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Melanoma: HELP
Articles by Celeste Lebbe
Based on 125 articles published since 2010
(Why 125 articles?)
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Between 2010 and 2020, C. Lebbe wrote the following 125 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5
1 Guideline French ENT Society (SFORL) guidelines for the management of immunodeficient patients with head and neck cancer of cutaneous origin. 2014

Bejar, C / Basset-Seguin, N / Faure, F / Fieschi, C / Frances, C / Guenne, C / Lebbe, C / Peraldi, M N / Roux, J / Lamas, G / Maubec, E / Anonymous6720788. ·Service de dermatologie, groupe hospitalier Bichat-Claude-Bernard, AP-HP, 46, rue Henri-Huchard, 75018 Paris, France. · Service de dermatologie, hôpital Saint-Louis, AP-HP, 1, avenue Claude-Vellefaux, 75010 Paris, France. · Service d'ORL, clinique Protestante, 1, chemin Penthod, 69300 Caluire et Cuire, France. · Service d'immunologie, hôpital Saint-Louis, AP-HP, 1, avenue Claude-Vellefaux, 75010 Paris, France. · Service de dermatologie, hôpital Tenon, AP-HP, 4, rue de la Chine, 75020 Paris, France. · Service d'ORL, hôpital Édouard-Herriot, 5, place d'Arsonval, 69437 Lyon cedex 03, France. · Service de néphrologie, hôpital Saint-Louis, AP-HP, 1, avenue Claude-Vellefaux, 75010 Paris, France. · Service d'ORL, hôpital Pitié-Salpêtrière, AP-HP, 47-83, boulevard de l'Hôpital, 75013 Paris, France. · Service de dermatologie, groupe hospitalier Bichat-Claude-Bernard, AP-HP, 46, rue Henri-Huchard, 75018 Paris, France. Electronic address: eve.maubec@inserm.fr. ·Eur Ann Otorhinolaryngol Head Neck Dis · Pubmed #24656876.

ABSTRACT: OBJECTIVES: The French ENT Society (SFORL) created a workgroup to draw up guidelines for the management of immunodeficient patients with head and neck cancer of cutaneous origin. The present guidelines cover diagnostic and therapeutic management and prevention of head and neck cancer of cutaneous origin in immunodeficient patients, and in particular in transplant patients and those with HIV infection. MATERIALS AND METHODS: The present guidelines were based on a critical multidisciplinary reading of the literature. Immunosuppression and its varieties are defined. The usual risk factors for skin cancer and those specific to immunodeficiency are presented. The prevention, assessment and management of cutaneous carcinoma, melanoma, Kaposi's sarcoma and lymphoma are dealt with. The level of evidence of the source studies was assessed so as to grade the various guidelines. When need be, expert opinions are put forward. RESULTS: Immunodeficient patients are at higher risk of head and neck skin tumors. The level of risk depends on the type of deficiency; there is an especially high risk of squamous cell carcinoma in transplant patients and of Kaposi's sarcoma in HIV-positive subjects. Various viruses are associated with skin cancers. Skin tumors are often evolutive in case of immunodeficiency, requiring rapid treatment. Management is generally the same as in immunocompetent subjects and should be discussed in a multidisciplinary team meeting. Immunosuppression may need to be modulated. In organ transplant patients, the only class of immunosuppressants with proven antitumoral efficacy are mTOR inhibitors, particularly in cutaneous squamous cell carcinoma. The rhythm of clinical surveillance should be adapted according to the risk of recurrence. Preventive measures should be undertaken. CONCLUSION: Skin cancers in immunodeficiency are highly evolutive, requiring the earliest possible treatment. Immunosuppression may need modulating. As the risk of recurrence may be elevated, careful surveillance should be implemented. Preventive measures should also be undertaken.

2 Editorial [Treating metastatic melanoma: Risk management]. 2017

Lebbe, C / Robert, C. ·Université Paris-Diderot, Sorbonne-Paris-Cité, APHP services de dermatologie et CIC, hôpital Saint-Louis-Paris, INSERM U976, 1, avenue Claude-Vellefaux, 75010 Paris, France. Electronic address: celeste.lebbe@aphp.fr. · Département de médecine, service de dermatologie, institut Gustave-Roussy, 114, rue Édouard-Vaillant, 94800 Villejuif, France; Université Paris-Sud, 114, rue Édouard-Vaillant, 94800 Villejuif, France. ·Ann Dermatol Venereol · Pubmed #28063593.

ABSTRACT: -- No abstract --

3 Editorial [Recent evolutions in metastatic melanoma]. 2014

Massard, Christophe / Lebbé, Céleste / Vignot, Stéphane. ·Département de médecine, Institut Gustave Roussy, 114, rue Édouard-Vaillant, 94805 Villejuif, France; Comité de rédaction du Bulletin du Cancer. · Service de dermatologie, Hôpital Saint-Louis, 1, avenue Claude-Vellefaux, 75010 Paris, France. · Comité de rédaction du Bulletin du Cancer; Service oncologie hématologie, Hôpital Louis-Pasteur, 4, rue Claude-Bernard, 28630 Le Coudray, France. ·Bull Cancer · Pubmed #25776765.

ABSTRACT: -- No abstract --

4 Review Atypical 2019

Dumaz, Nicolas / Jouenne, Fanélie / Delyon, Julie / Mourah, Samia / Bensussan, Armand / Lebbé, Céleste. ·INSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, France. nicolas.dumaz@inserm.fr. · Institut de Recherche Saint Louis (IRSL), Université de Paris, F-75010 Paris, France. nicolas.dumaz@inserm.fr. · Institut de Recherche Saint Louis (IRSL), Université de Paris, F-75010 Paris, France. · Département de Pharmacogénomique, Hôpital Saint Louis, AP-HP, F-75010 Paris, France. · INSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, France. · Département de Dermatologie, Hôpital Saint Louis, AP-HP, F-75010 Paris, France. ·Cancers (Basel) · Pubmed #31398831.

ABSTRACT: Primary mucosal melanomas represent a minority of melanomas, but have a significantly worse prognosis than cutaneous melanomas. A better characterization of the molecular pathogenesis of this melanoma subtype could help us understand the risk factors associated with the development of mucosal melanomas and highlight therapeutic targets. Because the Mitogen-Activated Protein Kinase (MAPK) pathway plays such a significant role in melanoma development, we explore v-raf murine sarcoma viral oncogene homolog B (

5 Review Practical clinical guide on the use of talimogene laherparepvec monotherapy in patients with unresectable melanoma in Europe. 2018

Gutzmer, Ralf / Harrington, Kevin J / Hoeller, Christoph / Lebbé, Celeste / Malvehy, Josep / Öhrling, Katarina / Downey, Gerald / Dummer, Reinhard. ·Haut-Tumour-Zentrum Hannover (HTZH), Klinik für Dermatologie, Allergologie und Venerologie, Medizinische Hochschule Hannover (MHH), Hannover, Germany. · NIHR Biomedical Research Centre, The Institute of Cancer Research, London, UK. · Universitätsklinik für Dermatologie, Medizinische Universität Wien, Wien, Austria. · APHP Dermatology and CIC department INSERM U976, Sorbonne Paris Cité, Université Paris Diderot, Hôpital Saint-Louis, Paris, France. · Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBER de Enfermedades Raras, FIS del Instituto de Salud Carlos III, Barcelona, Spain. · Medical Development, Amgen (Europe) GmbH, Rotkreuz, Switzerland. · Biostatistics, Amgen Ltd, Cambridge, UK. · Skin Cancer Centre/Dermatology Clinic, Universitätsspital Zürich, Zürich, Switzerland. ·Eur J Dermatol · Pubmed #30698145.

ABSTRACT: Talimogene laherparepvec, a herpes simplex virus type 1-based intralesional oncolytic immunotherapy, is approved in Europe for the treatment of adults with unresectable stage IIIB-IVM1a melanoma, with no bone, brain, lung or other visceral disease. It has direct oncolytic effects in injected lesions, leading to the release of tumour-derived antigens and systemic immune effects mediated by the induction of anti-tumour immunity, which is enhanced by the production of granulocyte macrophage colony-stimulating factor. Responses (which occur in >40% of stage IIIB-IVM1a patients) are often durable (>50% last ≥6 months) and occur in injected and uninjected lesions (in stage IIIB-IVM1c patients, 64%/34% of evaluable injected/uninjected non-visceral lesions, respectively, decreased in size by ≥50%). As with other immunotherapies, responses may be delayed or can arise after pseudoprogression. The pattern of treatment-emergent adverse events is distinct, being mostly grade 1/2, easy to manage, and rarely leading to treatment discontinuation. Systemic therapy represents the backbone of care for many metastatic melanoma patients. Nonetheless, the potential for durable locoregional control with a locally injected agent may make talimogene laherparepvec suitable for selected patients with stage IIIB/C disease, for whom surgery is not possible (e.g. with in-transit metastases, multiple melanoma lesions at different body sites, or those relapsing rapidly after repeated rounds of surgery) and slowly progressing disease. Here, we discuss which patients could be suitable for talimogene laherparepvec monotherapy based on the European indication, review the patterns/timing of response, and discuss the incidence/management of adverse events. Its potential use combined with immune checkpoint inhibitors is also discussed.

6 Review Autoimmune diabetes induced by PD-1 inhibitor-retrospective analysis and pathogenesis: a case report and literature review. 2017

Gauci, Marie-Léa / Laly, Pauline / Vidal-Trecan, Tiphaine / Baroudjian, Barouyr / Gottlieb, Jérémy / Madjlessi-Ezra, Nika / Da Meda, Laetitia / Madelaine-Chambrin, Isabelle / Bagot, Martine / Basset-Seguin, Nicole / Pages, Cécile / Mourah, Samia / Boudou, Philippe / Lebbé, Céleste / Gautier, Jean-François. ·AP-HP Dermatology Department, Saint-Louis Hospital, 1 avenue Claude Vellefaux, 75475, Paris Cedex 10, France. marie-lea.gauci@hotmail.fr. · INSERM U976, Université Paris Diderot-Paris VII, Sorbonne Paris Cité, Paris, France. marie-lea.gauci@hotmail.fr. · AP-HP Dermatology Department, Saint-Louis Hospital, 1 avenue Claude Vellefaux, 75475, Paris Cedex 10, France. · INSERM U976, Université Paris Diderot-Paris VII, Sorbonne Paris Cité, Paris, France. · AP-HP Diabetology Department, Lariboisière Hospital, Paris, France. · INSERM U1138, Université Paris Diderot-Paris VII, Sorbonne Paris Cité, Paris, France. · AP-HP Pharmacology Department, Saint-Louis Hospital, Paris, France. · AP-HP Pharmacogenomic Laboratory, Saint-Louis Hospital, Paris, France. · AP-HP Hormonology Department, Saint-Louis Hospital, Paris, France. · Université Paris Diderot-Paris VII, Sorbonne Paris Cité, Paris, France. ·Cancer Immunol Immunother · Pubmed #28634815.

ABSTRACT: Anti-PD-1 antibody treatment is approved in advanced melanoma and provides median overall survival over 24 months. The main treatment-related side effects are immune-related adverse events, which include rash, pruritus, vitiligo, thyroiditis, diarrhoea, hepatitis and pneumonitis. We report a case of autoimmune diabetes related to nivolumab treatment. A 73-year-old man was treated in second line with nivolumab at 3 mg/kg every two weeks for metastatic melanoma. At 6 weeks of treatment, he displayed diabetic ketoacidosis. Nivolumab was withheld 3.5 weeks and insulin therapy was initiated, enabling a normalization of glycaemia and the disappearance of symptoms. Laboratory investigations demonstrated the presence of islet cell autoantibodies, while C-peptide was undetectable. Retrospective explorations on serum banked at week 0 and 3 months before the start of nivolumab, already showed the presence of autoantibodies, but normal insulin, C-peptide secretion and glycaemia. Partial response was obtained at month 3, and nivolumab was then resumed at the same dose. The clinical context and biological investigations before, at and after nivolumab initiation suggest the autoimmune origin of this diabetes, most likely induced by anti-PD-1 antibody in a predisposed patient. The role of PD-1/PD-L1 binding is well known in the pathogenesis of type 1 diabetes. Therefore, this rare side effect can be expected in a context of anti-PD-1 treatment. Glycaemia should be monitored during PD-1/PD-L1 blockade. The presence of autoantibodies before treatment could identify individuals at risk of developing diabetes, but systematic titration may not be relevant considering the rarity of this side effect.

7 Review Treatment patterns of advanced malignant melanoma (stage III-IV) - A review of current standards in Europe. 2016

Harries, Mark / Malvehy, Josep / Lebbe, Céleste / Heron, Louise / Amelio, Justyna / Szabo, Zsolt / Schadendorf, Dirk. ·Guy's & St Thomas' Hospitals NHS Foundation Trust, London, UK. Electronic address: Mark.Harries@gstt.nhs.uk. · Servicio de Dermatología, Hospital Clínic de Barcelona, Catalonia, Spain. · Assistance Publique - Hôpitaux de Paris (AP-HP) Hôpital Saint-Louis, Dermatology Department Université Paris-Diderot, Sorbonne Paris Cité, INSERM UMR-S 976, Paris, France. · Adelphi Values, Bollington, UK. · Amgen Ltd., Uxbridge, London UK. · Amgen GmbH, Zug, Switzerland. · Klinik für Dermatologie, Universitätsklinikum Essen, Essen, Germany. ·Eur J Cancer · Pubmed #27118416.

ABSTRACT: AIMS AND BACKGROUND: With the recent emergence of immunotherapies and novel targeted treatments for advanced and metastatic melanoma such as selective B-Raf inhibitors and checkpoint inhibitors, the treatment landscape in Europe has changed considerably. The aim of this review was to provide an overview of current treatment pathways in Europe for the treatment of advanced melanoma, unresectable stage III-IV. METHODS: A literature search of four databases was conducted to identify publications reporting on the treatment patterns of advanced and metastatic melanoma (stage III-IV) in European populations. RESULTS: Seven full-text publications and two conference abstracts reported on observational studies of melanoma treatment practices in France, Italy and the United Kingdom. Treatment patterns were identified for two time periods: 2005-2009 and 2011-2012. Common treatments reported for both periods included chemotherapy with dacarbazine, fotemustine or temozolomide. The main differences between the two periods were the introduction and prescription of immunotherapy ipilimumab and targeted therapy vemurafenib between 2011 and 2012. Across the three countries studied, the types of treatments prescribed between 2005 and 2009 were relatively similar, however, with noticeable differences in the frequency and priority of administration. CONCLUSION: Treatment practices for advanced melanoma vary markedly across different European countries and continue to evolve with the introduction of new therapies. The results of this review highlight a considerable evidence gap with regards to recent treatment patterns for advanced melanoma in Europe, especially post-2011 after the introduction of novel therapeutic agents, and more recently with the introduction of programmed cell death 1 inhibitors.

8 Review [Melanoma, from diagnosis to treatment]. 2016

Baroudjian, Barouyr / Pagès, Cécile / Lebbé, Céleste. ·Unité d'oncodermatologie, service de dermatologie du Professeur Bagot, Hôpital Saint-Louis, 1 avenue Claude-Vellefaux, 75010, Paris, France. Electronic address: barouyr.baroudjian@aphp.fr. · Unité d'oncodermatologie, service de dermatologie du Professeur Bagot, Hôpital Saint-Louis, 1 avenue Claude-Vellefaux, 75010, Paris, France. ·Rev Infirm · Pubmed #26944639.

ABSTRACT: Skin cancers represent a major public health problem. Cutaneous melanoma, the incidence of which is constantly increasing, has the particularity of metastasising when it is detected too late. Its treatment at the metastatic stage has evolved significantly over recent years with the arrival of targeted therapies and immunotherapies which can increase patients' survival.

9 Review Integrating first-line treatment options into clinical practice: what's new in advanced melanoma? 2015

Dummer, Reinhard / Schadendorf, Dirk / Ascierto, Paolo A / Larkin, James / Lebbé, Celeste / Hauschild, Axel. ·aDepartment of Dermatology, University Hospital Zürich, Zürich, Switzerland bDepartment of Dermatology, University Hospital Essen, Essen cDepartment of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany dIstituto Nazionale Tumori Fondazione 'G. Pascale', Naples, Italy eRoyal Marsden NHS Foundation Trust, London, UK fAPHP Oncodermatology Unit, University Paris 7 Diderot U976, Paris, France. ·Melanoma Res · Pubmed #26426764.

ABSTRACT: Melanoma remains a serious form of skin cancer in Europe and worldwide. Localized, early-stage melanomas can usually be treated with surgical excision. However, the prognosis is poorer for patients with advanced disease. Before 2011, treatment for advanced melanoma included palliative surgery and/or radiotherapy, and chemotherapy with or without immunotherapy, such as interleukin-2. As none of these treatments had shown survival benefits in patients with advanced melanoma, European guidelines had recommended that patients be entered into clinical trials. The lack of approved first-line options and varying access to clinical trials meant that European clinicians relied on experimental regimens and chemotherapy-based treatments when no other options were available. Since 2011, ipilimumab, an immuno-oncology therapy, and vemurafenib and dabrafenib, targeted agents that inhibit mutant BRAF, have been approved by the European Medicines Agency for the treatment of advanced melanoma. More recently, the MEK inhibitor, trametinib, received European marketing authorization for use in patients with BRAF mutation-positive advanced melanoma. In 2014, the anti-PD-1 antibody nivolumab was approved as a first-line therapy in Japan. Whereas nivolumab and another anti-PD-1 antibody, pembrolizumab, were approved as second-line therapies in the USA, their recent approval in Europe are for first-line use based on new clinical trial data in this setting. Together these agents are changing clinical practice and making therapeutic decisions more complex. Here, we discuss current and emerging therapeutic options for the first-line treatment of advanced melanoma, and how these therapies can be optimized to provide the best possible outcomes for patients.

10 Review The ipilimumab lesson in melanoma: achieving long-term survival. 2015

Delyon, Julie / Maio, Michele / Lebbé, Celeste. ·AP-HP, Hôpital Saint-Louis, Département de Dermatologie, Paris, France; INSERM U976, Paris 7 University, Paris, France. · Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. · AP-HP, Hôpital Saint-Louis, Département de Dermatologie, Paris, France; INSERM U976, Paris 7 University, Paris, France; Université Paris-Diderot, Sorbonne Paris Cité, Paris, France. Electronic address: celeste.lebbe@sls.aphp.fr. ·Semin Oncol · Pubmed #25965357.

ABSTRACT: The anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) antibody ipilimumab is the first treatment that significantly improved the survival rates of metastatic melanoma patients, marking a new era in the treatment of melanoma. During its development, a hallmark of ipilimumab therapy was the extended duration of response, achieved in 20% of patients. The follow-up of patients included in phase II and phase III trials and in expanded access programs revealed that the survival rates remained stable after 3 years. These results demonstrated that ipilimumab induces an effective anti-tumor immune response persisting after the completion of treatment, and suggested a potential remission in a subset of patients. In this article we review the development of ipilimumab and highlight the long-term results. This approach emphasizes the need to optimize the use of ipilimumab in the future, by identifying the patients most likely to achieve long term survival after ipilimumab therapy, and by developing combined therapeutic approaches involving cytotoxic agents, targeted therapies or other immunotherapies to achieve durable control in a larger proportion of patients.

11 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).

12 Review [Molecular alterations in melanoma and targeted therapies]. 2014

Mourah, Samia / Lebbé, Céleste. ·AP-HP, Hôpital Saint-Louis, Laboratoire de pharmacologie-génétique, 1, avenue Claude-Vellefaux, 75010 Paris, France; Inserm, U976, 1, avenue Claude-Vellefaux, 75010 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, UMR-S-976, 1, avenue Claude-Vellefaux, 75010 Paris, France. Electronic address: samia.mourah@gmail.com. · Inserm, U976, 1, avenue Claude-Vellefaux, 75010 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, UMR-S-976, 1, avenue Claude-Vellefaux, 75010 Paris, France; Centre d'oncodermatologie, AP-HP, Hôpital Saint-Louis, Département de dermatologie, 1, avenue Claude-Vellefaux, 75010 Paris, France. ·Bull Cancer · Pubmed #25776766.

ABSTRACT: Melanoma is a skin cancer whose incidence is increasing steadily. The recent discovery of frequent and recurrent genetic alterations in cutaneous melanoma allowed a molecular classification of tumors into distinct subgroups, and paved the way for targeted therapy. Several signaling pathways are involved in the progression of this disease with oncogenic mutations affecting signaling pathways: MAPK, PI3K, cAMP and cyclin D1/CDK4. In each of these pathways, several potential therapeutic targets have been identified and specific inhibitors have already been developed and have shown clinical efficacy. The use of these inhibitors is often conditioned by tumors genotyping. In France, melanomas genotyping is supported by the platforms of the National Cancer Institute (INCA), which implemented a national program ensuring access to innovation for personalized medicine. The identification of new targets in melanoma supplies a very active dynamic development of innovative molecules contributing to changing the therapeutic landscape of this pathology.

13 Review [Targeted molecular therapies (except immunotherapy)]. 2014

Roux, Jennifer / Pages, Cécile / Lebbé, Céleste. ·Hôpital Saint-Louis, Service de dermatologie, 1, avenue Claude-Vellefaux, 75010 Paris, France. Electronic address: jennifer.roux@sls.aphp.fr. · Hôpital Saint-Louis, Service de dermatologie, 1, avenue Claude-Vellefaux, 75010 Paris, France. ·Bull Cancer · Pubmed #25776764.

ABSTRACT: Metastatic melanoma has been a very poor prognostic cancer with a median of survival between six to eight months. A lot of new therapies have been discovered these last years. Two types of treatment have emerged: immunotherapy and targeted therapy. Targeted therapies have been developed because of the discovery of new oncogenic mutations with a big impact of melanoma development. The efficacy is great with a high overall response and a good tolerance. However, most of patients escape in few months of targeted therapy. The sequence of drug using and their combination are the question for the next years.

14 Review Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. 2014

McDermott, David / Lebbé, Celeste / Hodi, F Stephen / Maio, Michele / Weber, Jeffrey S / Wolchok, Jedd D / Thompson, John A / Balch, Charles M. ·Department of Hematology/Oncology, Beth Israel Deaconess Medical Center, 375 Longwood Ave, Mailstop: MASCO 428, Boston, MA 02215, USA. Electronic address: dmcdermo@bidmc.harvard.edu. · APHP Department of Dermatology, CIC, U976 Hôpital Saint-Louis University Paris Diderot, 1 Avenue Claude Vellefaux, Paris 75010, France. Electronic address: celeste.lebbe@sls.aphp.fr. · Center for Immuno-Oncology, Melanoma Center, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA. Electronic address: Stephen_Hodi@dfci.harvard.edu. · Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Siena 53100, Italy. Electronic address: mmaiocro@gmail.com. · Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA. Electronic address: jeffrey.weber@moffitt.org. · Ludwig Center for Cancer Immunotherapy, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA. Electronic address: wolchokj@mskcc.org. · Seattle Cancer Care Alliance, 825 Eastlake Ave E, G4-830, Seattle, WA 98109, USA. Electronic address: jat@uw.edu. · Department of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA. Electronic address: charles.balch@utsouthwestern.edu. ·Cancer Treat Rev · Pubmed #25060490.

ABSTRACT: Historically, the median overall survival for patients with stage IV melanoma was less than 1 year and the 5-year survival rate was ∼10%. Recent advances in therapy have raised 5-year survival expectations to ∼20%. Notably, a subset of melanoma patients who receive immunotherapy with high-dose interleukin-2, and now ipilimumab, can achieve long-term survival of at least 5 years. A major goal in melanoma research is to increase the number of patients who experience this overall survival benefit. In this review, we discuss the attributes of immunotherapy and newer targeted agents, and consider how combination strategies might improve the chances of achieving durable benefit and long-term survival. We also discuss three areas that we believe will be critical to making further advances in melanoma treatment. To better understand the clinical profile of patients who achieve long-term survival with immunotherapy, we first present data from ipilimumab clinical trials in which a subset of patients experienced durable responses. Second, we discuss the limitations of traditional metrics used to evaluate the benefits of immunotherapies. Third, we consider emerging issues that clinicians are currently facing when making treatment decisions regarding immunotherapy. A better understanding of these novel treatments may improve survival outcomes in melanoma, increase the number of patients who experience this overall survival benefit, and inform the future use of these agents in the treatment of other cancer types.

15 Review [Clinical and biological heterogeneity of melanomas]. 2014

Delyon, Julie / Mourah, Samia / Lebbé, Céleste. · ·Rev Prat · Pubmed #24649551.

ABSTRACT: -- No abstract --

16 Clinical Trial Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. 2019

Robert, Caroline / Grob, Jean J / Stroyakovskiy, Daniil / Karaszewska, Boguslawa / Hauschild, Axel / Levchenko, Evgeny / Chiarion Sileni, Vanna / Schachter, Jacob / Garbe, Claus / Bondarenko, Igor / Gogas, Helen / Mandalá, Mario / Haanen, John B A G / Lebbé, Celeste / Mackiewicz, Andrzej / Rutkowski, Piotr / Nathan, Paul D / Ribas, Antoni / Davies, Michael A / Flaherty, Keith T / Burgess, Paul / Tan, Monique / Gasal, Eduard / Voi, Maurizio / Schadendorf, Dirk / Long, Georgina V. ·From Institut Gustave Roussy and Paris-Sud-Paris-Saclay University, Villejuif (C.R.), Aix-Marseille University, Marseille (J.J.G.), and Assistance Publique-Hôpitaux de Paris Dermatology and Clinical Investigation Center, Unité 976, Université de Paris, Hôpital Saint-Louis, Paris (C.L.) - all in France · Moscow City Oncology Hospital, Moscow (D. Stroyakovskiy), and the Petrov Research Institute of Oncology, St. Petersburg (E.L.) - both in Russia · Przychodnia Lekarska Komed, Konin (B.K.), the University of Medical Sciences, Poznań (A.M.), and the Maria Skłodowska-Curie Institute-Oncology Center, Warsaw (P.R.) - all in Poland · the University Hospital Schleswig-Holstein, Kiel (A.H.), the Department of Dermatology, University of Tübingen, Tübingen (C.G.), University Hospital Essen, Essen (D. Schadendorf), and the German Cancer Consortium, Heidelberg (D. Schadendorf) - all in Germany · the Veneto Institute of Oncology, Padua (V.C.S.), and Papa Giovanni XXIII Hospital, Bergamo (M.M.) - both in Italy · the Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Sheba Medical Center, Tel Hashomer (J.S.), and Sackler Medical School, Tel Aviv University, Tel Aviv (J.S.) - both in Israel · Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine (I.B.) · Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens (H.G.) · the Netherlands Cancer Institute, Amsterdam (J.B.A.G.H.) · Mount Vernon Cancer Centre, Northwood, United Kingdom (P.D.N.) · the University of California, Los Angeles, Los Angeles (A.R.) · the University of Texas M.D. Anderson Cancer Center, Houston (M.A.D.) · Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston (K.T.F.) · Novartis Pharma, Basel, Switzerland (P.B.) · Novartis Pharmaceuticals, East Hanover, NJ (M.T., E.G., M.V.) · and the Melanoma Institute Australia, the University of Sydney, and Royal North Shore and Mater Hospitals, Sydney (G.V.L.). ·N Engl J Med · Pubmed #31166680.

ABSTRACT: BACKGROUND: Patients who have unresectable or metastatic melanoma with a METHODS: We analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively. RESULTS: A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years. The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (95% CI, 62 to 79) at 5 years. CONCLUSIONS: First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a

17 Clinical Trial Checkpoint inhibitor treatment induces an increase in HbA1c in nondiabetic patients. 2019

Gauci, Marie-Léa / Boudou, Philippe / Squara, Pierre-Alexandre / Delyon, Julie / Allayous, Clara / Mourah, Samia / Resche-Rigon, Matthieu / Lebbé, Céleste / Baroudjian, Barouyr / Gautier, Jean-François / Anonymous3520981. ·AP-HP Department of Dermatology, INSERM U976. · AP-HP Derpartment of Hormonology. · AP-HP Department of Statistics. · AP-HP Pharmacogenomic Laboratory, INSERM U976, Saint-Louis Hospital. · AP-HP Department of Diabetology, INSERM U1138, Lariboisiére Hospital, Université Paris Diderot - Paris VII, Sorbonne Paris Cité, Paris, France. ·Melanoma Res · Pubmed #30817442.

ABSTRACT: Immunotherapy greatly improves clinical outcomes in treated patients with cancer. However, the long-lasting immune response and long duration of therapy could induce long-term adverse effects owing to the chronic inflammation induced. Type 2 diabetes is now recognized as an inflammatory disease. In addition, immunotherapy is concerned with increase in the production of tumor necrosis factor-α, interleukin-2, and interferon-γ, which are involved in the inflammatory process. Based on these observations, we hypothesized that anti-programmed cell death-1 (anti-PD-1) and/or anticytotoxic T-lymphocyte-associated protein-4 therapy could contribute to type 2 diabetes genesis in treated patients. Therefore, to evaluate this hypothesis, we studied HbA1c levels during follow-up in patients treated with anti-PD-1 and/or anticytotoxic T-lymphocyte-associated protein-4 therapy. A prospective and observational study was performed in an oncodermatology department (Saint-Louis Hospital, Paris, France) from March 2015 to February 2017. Sixty-two patients meeting the inclusion criteria were enrolled. Forty-three patients had paired HbA1c measurements during their follow-up period and were analyzed. The median follow-up was 3 months. We noted an increase in HbA1c levels from 5.3% [interquartile range (IQR): 5.1-5.5; range: 4.5-6.2) to 5.45% (IQR: 5.2-5.7; range: 4.7-6.2; P=0.037). This observation was confirmed in the subgroup of patients who did not receive concomitant glucocorticoids; their median HbA1c levels increased from 5.3% (IQR: 5.1-5.5; range: 4.7-6.2) to 5.5% (IQR: 5.2-5.7; range: 4.7-6.3; P=0.025). Variables such as age, BMI, and sex were not associated with the HbA1c level increase, but a tendency toward rising HbA1c levels was observed in treatments longer than 12 months. This study demonstrates that treatment with anti-PD-1 antibodies may impair glucose metabolism, as measured by increasing HbA1c levels.

18 Clinical Trial Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial. 2019

Lebbé, Celeste / Meyer, Nicolas / Mortier, Laurent / Marquez-Rodas, Ivan / Robert, Caroline / Rutkowski, Piotr / Menzies, Alexander M / Eigentler, Thomas / Ascierto, Paolo A / Smylie, Michael / Schadendorf, Dirk / Ajaz, Mazhar / Svane, Inge Marie / Gonzalez, Rene / Rollin, Linda / Lord-Bessen, Jennifer / Saci, Abdel / Grigoryeva, Elena / Pigozzo, Jacopo. ·1 Saint-Louis Hospital, Institut National de la Santé et de la Recherche Médicale U976, Université Paris Diderot, Paris, France. · 2 Université Paul Sabatier-Toulouse III, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1037-CRCT, Toulouse, France. · 3 Université de Lille, Institut National de la Santé et de la Recherche Médicale U1189, Lille, France. · 4 Hospital General Universitario Gregorio Marañón, Madrid, Spain. · 5 Gustave Roussy, Institut National de la Santé et de la Recherche Médicale U981, Paris, France. · 6 Maria Skłodowska-Curie Institute-Oncology Center, Warsaw, Poland. · 7 Melanoma Institute Australia, University of Sydney, and Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia. · 8 University Hospital Tübingen, Tübingen, Germany. · 9 Istituto Nazionale Tumori-Istituto di Ricovero e Cura a Carattere Scientifico Fondazione G. Pascale, Naples, Italy. · 10 Cross Cancer Institute, Edmonton, Alberta, Canada. · 11 University Hospital, Essen, Germany. · 12 German Cancer Consortium, Heidelberg, Germany. · 13 St George's University Hospitals National Health Service Foundation Trust, Tooting, London, United Kingdom. · 14 Herlev Hospital, University of Copenhagen, Herlev, Denmark. · 15 University of Colorado, Denver, CO. · 16 Bristol-Myers Squibb, Princeton, NJ. · 17 Veneto Institute of Oncology-Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy. ·J Clin Oncol · Pubmed #30811280.

ABSTRACT: PURPOSE: Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1+IPI3) is approved for first-line treatment of patients with advanced melanoma in several countries. We conducted a phase IIIb/IV study (CheckMate 511) to determine if nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (NIVO3+IPI1) improves the safety profile of the combination. PATIENTS AND METHODS: Patients (N = 360) age 18 years or older with previously untreated, unresectable stage III or IV melanoma were randomly assigned 1:1 to NIVO3+IPI1 or NIVO1+IPI3 once every 3 weeks for four doses. After 6 weeks, all patients received NIVO 480 mg once every 4 weeks until disease progression or unacceptable toxicity. The primary end point was a comparison of the incidence of treatment-related grade 3 to 5 adverse events (AEs) between groups. Secondary end points included descriptive analyses of objective response rate, progression-free survival, and overall survival. The study was not designed to formally demonstrate noninferiority of NIVO3+IPI1 to NIVO1+IPI3 for efficacy end points. RESULTS: At a minimum follow-up of 12 months, incidence of treatment-related grade 3 to 5 AEs was 34% with NIVO3+IPI1 versus 48% with NIVO1+IPI3 ( P = .006). In descriptive analyses, objective response rate was 45.6% in the NIVO3+IPI1 group and 50.6% in the NIVO1+IPI3 group, with complete responses in 15.0% and 13.5% of patients, respectively. Median progression-free survival was 9.9 months in the NIVO3+IPI1 group and 8.9 months in the NIVO1+IPI3 group. Median overall survival was not reached in either group. CONCLUSION: The CheckMate 511 study met its primary end point, demonstrating a significantly lower incidence of treatment-related grade 3-5 AEs with NIVO3+IPI1 versus NIVO1+IPI3. Descriptive analyses showed that there were no meaningful differences between the groups for any efficacy end point, although longer follow up may help to better characterize efficacy outcomes.

19 Clinical Trial Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. 2019

Ascierto, Paolo A / Long, Georgina V / Robert, Caroline / Brady, Benjamin / Dutriaux, Caroline / Di Giacomo, Anna Maria / 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 / Ny, Lars / Arance, Ana / Svane, Inge Marie / Schadendorf, Dirk / Gogas, Helen / Saci, Abdel / Jiang, Joel / Rizzo, Jasmine / Atkinson, Victoria. ·Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. · Melanoma Institute Australia, Sydney, New South Wales, Australia. · Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. · Department of Medical Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, New South Wales, Australia. · Department of Medicine, Institute Gustave Roussy, Villejuif, France. · Medical Oncology and Haematology, Cabrini Health, Melbourne, Victoria, Australia. · Dermatology Service, University Hospital of Bordeaux, Bordeaux, France. · UOC Oncological Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. · Clinique de Dermatologie, Unité d'Onco-Dermatologie, Institut National de la Santé et de la Recherche Médicale (INSERM) U1189, Centre Hospitalier Régional Universitaire de Lille, Lille, France. · Department of Dermatology, University Hospital Heidelberg and National Center for Tumor Diseases, Heidelberg, Germany. · Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland. · Chris O'Brien Lifehouse, Melanoma Institute Australia, Camperdown, New South Wales. · Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia. · Polish Mother's Memorial Hospital Research Institute, Lodz, Poland. · Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada. · Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland. · Assistance Publique-Hôpitaux de Paris Dermatology and Centre d'Investigation Clinique, University Paris Diderot INSERM U976, Saint Louis Hospital, Paris, France. · Institute for Advanced Biosciences, Université Grenoble Alpes/INSERM U1209/CNRS UMR 5309 Joint Research Center, Grenoble, France. · Dermatology Department, Grenoble Alpes University Hospital, Grenoble, France. · Department of Oncology, McGill University, Montreal, Quebec, Canada. · Melanoma Cancer Unit, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy. · Department of Dermatology, University Hospital Cologne, Cologne, Germany. · Division of Oncology, Regina Elena Institute, Rome, Italy. · Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden. · Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain. · Center for Cancer Immune Therapy, Herlev Hospital, Herlev, Denmark. · Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. · Department of Dermatology, University Hospital Essen, Essen, Germany. · German Cancer Consortium, Heidelberg, Germany. · First Department of Medicine, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. · Global Biometric Sciences, Bristol-Myers Squibb, Princeton, New Jersey. · Oncology Clinical Development, Bristol-Myers Squibb, Princeton, New Jersey. · Princess Alexandra Hospital, University of Queensland, Woolloongabba, Queensland, Australia. · Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, Queensland, Australia. ·JAMA Oncol · Pubmed #30422243.

ABSTRACT: Importance: This analysis provides long-term follow-up in patients with BRAF wild-type advanced melanoma receiving first-line therapy based on anti-programmed cell death 1 receptor inhibitors. Objective: To compare the 3-year survival with nivolumab vs that with dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma. Design, Setting, and Participants: This follow-up of a randomized phase 3 trial analyzed 3-year overall survival data from the randomized, controlled, double-blind CheckMate 066 phase 3 clinical trial. For this ongoing, multicenter academic institution trial, patients were enrolled from January 2013 through February 2014. Eligible patients were 18 years or older with confirmed unresectable previously untreated stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 but without a BRAF mutation. Interventions: Patients were treated until progression or unacceptable toxic events with nivolumab (3 mg/kg every 2 weeks plus dacarbazine-matched placebo every 3 weeks) or dacarbazine (1000 mg/m2 every 3 weeks plus nivolumab-matched placebo every 2 weeks). Main Outcome and Measure: Overall survival. Results: At minimum follow-ups of 38.4 months among 210 participants in the nivolumab group (median age, 64 years [range, 18-86 years]; 57.6% male) and 38.5 months among 208 participants in the dacarbazine group (median age, 66 years [range, 25-87 years]; 60.1% male), 3-year overall survival rates were 51.2% (95% CI, 44.1%-57.9%) and 21.6% (95% CI, 16.1%-27.6%), respectively. The median overall survival was 37.5 months (95% CI, 25.5 months-not reached) in the nivolumab group and 11.2 months (95% CI, 9.6-13.0 months) in the dacarbazine group (hazard ratio, 0.46; 95% CI, 0.36-0.59; P < .001). Complete and partial responses, respectively, were reported for 19.0% (40 of 210) and 23.8% (50 of 210) of patients in the nivolumab group compared with 1.4% (3 of 208) and 13.0% (27 of 208) of patients in the dacarbazine group. Additional analyses were performed on outcomes with subsequent therapies. Treatment-related grade 3/4 adverse events occurred in 15.0% (31 of 206) of nivolumab-treated patients and in 17.6% (36 of 205) of dacarbazine-treated patients. There were no deaths due to study drug toxic effects. Conclusions and Relevance: Nivolumab led to improved 3-year overall survival vs dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma. Trial Registration: ClinicalTrials.gov identifier: NCT01721772.

20 Clinical Trial Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma. 2018

Chesney, Jason / Puzanov, Igor / Collichio, Frances / Singh, Parminder / Milhem, Mohammed M / Glaspy, John / Hamid, Omid / Ross, Merrick / Friedlander, Philip / Garbe, Claus / Logan, Theodore F / Hauschild, Axel / Lebbé, Celeste / Chen, Lisa / Kim, Jenny J / Gansert, Jennifer / Andtbacka, Robert H I / Kaufman, Howard L. ·Jason Chesney, J. Graham Brown Cancer Center, University of Louisville, Louisville, KY · Igor Puzanov, Roswell Park Cancer Institute, Buffalo · Philip Friedlander, Mt Sinai School of Medicine, New York, NY · Frances Collichio, The University of North Carolina at Chapel Hill, Chapel Hill, NC · Parminder Singh, Mayo Clinic, Phoenix, AZ · Mohammed M. Milhem, University of Iowa Hospitals and Clinics, Iowa City, IA · John Glaspy, University of California Los Angeles School of Medicine · Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles · Lisa Chen, Jenny J. Kim, and Jennifer Gansert, Amgen, Thousand Oaks, CA · Merrick Ross, MD Anderson Cancer Center, Houston, TX · Claus Garbe, University Hospital Tuebingen, Tuebingen · Axel Hauschild, University of Kiel, Kiel, Germany · Theodore F. Logan, Indiana University Simon Cancer Center, Indianapolis, IN · Celeste Lebbé, Assistance Publique-Hôpital De Paris Dermatology and CIC Hôpital Saint Louis University Paris Diderot Sorbonne, Institut National de la Santé et de la Recherche Médicale U976, Paris, France · Robert H.I. Andtbacka, University of Utah, Salt Lake City, UT · and Howard L. Kaufman, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ. ·J Clin Oncol · Pubmed #28981385.

ABSTRACT: Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 10

21 Clinical Trial STAT3 Mediates Nilotinib Response in KIT-Altered Melanoma: A Phase II Multicenter Trial of the French Skin Cancer Network. 2018

Delyon, Julie / Chevret, Sylvie / Jouary, Thomas / Dalac, Sophie / Dalle, Stephane / Guillot, Bernard / Arnault, Jean-Philippe / Avril, Marie-Françoise / Bedane, Christophe / Bens, Guido / Pham-Ledard, Anne / Mansard, Sandrine / Grange, Florent / Machet, Laurent / Meyer, Nicolas / Legoupil, Delphine / Saiag, Philippe / Idir, Zakia / Renault, Victor / Deleuze, Jean-François / Hindie, Elif / Battistella, Maxime / Dumaz, Nicolas / Mourah, Samia / Lebbe, Celeste / Anonymous2300917. ·Service de Dermatologie, and CIC (Centre d'Investigations Cliniques), AP-HP, Hôpital Saint-Louis, Paris, France; INSERM, UMR-976, AP-HP, Hôpital Saint-Louis, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France. Electronic address: julie.delyon@aphp.fr. · Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Service de Biostatistique et Information Médicale, AP-HP, Hôpital Saint-Louis, Paris, France. · Unité Onco-dermatologie, Hôpital François Mitterrand, Pau, France. · Service de Dermatologie, CHU Dijon Bourgogne, Dijon, France. · Cancer Research Center of Lyon, INSERM U1052, CNRS UMR5286, Claude Bernard Lyon 1 University, Institut de Cancérologie des Hospices Civils de Lyon, Lyon, France. · Montpellier University Hospital, Montpellier, France. · Service de Dermatologie, CHU Amiens-Picardie, Amiens, France. · Service de Dermatologie, AP-HP, Hôpital Cochin, Paris, France; Université Paris Descartes, Paris, France. · Unité d'oncologie thoracique et cutanée, Hopital Dupuytren, Limoges, France. · Service de Dermatologie, Centre hospitalier régional d'Orléans, Orléans, France. · Dermatology Department, CHU de Bordeaux, Bordeaux, France. · Dermatology Department, CHU de Clermont Ferrand, Clermont Ferrand, France. · Dermatology Department, Reims University Hospital, Reims, France. · Department of Dermatology, Centre Hospitalier Regional et Universitaire (CHRU) de Tours, Tours, France; Inserm U930, University Francois Rabelais de Tours, Tours, France. · Dermatologie, Institut Universitaire du Cancer et CHU de Toulouse, Toulouse, France; Inserm UMR 1037, CRCT, Toulouse, France. · Dermatology Department, University Hospital of Brest, Brest, France. · Université de Versailles St-Quentin, EA 4340, Boulogne-Billancourt, France; Service de Dermatologie Générale et Oncologique, AP-HP, Hôpital Ambroise Paré, Boulogne-Billancourt, France. · AP-HP, Département de la Recherche Clinique et du Développement, AP-HP, Hôpital Saint-Louis, Paris, France. · Laboratory for Bioinformatics, CEPH-Fondation Jean Dausset, Paris, France. · Centre National de Génotypage, CEA, Evry, France; CEPH-Fondation Jean Dausset, Paris, France. · Service de Médecine Nucléaire, CHU de Bordeaux, LabEx TRAIL, Université de Bordeaux, Bordeaux, France. · Université Paris Diderot, Sorbonne Paris Cité, Paris, France; INSERM, UMR_S1165, Paris, France; Pathology department, Hopital Saint-Louis, AP-HP, Paris, France. · INSERM, UMR-976, AP-HP, Hôpital Saint-Louis, Paris, France. · INSERM, UMR-976, AP-HP, Hôpital Saint-Louis, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Laboratoire de Pharmacologie Biologique, AP-HP, Hôpital Saint-Louis, Paris, France. · Service de Dermatologie, and CIC (Centre d'Investigations Cliniques), AP-HP, Hôpital Saint-Louis, Paris, France; INSERM, UMR-976, AP-HP, Hôpital Saint-Louis, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France. ·J Invest Dermatol · Pubmed #28843487.

ABSTRACT: Mutated oncogenic KIT is a therapeutic target in melanoma. We conducted a multicenter phase II trial on the KIT inhibitor nilotinib in patients with unresectable melanoma harboring KIT alteration. The primary endpoint was the response rate (complete response or partial response following Response Evaluation Criteria in Solid Tumors criteria) at 6 months. Pharmacodynamic studies using KIT sequencing, qPCR array, and immunostaining of downstream KIT effectors were performed during treatment. Twenty-five patients were included and received 400 mg oral nilotinib twice daily. At 6 months, nilotinib induced tumor response in four patients. The best overall response rate was 20% and the disease control rate was 56%, limited to patients harboring exon 11 or 13 mutations. Four patients exhibited durable response, including three persisting (3.6 and 2.8 years for two patients with stage IIIC and 2.5 years for one with IVM1b melanoma). A reduction in signal transducer and activator of transcription (STAT) 3 phosphorylation and its effectors (BCL-2, MCL-1) in tumors during follow-up was significantly associated with clinical response. In the KIT-mutated melanoma cell line M230, nilotinib reduced STAT3 signaling and STAT inhibitors were as efficient as KIT inhibitors in reducing cell proliferation. Our study evidences a significant association between STAT3 inhibition and response to nilotinib, and provides a rationale for future research assessing STAT inhibitors in KIT-mutated melanoma.

22 Clinical Trial Patient-reported outcomes in KEYNOTE-006, a randomised study of pembrolizumab versus ipilimumab in patients with advanced melanoma. 2017

Petrella, Teresa M / Robert, Caroline / Richtig, Erika / Miller, Wilson H / Masucci, Giuseppe V / Walpole, Euan / Lebbe, Celeste / Steven, Neil / Middleton, Mark R / Hille, Darcy / Zhou, Wei / Ibrahim, Nageatte / Cebon, Jonathan. ·Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave, T2-041, Toronto, ON, M4N 3M5, Canada. Electronic address: teresa.petrella@sunnybrook.ca. · Gustave Roussy and Université Paris-Sud, 114 Rue Edouard Vaillant, 94800 Villejuif, France. Electronic address: caroline.robert@gustaveroussy.fr. · Medical University of Graz, Auenbruggerpl. 2, 8036 Graz, Graz, Austria. Electronic address: erika.richtig@medunigraz.at. · Segal Cancer Centre, Jewish General Hospital, Rossy Cancer Network, and McGill University, 3755 Ch de la Côte-Sainte-Catherine, Montreal, QC, H3T 1E2, Canada. Electronic address: wilsonmiller@gmail.com. · Karolinska Institute, Solnavägen 1, 171 77 Solna, Stockholm, Sweden. Electronic address: giuseppe.masucci@ki.se. · Princess Alexandra Hospital and The University of Queensland, 199 Ipswich Rd, Woolloongabba, Brisbane, QLD 4102, Australia. Electronic address: euan.walpole@health.qld.gov.au. · APHP, Dermatology and CIC, Université Paris Diderot, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France. Electronic address: celeste.lebbe@aphp.fr. · Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Birmingham B15 2TH, UK. Electronic address: N.M.Steven@bham.ac.uk. · The Churchill Hospital and The University of Oxford, Old Rd, Headington, Oxford OX3 7LE, UK. Electronic address: mark.middleton@oncology.ox.ac.uk. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: darcy_hille@merck.com. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: wei.zhou2@merck.com. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: nageatte.ibrahim@merck.com. · Olivia Newton-John Cancer Research Institute, Austin Health, School of Cancer Medicine, La Trobe University, 145 Studley Road, Heidelberg VIC 3084, Melbourne, Australia. Electronic address: jonathan.cebon@onjcri.org.au. ·Eur J Cancer · Pubmed #28987768.

ABSTRACT: OBJECTIVE: Report results of patient-reported health-related quality of life (HRQoL) and symptoms from phase III KEYNOTE-006 study of pembrolizumab versus ipilimumab in patients with ipilimumab-naive advanced melanoma. PATIENTS AND METHODS: Patients received pembrolizumab 10 mg/kg every 2 (Q2W) or every 3 weeks (Q3W) for up to 2 years, or four cycles of ipilimumab 3 mg/kg Q3W. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) was administered at baseline and throughout the study. Patient-reported outcome (PRO) analyses were pre-specified exploratory endpoints; the primary PRO assessment was the score change from baseline to week 12 in EORTC QLQ-C30 global health status (GHS)/HRQoL score between the arms using constrained longitudinal data analysis. RESULTS: The PRO analysis population included 776 patients: pembrolizumab Q2W (n = 270); pembrolizumab Q3W (n = 266); ipilimumab (n = 240). Baseline GHS was similar across arms. QLQ-C30 compliance rates at week 12 were 87% (n = 214), 97% (n = 226), and 96% (n = 178), for the pembrolizumab Q2W, pembrolizumab Q3W, and ipilimumab arms, respectively. From baseline to week 12, GHS/HRQoL scores were better maintained with pembrolizumab than with ipilimumab (decrease of -1.9 and -2.5 for pembrolizumab versus -10.0 for ipilimumab; p < 0.001 for each pembrolizumab arm versus ipilimumab). Fewer patients treated with pembrolizumab experienced deterioration in GHS at week 12 (31% for pembrolizumab Q2W; 29% for Q3W and 44% for ipilimumab), with similar trends observed for individual functioning and symptoms scales. CONCLUSIONS: HRQoL was better maintained with pembrolizumab than with ipilimumab in patients with ipilimumab-naive advanced melanoma. CLINICALTRIALS. GOV IDENTIFIER: NCT01866319.

23 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 / Anonymous9301111. ·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 .).

24 Clinical Trial Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. 2017

Wolchok, Jedd D / Chiarion-Sileni, Vanna / Gonzalez, Rene / Rutkowski, Piotr / Grob, Jean-Jacques / Cowey, C Lance / Lao, Christopher D / Wagstaff, John / Schadendorf, Dirk / Ferrucci, Pier F / Smylie, Michael / Dummer, Reinhard / Hill, Andrew / Hogg, David / Haanen, John / Carlino, Matteo S / Bechter, Oliver / Maio, Michele / Marquez-Rodas, Ivan / Guidoboni, Massimo / McArthur, Grant / Lebbé, Celeste / Ascierto, Paolo A / Long, Georgina V / Cebon, Jonathan / Sosman, Jeffrey / Postow, Michael A / Callahan, Margaret K / Walker, Dana / Rollin, Linda / Bhore, Rafia / Hodi, F Stephen / Larkin, James. ·From the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (J.D.W., M.A.P., M.K.C.) · Oncology Institute of Veneto Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua (V.C.-S.), European Institute of Oncology, Milan (P.F.F.), Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena (M.M.), the Immunotherapy and Somatic Cell Therapy Unit, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (M.G.), and Istituto Nazionale Tumori Fondazione Pascale, Naples (P.A.A.) - all in Italy · University of Colorado, Denver (R.G.) · Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.) · Aix-Marseille University, Hôpital de la Timone, Marseille (J.-J.G.), and Assistance Publique-Hôpitaux de Paris, Dermatology and Centres d'Investigation Clinique, INSERM Unité 976, Hôpital Saint-Louis, Université Paris Diderot, Paris (C.L.) - both in France · Texas Oncology-Baylor Cancer Center, Dallas (C.L.C.) · University of Michigan, Ann Arbor (C.D.L.) · the College of Medicine, Swansea University, Swansea (J.W.), and Royal Marsden NHS Foundation Trust, London (J.L.) - both in the United Kingdom · the Department of Dermatology, University of Essen, Essen, and the German Cancer Consortium, Heidelberg - both in Germany (D.S.) · Cross Cancer Institute, Edmonton, AB (M.S.), and Princess Margaret Cancer Centre, Toronto (D.H.) - both in Canada · Universitäts Spital, Zurich, Switzerland (R.D.) · Tasman Oncology Research, Southport Gold Coast, QLD (A.H.), Crown Princess Mary Cancer Centre, Melanoma Institute Australia, University of Sydney (M.S.C.), and Melanoma Institute Australia, University of Sydney, and Royal North Shore and Mater Hospitals (G.V.L.), Sydney, and Peter MacCallum Cancer Centre (G.M.) and the Olivia Newton-John Cancer Research Institute, University of Melbourne (J.C.), Melbourne, VIC - all in Australia · Netherlands Cancer Institute, Amsterdam (J.H.) · University Hospitals Leuven, KU Leuven, Leuven, Belgium (O.B.) · General University Hospital Gregorio Marañón, Madrid (I.M.-R.) · Northwestern University, Chicago (J.S.) · Bristol-Myers Squibb, Princeton, NJ (D.W., L.R., R.B.) · and the Dana-Farber Cancer Institute, Boston (F.S.H.). ·N Engl J Med · Pubmed #28889792.

ABSTRACT: BACKGROUND: Nivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial. METHODS: We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group versus the ipilimumab group. RESULTS: At a minimum follow-up of 36 months, the median overall survival had not been reached in the nivolumab-plus-ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group. CONCLUSIONS: Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505 .).

25 Clinical Trial Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials. 2017

Schadendorf, Dirk / Long, Georgina V / Stroiakovski, Daniil / Karaszewska, Boguslawa / Hauschild, Axel / Levchenko, Evgeny / Chiarion-Sileni, Vanna / Schachter, Jacob / Garbe, Claus / Dutriaux, Caroline / Gogas, Helen / Mandalà, Mario / Haanen, John B A G / Lebbé, Céleste / Mackiewicz, Andrzej / Rutkowski, Piotr / Grob, Jean-Jacques / Nathan, Paul / Ribas, Antoni / Davies, Michael A / Zhang, Ying / Kaper, Mathilde / Mookerjee, Bijoyesh / Legos, Jeffrey J / Flaherty, Keith T / Robert, Caroline. ·Department of Dermatology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany; German Cancer Consortium, 69117 Heidelberg, Germany. Electronic address: Dirk.Schadendorf@uk-essen.de. · Melanoma Institute Australia, The University of Sydney, NSW, Australia; Mater Hospital, North Sydney, NSW, Australia; Royal North Shore Hospital, St Leonards, NSW, Australia. · Moscow City Oncology Hospital No 62, Moscow 143423, Russia. · Przychodnia Lekarska KOMED, Wojska Polskiego 6, 62-500 Konin, Poland. · Department of Dermatology, University Medical Center Schleswig-Holstein, Arnold-Heller-Straße 3, 24105 Kiel, Germany. · Petrov Research Institute of Oncology, 68 Leningradskaya Street, Saint Petersburg 197758, Russia. · Melanoma and Esophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Via Gattamelata 64, 35128 Padova, Italy. · Oncology Division, Sheba Medical Center, Tel HaShomer, Emek HaEla St 1, Ramat Gan, Israel. · Department of Dermatology, University of Tübingen, Geschwister-Scholl-Platz, 72074 Tübingen, Germany. · Service de Dermatologie et Dermatologie Pédiatrique, Hôpital Saint-André, 1 Rue Jean Burguet, 33000 Bordeaux, France. · First Department of Medicine, "Laiko" General Hospital, National and Kapodistrian University of Athens, Athens 157 72, Greece. · Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. · Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. · APHP Dermatology and CIC Departments, INSERM U976, University Paris Diderot, Paris, France. · Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary Street, 61-866 Poznań, Poland. · Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Wawelska 15B, 02-034 Warsaw, Poland. · Department of Dermatology, University Hospital Center, Timone Hospital, Aix Marseille University, 264 Rue St Pierre, 13885 Marseille Cedex 05, France. · Mount Vernon Cancer Centre, Rickmansworth Road, HA6 2RN Northwood, UK. · Department of Medicine, Hematology/Oncology, UCLA Medical Center, 100 UCLA Medical Plaza, Suite 550, Los Angeles, CA, USA. · Melanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, TX, USA. · Novartis Pharmaceuticals Corporation, 1 Health Plaza, East Hanover 07936, NJ, USA. · Developmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston 02114, MA, USA. · Department of Medical Oncology, Dermatology Service, Gustave Roussy Comprehensive Cancer Center and Faculty of Medicine, University Paris-South, F-94805, Villejuif, France. ·Eur J Cancer · Pubmed #28648698.

ABSTRACT: AIM: Understanding predictors of long-term benefit with currently available melanoma therapies is the key for optimising individualised treatments. A prior pooled analysis of dabrafenib plus trametinib (D + T)-randomised trials (median follow-up, 20.0 months) identified baseline lactate dehydrogenase (LDH) and number of organ sites with metastasis as predictive factors for progression-free (PFS) and overall (OS) survival. However, longer-term follow-up analyses are needed to confirm which patients treated with D + T can achieve maximum benefit. METHODS: Three-year landmark data were retrospectively pooled for D + T patients in phase 3 trials (COMBI-d [NCT01584648]; COMBI-v [NCT01597908]). Univariate and multivariate analyses assessed prognostic values of predefined baseline factors; regression tree analysis determined hierarchy and interactions between variables. RESULTS: Long-term pooled outcomes were consistent with individual trial results (N = 563; 3-year PFS, 23%; 3-year OS, 44%). Baseline LDH level and number of organ sites remained strongly associated with and/or predictive of PFS and OS. In addition, baseline sum of lesion diameters (SLD) was identified as a predictor for progression. In the most favourable prognostic group (normal LDH, SLD <66 mm, <3 organ sites; n = 183/563 [33%]), 3-year PFS was 42%. Baseline number of organ sites was also predictive of outcomes in patients with PFS ≥ 6 months. CONCLUSION: Using the largest phase 3 data set available for BRAF/MEK inhibitor combination therapy in melanoma, these results demonstrate that durable responses lasting ≥3 years are possible in subsets of patients with BRAF-mutant melanoma receiving D + T. Although the best predictive model evolved with longer follow-up, factors predicting clinical outcomes with the combination remained consistent with previous analyses.

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