothesis that imiquimod and 5-fluorouracil have synergistic antitumor properties, we used this topical combination to treat several patients. AIM: Our objective was to investigate the treatment combination in a small cohort of patients with surgically non-resectable melanoma metastases. METHODS: The lesions of 5 patients with multiple cutaneous metastases were treated topically, 5 days per week, with 5-fluorouracil in the morning and imiquimod at night. RESULTS: 45 lesions were treated. A clinical response was seen in 44 lesions, with a complete response in 19 lesions and a partial response in 25. Stable disease was confirmed in the 1 remaining lesion. No patients developed new lesions during treatment. However, one patient had a recurrence 6 months after treatment discontinuation, followed by a partial response when rechallenged. CONCLUSIONS: The imiquimod and 5-fluorouracil combination is effective. That patients did not develop new, distant lesions suggests the achievement of locoregional control, probably by the induction of antitumor immune response.

21 Clinical Trial Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). 2011

Patel, Poulam M / Suciu, Stefan / Mortier, Laurent / Kruit, Wim H / Robert, Caroline / Schadendorf, Dirk / Trefzer, Uwe / Punt, Cornelis J A / Dummer, Reinhard / Davidson, Neville / Becker, Juergen / Conry, Robert / Thompson, John A / Hwu, Wen-Jen / Engelen, Kristel / Agarwala, Sanjiv S / Keilholz, Ulrich / Eggermont, Alexander M M / Spatz, Alain / Anonymous2540695. ·Academic Unit of Clinical Oncology, University of Nottingham, Nottingham, United Kingdom. poulam.patel@nottingham.ac.uk ·Eur J Cancer · Pubmed #21600759.

ABSTRACT: PURPOSE: To compare the efficacy of an extended schedule escalated dose of temozolomide versus standard dose dacarbazine in a large population of patients with stage IV melanoma. PATIENTS AND METHODS: A total of 859 patients were randomised to receive oral temozolomide at 150 mg/m(2)/day for seven consecutive days every 2 weeks or dacarbazine, administered as an intravenous infusion at 1000 mg/m(2)/day on day 1 every 3 weeks. The primary endpoint was overall survival (OS), using an intent-to-treat principle. EudraCT number 2004-000654-23 NCI registration number NCT00005052. RESULTS: Median OS was 9.1 months in the temozolomide arm and 9.4 months in the dacarbazine arm, with a hazard ratio (HR) of 1.00 (95%confidence interval [CI]: 0.86, 1.17; P=0.99). Median progression-free survival (PFS) was 2.3 months in the temozolomide arm and 2.2 months in the dacarbazine arm, with a HR of 0.92 (95%CI: 0.80, 1.06; P=0.27). In patients with measurable disease, overall response rate was higher in the temozolomide arm than in the dacarbazine arm (14.5% versus 9.8%, respectively), but the median duration of response was longer for dacarbazine. The extended schedule, escalated dose temozolomide arm showed more toxicity than the standard dose, single agent dacarbazine arm. The most common non-haematological treatment emergent adverse events reported in both treatment arms were nausea, fatigue and vomiting and constipation. CONCLUSION: Extended schedule escalated dose Temozolomide (7 days on 7 days off) is feasible and has an acceptable safety profile, but does not improve OS and PFS in metastatic melanoma when compared to standard dose dacarbazine.

22 Article Severe skin toxicity with organ damage under the combination of targeted therapy following immunotherapy in metastatic melanoma. 2018

Lamiaux, Marie / Scalbert, Camille / Lepesant, Pauline / Desmedt, Eve / Templier, Carole / Dziwniel, Véronique / Staumont-Sallé, Delphine / Mortier, Laurent. ·Department of Dermatology, Claude Huriez Hospital, CHRU Lille. · Department of Health, Lille 2 University. · Department of Modern Languages, Centrale Lille, Villeneuve d'Ascq. · Image-Assisted Laser Therapies for Oncology: ONCO-THAI, Inserm U1189, Lille, France. ·Melanoma Res · Pubmed #29985833.

ABSTRACT: Targeted therapy combination (TTC: antiRAF+antiMEK) is known to improve metastatic melanoma survival. Few severe skin toxicities (grade ≥3) are described with first-line TTC (17% for vemurafenib+cobimetinib and none for dabrafenib+trametinib) in a phase III trial. Among our 42 patients treated by TTC between January 2014 and March 2017, 4.8% (2/42) of those treated in the first line presented severe skin rash versus 19% (8/42) of patients treated in the second line after previous immunotherapy. In particular, we observed one case of Stevens-Johnson syndrome and four cases of severe drug reaction with eosinophilia and systemic symptoms syndrome under TTC in patients who had received immunotherapy previously. Thus, previous immunotherapy appears to play an important role in the skin rash onset and severity induced by TTC.

23 Article Chemical meningitis related to intra-CSF liposomal cytarabine. 2017

Durand, Bénédicte / Zairi, Fahed / Boulanger, Thomas / Bonneterre, Jacques / Mortier, Laurent / Le Rhun, Emilie. ·Lille University, F-59000 Lille, France. · Oscar Lambret Center, Medical Oncology Department, F-59000 Lille, France. · Inserm, U-1192, F-59000 Lille, France. · CHU Lille, Neurosurgery Department, F-59000Lille, France. · Oscar Lambret Center, Department of Radiology, F-59000 Lille, France. · CHU Lille, Dermatology Department, F-59000Lille, France. ·CNS Oncol · Pubmed #29057672.

ABSTRACT: Therapeutic options of leptomeningeal metastases include intra-cerebrospinal fluid (CSF) chemotherapy. Among intra-CSF agents, liposomal cytarabine has advantages but can induce specific toxicities. A BRAF-V600E-mutated melanoma leptomeningeal metastases patient, treated by dabrafenib and liposomal cytarabine, presented after the first injection of liposomal cytarabine with hyperthermia and headaches. Despite sterile CSF/blood analyses, extended intravenous antibiotics were given and the second injection was delayed. The diagnosis of chemical meningitis was finally made. Dose reduction and appropriate symptomatic treatment permitted the administration of 15 injections of liposomal cytarabine combined with dabrafenib. A confirmation of the diagnosis of chemical meningitis is essential in order (1) not to delay intra-CSF or systemic chemotherapy or (2) to limit the administration of unnecessary but potentially toxic antibiotics.

24 Article Hemophagocytic lymphohistiocytosis in patients with metastatic malignant melanoma. 2017

Stabler, Sarah / Becquart, Coralie / Dumezy, Florent / Terriou, Louis / Mortier, Laurent. ·Departments of aDermatology bInternal Medicine, Hôpital Huriez cDepartment of Biological Hematology, Biology and Pathology Center, University of Lille Medical School, Lille, France. ·Melanoma Res · Pubmed #28471834.

ABSTRACT: Hemophagocytic lymphohistiocytosis (HLH) is an autoinflammatory disease that classically occurs because of infections, autoinflammatory, or autoimmune diseases, hematologic cancers, and rarely because of solid tumor. We report a rare case of HLH attributed to metastatic malignant melanoma treated without corticosteroid and with a nonfatal outcome thanks to specific therapies: etoposide for HLH and a selective inhibitor of mutated forms of BRAF kinase associated with a MEK inhibitor for melanoma.

25 Article BRAF inhibitor discontinuation and rechallenge in advanced melanoma patients with a complete initial treatment response. 2017

Desvignes, Céline / Abi Rached, Henry / Templier, Carole / Drumez, Elodie / Lepesant, Pauline / Desmedt, Eve / Mortier, Laurent. ·aDepartment of Dermatology, Lille University Hospital, Claude Huriez Hospital bLille University cDepartment of Biostatistics, Univ. Lille, CHU Lille, EA 2694 - Santé publique: épidémiologie et qualité des soins dINSERM U1189 ONCO-THAI, F-59000 Lille, France. ·Melanoma Res · Pubmed #28240681.

ABSTRACT: BRAF inhibitors (BRAFi), a targeted therapy, are used to treat metastatic late-stage melanomas harbouring the BRAF-V600 mutation (found in about 50% of melanomas). The targeted therapy is generally maintained until tumour progression or major toxicity occurs, although responses are often limited in time. It is unknown whether melanoma patients achieving a complete response with targeted therapy can safely discontinue treatment. We retrospectively observed the clinical course of patients with metastatic melanoma who discontinued BRAFi therapy after achieving a complete response and those with an incomplete response combined with surgical removal of the remaining tumours. We also evaluated the effectiveness of BRAFi in these patients after recurrence. In 11 patients, the best response was diagnosed after a median BRAFi treatment duration of 105 (29-341) days. The median follow-up after BRAFi initiation was 769 (435-1765) days. Recurrence was observed in all 11 patients (100%), median: 82 (27-322) days. Five patients achieved a complete response, with a median progression-free survival after cessation of 136.5 (34-322) days versus 82 (27-144) days for six patients with an incomplete response combined with surgical removal of remaining tumours. Baseline characteristics and time to best response and to discontinuation did not influence the rate of relapse. Subsequently, eight patients were rechallenged with a BRAFi. The median progression-free survival time after BRAFi rechallenge was 222.5 (15-425) days. The three remaining patients received treatments other than BRAFi. Our findings may be valuable with respect to ongoing clinical trials of combinations of targeted therapies and immunomodulatory antibodies.

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