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Melanoma: HELP
Articles by Piotr Rutkowski
Based on 56 articles published since 2008
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Between 2008 and 2019, P. Rutkowski wrote the following 56 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Editorial News from the melanoma sessions of the European Cancer Congress 2017. 2017

Rutkowski, Piotr / Kozak, Katarzyna. ·Department of Soft Tissue/Bone Sarcoma and Melanoma; Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, Warsaw, 02-781, Poland. ·BMC Med · Pubmed #28302128.

ABSTRACT: During the European Cancer Congress, the melanoma sessions focused on practice changing trials. Recent developments and approvals in immunotherapy and targeted agents have significantly changed the landscape of melanoma therapy in the metastatic setting and provide great promise for adjuvant and neoadjuvant treatment in high-risk locoregional disease. Perioperative (combined pre- and postoperative) strategies may be extremely beneficial for patients with bulky stage IIIC disease. The long-term results of the European Organisation for Research and Treatment of Cancer (EORTC) 18071 adjuvant trial ipilimumab versus placebo after complete resection of high-risk stage III melanoma, demonstrating improvement in overall survival, has established the reference bar for further trials with postoperative therapy.

2 Editorial Introduction to the special issue of European Journal of Surgical Oncology: New roads in melanoma management. 2017

Rutkowski, P. ·Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Department of Soft Tissue/Bone Sarcoma and Melanoma, Roentgena Str. 5, 02-781 Warsaw, Poland. Electronic address: piotr.rutkowski@coi.pl. ·Eur J Surg Oncol · Pubmed #28034500.

ABSTRACT: -- No abstract --

3 Review Rational combination of cancer immunotherapy in melanoma. 2019

Mandalà, Mario / Rutkowski, Piotr. ·Unit of Medical Oncology, Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Piazza OMS 1, 24100, Bergamo, Italy. mariomandala@tin.it. · Maria Sklodowska-Curie Institute, Oncology Center, Warsaw, Poland. ·Virchows Arch · Pubmed #30552520.

ABSTRACT: The recent advances in cancer immunotherapy with unprecedented success in therapy of advanced melanoma represent a turning point in the landscape of melanoma treatment. Given the complexity of activation of immunological system and the physiologic multifactorial homeostatic mechanisms controlling immune responses, combinatorial strategies are eagerly needed in melanoma therapy. Nevertheless, rational selection of immunotherapy combinations should be more biomarker-guided, including not only the cancer immunogram, PD-L1 expression, interferon gene expression signature, mutational burden, and tumor infiltration by CD8+ T cells but also intratumoral T cell exhaustion and microbiota composition. In this review, we summarize the rationale to develop combination treatment strategies in melanoma and discuss biological background that could help to design new combinations in order to improve patients' outcome.

4 Review ECCO essential requirements for quality cancer care: Melanoma. 2018

Wouters, Michel W / Michielin, Olivier / Bastiaannet, Esther / Beishon, Marc / Catalano, Orlando / Del Marmol, Veronique / Delgado-Bolton, Roberto / Dendale, Rémi / Trill, Maria Die / Ferrari, Andrea / Forsea, Ana-Maria / Kreckel, Hannelore / Lövey, József / Luyten, Gre / Massi, Daniela / Mohr, Peter / Oberst, Simon / Pereira, Philippe / Prata, João Paulo Paiva / Rutkowski, Piotr / Saarto, Tiina / Sheth, Sapna / Spurrier-Bernard, Gilly / Vuoristo, Meri-Sisko / Costa, Alberto / Naredi, Peter. ·European Society of Surgical Oncology (ESSO); Department of Surgery, Netherlands Cancer Institute, Amsterdam, The Netherlands. · European Society for Medical Oncology (ESMO); Department of Oncology, CHUV, University Hospital of Lausanne, Lausanne, Switzerland. · International Society of Geriatric Oncology (SIOG); Department of Surgery/Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands. · European School of Oncology (ESO), Milan, Italy. · European Society of Radiology (ESR); Department of Radiology, National Cancer Institute Fondazione Pascale, Naples, Italy. · Association of European Cancer Leagues (ECL); Euromelanoma, European Academy of Dermatology and Venereology (EADV); Department of Dermatology and Venereology, Erasme Hospital, ULB, Brussels, Belgium. · European Association of Nuclear Medicine (EANM); Department of Diagnostic Imaging (Radiology) and Nuclear Medicine, San Pedro Hospital and Centre for Biomedical Research of La Rioja (CIBIR), University of La Rioja, Logroño, La Rioja, Spain. · European Society for Radiotherapy and Oncology (ESTRO); Radiation Oncology Department, Institut Curie, Paris, France. · International Psycho-Oncology Society (IPOS); ATRIUM: Psycho-Oncology & Clinical Psychology, Madrid, Spain. · European Society for Paediatric Oncology (SIOPE); Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. · European Association of Dermato Oncology (EADO); Dermatology Department, Elias University Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. · European Society of Oncology Pharmacy (ESOP); Pharmacy Department, University Hospital Giessen and Marburg, Giessen, Germany. · Organisation of European Cancer Institutes (OECI); National Institute of Oncology, Budapest, Hungary. · Ocular Oncology Group (OOG); Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands. · European Society of Pathology (ESP); Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy. · European Society of Skin Cancer Prevention (EUROSKIN); Elbe-Klinikum Buxtehude, Buxtehude, Germany. · Organisation of European Cancer Institutes (OECI); Cambridge Cancer Centre, Cambridge, UK. · Cardiovascular and Interventional Radiological Society of Europe (CIRSE); Clinic for Radiology, Minimally-Invasive Therapies and Nuclear Medicine, SLK-Clinics Heilbronn, Karl-Ruprecht-University of Heidelberg, Heilbronn, Germany. · European Oncology Nursing Society (EONS); Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal. · European Organisation for Research and Treatment of Cancer (EORTC); Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland. · European Association for Palliative Care (EAPC); Comprehensive Cancer Center, Department of Palliative Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. · European CanCer Organisation, Brussels, Belgium. · European CanCer Organisation (ECCO) Patient Advisory Committee; Melanoma Patient Network Europe; Paris, France. · Association of European Cancer Leagues (ECL); Pirkanmaa Cancer Society, Tampere, Finland. · European CanCer Organisation (ECCO); Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address: peter.naredi@gu.se. ·Crit Rev Oncol Hematol · Pubmed #29458785.

ABSTRACT: BACKGROUND: ECCO essential requirements for quality cancer care (ERQCC) are explanations and descriptions of challenges, organisation and actions that are necessary to give high-quality care to patients who have a specific type of cancer. They are written by European experts representing all disciplines involved in cancer care. ERQCC papers give oncology teams, patients, policymakers and managers an overview of the elements needed in any healthcare system to provide high quality of care throughout the patient journey. References are made to clinical guidelines and other resources where appropriate, and the focus is on care in Europe. MELANOMA: ESSENTIAL REQUIREMENTS FOR QUALITY CARE: CONCLUSION: Taken together, the information presented in this paper provides a comprehensive description of the essential requirements for establishing a high-quality service for melanoma. The ERQCC expert group is aware that it is not possible to propose a 'one size fits all' system for all countries, but urges that access to multidisciplinary teams and specialised treatments is guaranteed to all patients with melanoma.

5 Review Treatment algorithms in stage IV melanoma. 2015

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

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

6 Review Dabrafenib for the treatment of BRAF V600-positive melanoma: a safety evaluation. 2014

Rutkowski, Piotr / Blank, Christian. ·Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Department of Soft Tissue/Bone Sarcoma and Melanoma , Roentgena 5, 02-781 Warsaw , Poland +48 22 6439375 ; +48 22 6439791 ; rutkowskip@coi.waw.pl. ·Expert Opin Drug Saf · Pubmed #25014231.

ABSTRACT: INTRODUCTION: V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors are emerging as the standard of care for treating advanced melanomas harboring the BRAF V600 oncogenic mutation. Dabrafenib is the second approved selective BRAF inhibitor (after vemurafenib) for the treatment of unresectable or metastatic BRAF V600-positive melanoma. AREAS COVERED: This review covers the current data on the efficacy and safety of the selective BRAF inhibitor dabrafenib in patients with metastatic BRAF V600 positive melanoma. The pharmacological, safety and efficacy data are discussed from Phase I, II, and III studies of dabrafenib monotherapy as well as in combination with the MEK inhibitor trametinib. EXPERT OPINION: Dabrafenib has demonstrated comparable efficacy to vemurafenib in BRAF V600E mutant melanoma patients. Dabrafenib is well tolerated in patients with metastatic melanoma, including patients with brain metastases. Nevertheless side effects are common, but usually manageable. In the Phase III study testing dabrafenib, 53% of patients reported grade 2 or higher adverse events (AEs). Toxicities were similar to those seen in the early-phase trials, with the most common being cutaneous manifestations (hyperkeratosis, papillomas, palmar-plantar erythrodysesthesia), pyrexia, fatigue, headache, and arthralgia. Combining a BRAF inhibitor with a MEK inhibitor, which may block paradoxical MAPK activation in BRAF wild type (skin) cells, may lower the incidence of squamoproliferative eruptions.

7 Review Surgery and radiotherapy in the treatment of cutaneous melanoma. 2009

Testori, A / Rutkowski, P / Marsden, J / Bastholt, L / Chiarion-Sileni, V / Hauschild, A / Eggermont, A M M. ·European Institute of Oncology, Division of Melanoma, Milan, Italy. alessandro.testori@ieo.it ·Ann Oncol · Pubmed #19617294.

ABSTRACT: Adequate surgical management of primary melanoma and regional lymph node metastasis, and rarely distant metastasis, is the only established curative treatment. Surgical management of primary melanomas consists of excisions with 1-2 cm margins and primary closure. The recommended method of biopsy is excisional biopsy with a 2 mm margin and a small amount of subcutaneous fat. In specific situations (very large lesions or certain anatomical areas), full-thickness incisional or punch biopsy may be acceptable. Sentinel lymph node biopsy provides accurate staging information for patients with clinically unaffected regional nodes and without distant metastases, although survival benefit has not been proved. In cases of positive sentinel node biopsy or clinically detected regional nodal metastases (palpable, positive cytology or histopathology), radical removal of lymph nodes of the involved basin is indicated. For resectable local/in-transit recurrences, excision with a clear margin is recommended. For numerous or unresectable in-transit metastases of the extremities, isolated limb perfusion or infusion with melphalan should be considered. Decisions about surgery of distant metastases should be based on individual circumstances. Radiotherapy is indicated as a treatment option in select patients with lentigo maligna melanoma and as an adjuvant in select patients with regional metastatic disease. Radiotherapy is also indicated for palliation, especially in bone and brain metastases.

8 Clinical Trial Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. 2018

Hodi, Frank Stephen / Chiarion-Sileni, Vanna / Gonzalez, Rene / Grob, Jean-Jacques / Rutkowski, Piotr / Cowey, Charles Lance / Lao, Christopher D / Schadendorf, Dirk / Wagstaff, John / Dummer, Reinhard / Ferrucci, Pier Francesco / Smylie, Michael / Hill, Andrew / Hogg, David / Marquez-Rodas, Ivan / Jiang, Joel / Rizzo, Jasmine / Larkin, James / Wolchok, Jedd D. ·Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: stephen_hodi@dfci.harvard.edu. · Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. · University of Colorado Cancer Center, Denver, CO, USA. · Aix-Marseille University and APHM Hospital CHU Timone, Marseille, France. · Maria Skłodowska-Curie Institute - Oncology Centre, Warsaw, Poland. · Texas Oncology-Baylor Charles A Sammons Cancer Center, Dallas, TX, USA. · Department of Oncology, University of Michigan, Ann Arbor, MI, USA. · Department of Dermatology, University of Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. · The College of Medicine, Swansea University, Swansea, UK. · Department of Dermatology, Universitäts Spital, Zürich, Switzerland. · European Institute of Oncology, Milan, Italy. · Cross Cancer Institute, Edmonton, AB, Canada. · Tasman Oncology Research, Southport, QLD, Australia. · Princess Margaret Cancer Centre, Toronto, ON, Canada. · General University Hospital Gregorio Marañón, Madrid, Spain. · Bristol-Myers Squibb, Princeton, NJ, USA. · The Royal Marsden NHS Foundation Trust, London, UK. · Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. ·Lancet Oncol · Pubmed #30361170.

ABSTRACT: BACKGROUND: Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study. METHODS: In this phase 3 trial, eligible patients were aged 18 years or older with previously untreated, unresectable, stage III or stage IV melanoma, known BRAF FINDINGS: Between July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315). Median follow-up was 46·9 months (IQR 10·9-51·8) in the nivolumab plus ipilimumab group, 36·0 months (10·5-51·4) in the nivolumab group, and 18·6 months (7·6-49·5) in the ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38·2-not reached) in the nivolumab plus ipilimumab group, 36·9 months (28·3-not reached) in the nivolumab group, and 19·9 months (16·9-24·6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0·54 (95% CI 0·44-0·67; p<0·0001) and for nivolumab versus ipilimumab was 0·65 (0·53-0·79; p<0·0001). Median progression-free survival was 11·5 months (95% CI 8·7-19·3) in the nivolumab plus ipilimumab group, 6·9 months (5·1-10·2) in the nivolumab group, and 2·9 months (2·8-3·2) in the ipilimumab group. The hazard ratio for progression-free survival for the combination versus ipilimumab was 0·42 (95% CI 0·35-0·51; p<0·0001) and for nivolumab versus ipilimumab was 0·53 (0·44-0·64; p<0·0001). Treatment-related grade 3-4 adverse events were reported in 185 (59%) of 313 patients who received nivolumab plus ipilimumab, 70 (22%) of 313 who received nivolumab, and 86 (28%) of 311 who received ipilimumab. The most common treatment-related grade 3 adverse events were diarrhoea in the nivolumab plus ipilimumab group (29 [9%] of 313) and in the nivolumab group (nine [3%] of 313) and colitis in the ipilimumab group (23 [7%] of 311); the most common grade 4 adverse event in all three groups was increased lipase (15 [5%] of 313 in the combination group, ten [3%] of 313 in the nivolumab group, and four [1%] of 311 in the ipilimumab group). Serious adverse events were not analysed for the 4-year follow-up. In total for the study, there were four treatment-related deaths: two in the nivolumab plus ipilimumab group (one cardiomyopathy and one liver necrosis), one in the nivolumab group (neutropenia), and one in the ipilimumab group (colon perforation). No additional treatment-related deaths have occurred since the previous (3-year) analysis. INTERPRETATION: The results of this analysis at 4 years of follow-up show that a durable, sustained survival benefit can be achieved with first-line nivolumab plus ipilimumab or nivolumab alone in patients with advanced melanoma. FUNDING: Bristol-Myers Squibb.

9 Clinical Trial MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial. 2018

Dreno, Brigitte / Thompson, John F / Smithers, Bernard Mark / Santinami, Mario / Jouary, Thomas / Gutzmer, Ralf / Levchenko, Evgeny / Rutkowski, Piotr / Grob, Jean-Jacques / Korovin, Sergii / Drucis, Kamil / Grange, Florent / Machet, Laurent / Hersey, Peter / Krajsova, Ivana / Testori, Alessandro / Conry, Robert / Guillot, Bernard / Kruit, Wim H J / Demidov, Lev / Thompson, John A / Bondarenko, Igor / Jaroszek, Jaroslaw / Puig, Susana / Cinat, Gabriela / Hauschild, Axel / Goeman, Jelle J / van Houwelingen, Hans C / Ulloa-Montoya, Fernando / Callegaro, Andrea / Dizier, Benjamin / Spiessens, Bart / Debois, Muriel / Brichard, Vincent G / Louahed, Jamila / Therasse, Patrick / Debruyne, Channa / Kirkwood, John M. ·Department of Dermatooncology, Hotel Dieu Nantes University Hospital, Nantes, France. · Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. · Queensland Melanoma Project, Discipline of Surgery, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD, Australia. · Melanoma Sarcoma Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. · Service d'Oncologie Médicale, Hôpital François Mitterrand, Pau, France. · Skin Cancer Center Hannover, Department of Dermatology, Hannover Medical School, Hannover, Germany. · Petrov Research Institute of Oncology, St Petersburg, Russia. · Department of Soft Tissue, Bone Sarcoma, and Melanoma, Maria Sklodowska-Curie Institute, Oncology Center, Warsaw, Poland. · Department of Dermatology and Skin Cancers, La Timone APHM Hospital, Aix-Marseille University, Marseille, France. · Department of Skin and Soft Tissue Tumours, National Cancer Institute, Kiev, Ukraine. · Swissmed Centrum Zdrowia, Gdansk, Poland; Department of Surgical Oncology, Gdansk Medical University, Gdansk, Poland. · Dermatology Department, Hôpital Robert Debré, Université de Reims Champagne-Ardenne, Reims, France. · Department of Dermatology, Centre Hospitalier Universitaire, Tours, France; UFR de Médecine, Université François-Rabelais, Tours, France. · Melanoma Immunology and Oncology Group, Centenary Institute, University of Sydney, Sydney, NSW, Australia; Melanoma Institute Australia, Sydney, NSW, Australia. · Dermato-oncology Department, General University Hospital, Prague, Czech Republic. · Columbus Clinic Center, Milan, Italy. · Division of Hematology & Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. · Département de Dermatologie, Centre Hospitalier Universitaire, Hôpital Saint-Éloi, Montpellier, France. · Department of Medical Oncology, Erasmus MC Cancer institute, Rotterdam, Netherlands. · Cancer Research Center, Moscow, Russia. · Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Seattle Cancer Care Alliance, University of Washington, Seattle, WA, USA. · Department of Oncology and Medical Radiology, Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine. · Centrum Medyczne Bieńkowski, Klinika Chirurgii Plastycznej, Bydgoszcz, Poland; Department of Oncological Surgery, Oncology Center, Bydgoszcz, Poland. · Melanoma Unit, Dermatology Department, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain. · Instituto de Oncología Ángel H Roffo, Universidad de Buenos Aires, Buenos Aires, Argentina. · Department of Dermatology, Venereology, and Allergology, University Hospital Schleswig-Holstein, Kiel, Germany. · Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands. · GlaxoSmithKline, Rixensart, Belgium. Electronic address: fernando.x.ulloa-montoya@GSK.com. · GlaxoSmithKline, Rixensart, Belgium. · GlaxoSmithKline, Rixensart, Belgium; Immunology Translational Medicine, UCB, Brussels, Belgium. · GlaxoSmithKline, Rixensart, Belgium; Biostatistics Department, Janssen Research & Development, Beerse, Belgium. · GlaxoSmithKline, Rixensart, Belgium; ViaNova Biosciences, Brussels, Belgium. · GlaxoSmithKline, Rixensart, Belgium; Laboratoires Servier, Paris, France. · GlaxoSmithKline, Rixensart, Belgium; University Hospitals Leuven, Leuven, Belgium. · UPMC Hillman Cancer Center, Pittsburgh, PA, USA. ·Lancet Oncol · Pubmed #29908991.

ABSTRACT: BACKGROUND: Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting. METHODS: DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 μg MAGE-A3 antigen plus 420 μg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445. FINDINGS: Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3-35·5] in the MAGE-A3 group and 28·1 months [23·7-36·9] in the placebo group. Median disease-free survival was 11·0 months (95% CI 10·0-11·9) in the MAGE-A3 group and 11·2 months (8·6-14·1) in the placebo group (hazard ratio [HR] 1·01, 0·88-1·17, p=0·86). In the GS-positive population, median disease-free survival was 9·9 months (95% CI 5·7-17·6) in the MAGE-A3 group and 11·6 months (5·6-22·3) in the placebo group (HR 1·11, 0·83-1·49, p=0·48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [<1%] for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment. INTERPRETATION: An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped. FUNDING: GlaxoSmithKline Biologicals SA.

10 Clinical Trial Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. 2018

Eggermont, Alexander M M / Blank, Christian U / Mandala, Mario / Long, Georgina V / Atkinson, Victoria / Dalle, Stéphane / Haydon, Andrew / Lichinitser, Mikhail / Khattak, Adnan / Carlino, Matteo S / Sandhu, Shahneen / Larkin, James / Puig, Susana / Ascierto, Paolo A / Rutkowski, Piotr / Schadendorf, Dirk / Koornstra, Rutger / Hernandez-Aya, Leonel / Maio, Michele / van den Eertwegh, Alfonsus J M / Grob, Jean-Jacques / Gutzmer, Ralf / Jamal, Rahima / Lorigan, Paul / Ibrahim, Nageatte / Marreaud, Sandrine / van Akkooi, Alexander C J / Suciu, Stefan / Robert, Caroline. ·From the Gustave Roussy Cancer Campus Grand Paris and University Paris-Saclay, Villejuif (A.M.M.E., C.R.), Hospices Civils de Lyon Cancer Institute, Cancer Research Center of Lyon, Lyon University, Lyon (S.D.), and Aix-Marseille University, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille (J.-J.G.) - all in France · Netherlands Cancer Institute-Antoni van Leeuwenhoek (C.U.B., A.C.J.A.) and VU University Medical Center (A.J.M.E.), Amsterdam, and Radboud University Medical Center Nijmegen, Nijmegen (R.K.) - all in the Netherlands · Azienda Ospedaliera Papa Giovanni XXIII, Bergamo (M. Mandala), Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Fondazione G. Pascale, Naples (P.A.A.), and Universita Degli Studi Di Siena-Policlinico le Scotte, Siena (M. Maio) - all in Italy · Melanoma Institute Australia, the University of Sydney, and Mater and Royal North Shore Hospitals (G.V.L.) and Westmead and Blacktown Hospitals, Melanoma Institute Australia and the University of Sydney (M.S.C.), Sydney, Princess Alexandra Hospital, University of Queensland, Brisbane (V.A.), Alfred Hospital (A.H.) and Peter MacCallum Cancer Centre (S. Sandhu), Melbourne, VIC, and Fiona Stanley Hospital-University of Western Australia-Edith Cowan University Perth, Perth (A.K.) - all in Australia · Cancer Research Center, Moscow (M.L.) · Royal Marsden Hospital, London (J.L.) · Hospital Clinic Universitari de Barcelona, Barcelona (S.P.) · Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.) · University Hospital Essen, Essen and German Cancer Consortium, Heidelberg (D.S.), and the Skin Cancer Center, Department of Dermatology, Hannover Medical School, Hannover (R.G.) - all in Germany · Washington University School of Medicine, St. Louis (L.H.-A.) · Centre Hospitalier de l'Université de Montréal (CHUM), Centre de Recherche du CHUM, Montreal (R.J.) · Christie NHS Foundation Trust, Manchester, United Kingdom (P.L.) · Merck, Kenilworth, NJ (N.I.) · and the European Organization for the Research and Treatment of Cancer Headquarters, Brussels (S.M., S. Suciu). ·N Engl J Med · Pubmed #29658430.

ABSTRACT: BACKGROUND: The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma. METHODS: Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated. RESULTS: At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group. CONCLUSIONS: As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .).

11 Clinical Trial Adjuvant vemurafenib in resected, BRAF 2018

Maio, Michele / Lewis, Karl / Demidov, Lev / Mandalà, Mario / Bondarenko, Igor / Ascierto, Paolo A / Herbert, Christopher / Mackiewicz, Andrzej / Rutkowski, Piotr / Guminski, Alexander / Goodman, Grant R / Simmons, Brian / Ye, Chenglin / Yan, Yibing / Schadendorf, Dirk / Anonymous33031188. ·Division of Medical Oncology and Immunotherapy, Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy. Electronic address: mmaiocro@gmail.com. · University of Colorado Comprehensive Cancer Center, Aurora, CO, USA. · N N Blokhin Russian Cancer Research Center, Ministry of Health, Moscow, Russia. · Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy. · Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine. · Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. · Bristol Haematology and Oncology Centre, Bristol, UK. · Department of Cancer Immunology, Poznan University for Medical Sciences, Med-POLONIA, Poznan, Poland. · Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland. · Melanoma Translational Research Group, Melanoma Institute Australia, Wollstonecraft, NSW, Australia. · Genentech, Inc, South San Francisco, CA, USA. · Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. ·Lancet Oncol · Pubmed #29477665.

ABSTRACT: BACKGROUND: Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC-III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAF METHODS: BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC-IIIA-IIIB (cohort 1) or stage IIIC (cohort 2) BRAF FINDINGS: The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9-41·6) in cohort 2 and 30·8 months (25·5-40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6-26·5) in the vemurafenib group versus 15·4 months (11·1-35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54-1·18; log-rank p=0·26). In cohort 1 (patients with stage IIC-IIIA-IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4-not estimable) in the placebo group (HR 0·54 [95% CI 0·37-0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3-4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3-4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3-4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug. INTERPRETATION: The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC-IIIA-IIIB BRAF FUNDING: F Hoffman-La Roche Ltd.

12 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 .).

13 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 .).

14 Clinical Trial Health-related quality of life results from the phase III CheckMate 067 study. 2017

Schadendorf, Dirk / Larkin, James / Wolchok, Jedd / Hodi, F Stephen / Chiarion-Sileni, Vanna / Gonzalez, Rene / Rutkowski, Piotr / Grob, Jean-Jacques / Cowey, C Lance / Lao, Christopher / Wagstaff, John / Callahan, Margaret K / Postow, Michael A / Smylie, Michael / Ferrucci, Pier Francesco / Dummer, Reinhard / Hill, Andrew / Taylor, Fiona / Sabater, Javier / Walker, Dana / Kotapati, Srividya / Abernethy, Amy / Long, Georgina V. ·Department of Dermatology, University of Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. · Royal Marsden Hospital, London, UK. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Istituto Oncologico Veneto, Veneto, Italy. · University of Colorado, Denver, CO, USA. · Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. · Hospital de la Timone, Marseille, France. · Texas Oncology-Baylor Cancer Center, Dallas, TX, USA. · University of Michigan, Ann Arbor, MI, USA. · The College of Medicine, Swansea University, Swansea, UK. · Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. · Cross Cancer Institute, Edmonton, Alberta, Canada. · Istituto Europeo di Oncologia, Milan, Italy. · University of Zurich, Zurich, Switzerland. · Tasman Oncology Research, Brisbane, QLD, Australia. · Adelphi Values, Boston, MA, USA. · Bristol-Myers Squibb, Princeton, NJ, USA. · Duke University Medical Center, Durham, NC, USA. · Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au. ·Eur J Cancer · Pubmed #28651159.

ABSTRACT: BACKGROUND: Nivolumab, a monoclonal antibody of immune checkpoint programmed death 1 on T cells (PD-1), combined with ipilimumab, an immune checkpoint cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, as combination therapy on the one hand and nivolumab as monotherapy on the other, have both demonstrated improved efficacy compared with ipilimumab alone in the CheckMate 067 study. However, the combination resulted in a higher frequency of grade 3/4 adverse events (AEs), which could result in diminished health-related quality of life (HRQoL). Here we report analyses of HRQoL for patients with advanced melanoma in clinical trial CheckMate 067. PATIENTS AND METHODS: HRQoL was assessed at weeks 1 and 5 per 6-week cycle for the first 6 months, once every 6 weeks thereafter, and at two follow-up visits using the European Organization for Research and Treatment of Care Core Quality of Life Questionnaire and the EuroQoL Five Dimensions Questionnaire. In addition to the randomised population, patient subgroups, including BRAF mutation status, partial or complete response, treatment-related AEs of grade 3/4, and those who discontinued due to any reason and due to an AE, were investigated. RESULTS: Nivolumab and ipilimumab combination and nivolumab alone both maintained HRQoL, and no clinically meaningful deterioration was observed over time compared with ipilimumab. In addition, similar results were observed across patient subgroups, and no clinically meaningful changes in HRQoL were observed during follow-up visits for patients who discontinued due to any cause. CONCLUSION: These results further support the clinical benefit of nivolumab monotherapy and nivolumab and ipilimumab combination therapy in patients with advanced melanoma. The finding that the difference in grade 3/4 AEs between the arms did not translate into clinically meaningful differences in the reported HRQoL may be relevant in the clinical setting. STUDY NUMBER: NCT01844505.

15 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.

16 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.

17 Clinical Trial Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. 2017

Dummer, Reinhard / Schadendorf, Dirk / Ascierto, Paolo A / Arance, Ana / Dutriaux, Caroline / Di Giacomo, Anna Maria / Rutkowski, Piotr / Del Vecchio, Michele / Gutzmer, Ralf / Mandala, Mario / Thomas, Luc / Demidov, Lev / Garbe, Claus / Hogg, David / Liszkay, Gabriella / Queirolo, Paola / Wasserman, Ernesto / Ford, James / Weill, Marine / Sirulnik, L Andres / Jehl, Valentine / Bozón, Viviana / Long, Georgina V / Flaherty, Keith. ·Department of Dermatology, University Hospital Zürich Skin Cancer Center, Zürich, Switzerland. Electronic address: reinhard.dummer@usz.ch. · Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. · Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori Fondazione Pascale, Via Mariano Semmola, Naples, Italy. · Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain. · Department of Oncologic Dermatology, Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux, France. · Medical Oncology and Immunotherapy, University Hospital of Siena, Viale Bracci, Siena, Italy. · Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. · Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, Milan, Italy. · Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany. · Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy. · Department of Dermatology, Centre Hospitalier Lyon Sud, Lyons Cancer Research Center, Lyon 1 University, Pierre Bénite, France. · N N Blokhin Russian Cancer Research Center, Ministry of Health, Moscow, Russian Federation. · Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany. · Department of Medicine, University Health Network/Princess Margaret Hospital, Toronto, ON, Canada. · Department of Dermatology, National Institute of Oncology, Budapest, Hungary. · Department of Medical Oncology, Institute for Cancer Research, IRCCS San Martino, Largo Rosanna Benzi, Genova, Italy. · Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, USA. · Novartis Pharma AG, Basel, Switzerland. · Array BioPharma, Boulder, CO, USA. · Melanoma Institute Australia, The University of Sydney, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. · Department of Medical Oncology, Massachusetts General Hospital, Boston, MA, USA. ·Lancet Oncol · Pubmed #28284557.

ABSTRACT: BACKGROUND: There are no established therapies specific for NRAS-mutant melanoma despite the emergence of immunotherapy. We aimed to assess the efficacy and safety of the MEK inhibitor binimetinib versus that of dacarbazine in patients with advanced NRAS-mutant melanoma. METHODS: NEMO is an ongoing, randomised, open-label phase 3 study done at 118 hospitals in 26 countries. Patients with advanced, unresectable, American Joint Committee on Cancer stage IIIC or stage IV NRAS-mutant melanoma who were previously untreated or had progressed on or after previous immunotherapy were randomised (2:1) to receive either binimetinib 45 mg orally twice daily or dacarbazine 1000 mg/m FINDINGS: Between Aug 19, 2013, and April 28, 2015, 402 patients were enrolled and randomly assigned, 269 to binimetinib and 133 to dacarbazine. Median follow-up was 1·7 months (IQR 1·4-4·1). Median progression-free survival was 2·8 months (95% CI 2·8-3·6) in the binimetinib group and 1·5 months (1·5-1·7) in the dacarbazine group (hazard ratio 0·62 [95% CI 0·47-0·80]; one-sided p<0·001). Grade 3-4 adverse events seen in at least 5% of patients the safety population in either group were increased creatine phosphokinase (52 [19%] of 269 patients in the binimetinib group vs none of 114 in the dacarbazine group), hypertension (20 [7%] vs two [2%]), anaemia (five [2%] vs six [5%]), and neutropenia (two [1%] vs ten [9%]). Serious adverse events (all grades) occurred in 91 (34%) patients in the binimetinib group and 25 (22%) patients in the dacarbazine group. INTERPRETATION: Binimetinib improved progression-free survival compared with dacarbazine and was tolerable. Binimetinib might represent a new treatment option for patients with NRAS-mutant melanoma after failure of immunotherapy. FUNDING: Array BioPharma and Novartis Pharmaceuticals Corporation.

18 Clinical Trial Electrochemotherapy in the treatment of metastatic malignant melanoma: a prospective cohort study by InspECT. 2017

Kunte, C / Letulé, V / Gehl, J / Dahlstroem, K / Curatolo, P / Rotunno, R / Muir, T / Occhini, A / Bertino, G / Powell, B / Saxinger, W / Lechner, G / Liew, S-H / Pritchard-Jones, R / Rutkowski, P / Zdzienicki, M / Mowatt, D / Sykes, A J / Orlando, A / Mitsala, G / Rossi, C R / Campana, L / Brizio, M / de Terlizzi, F / Quaglino, P / Odili, J / Anonymous4800894. ·Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich, Germany. · Center for Experimental Drug and Gene Electrotransfer, Department of Oncology, Copenhagen University Hospital Herlev, Herlev, Denmark. · Department of Plastic Surgery, Copenhagen University Hospital Herlev, Denmark. · Department of Dermatology and Plastic Surgery, Dermatologic Clinic, University of Rome 'La Sapienza', Rome, Italy. · Department of Reconstructive Plastic Surgery, James Cook University Hospital, Middlesbrough, U.K. · Department of Otolaryngology Head & Neck Surgery, University of Pavia, IRCCS Policlinico San Matteo Foundation, Pavia, Italy. · Department of Plastic Surgery, St George's Hospital, London, U.K. · Department of Dermatology, Klinikum Wels-Grieskirchen, Wels, Austria. · Department of Plastic Surgery, Whiston Hospital, Prescot, Merseyside, U.K. · Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. · Department of Plastic Surgery. · Department of Clinical Oncology, Christie Hospital, NHS Foundation Trust, Manchester, U.K. · Department of Plastic and Reconstructive Surgery, Southmead Hospital, North Bristol NHS Trust, Bristol, U.K. · Veneto Institute of Oncology IOV-IRCCS, Padova, Italy. · Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy. · Department of Medical Sciences, Dermatologic Clinic, University of Torino, Torino, Italy. · Scientific and Medical Department, IGEA S.p.A., Carpi, Italy. ·Br J Dermatol · Pubmed #28118487.

ABSTRACT: BACKGROUND: (ECT) is an effective local treatment for cutaneous metastasis. Treatment involves the administration of chemotherapeutic drugs followed by delivery of electrical pulses to the tumour. OBJECTIVES: To investigate the effectiveness of ECT in cutaneous metastases of melanoma and to identify factors that affect (beneficially or adversely) the outcome. METHODS: Thirteen cancer centres in the International Network for Sharing Practices on Electrochemotherapy consecutively and prospectively uploaded data to a common database. ECT consisted of intratumoral or intravenous injection of bleomycin, followed by application of electric pulses under local or general anaesthesia. RESULTS: In total, 151 patients with metastatic melanoma were identified from the database, 114 of whom had follow-up data of 60 days or more. Eighty-four of these patients (74%) experienced an overall response (OR = complete response + partial response). Overall, 394 lesions were treated, of which 306 (78%) showed OR, with 229 showing complete response (58%). In multivariate analysis, factors positively associated with overall response were coverage of deep margins, absence of visceral metastases, presence of lymphoedema and treatment of nonirradiated areas. Factors significantly associated with complete response to ECT treatment were coverage of deep margins, previous irradiation of the treated area and tumour size (< 3 cm). One-year overall survival in this cohort of patients was 67% (95% confidence interval 57-77%), while melanoma-specific survival was 74% (95% confidence interval 64-84%). No serious adverse events were reported, and the treatment was in general very well tolerated. CONCLUSIONS: ECT is a highly effective local treatment for melanoma metastases in the skin, with no severe adverse effects noted in this study. In the presence of certain clinical factors, ECT may be considered for local tumour control as an alternative to established local treatments, or as an adjunct to systemic treatments.

19 Clinical Trial Prospective assessment of a gene signature potentially predictive of clinical benefit in metastatic melanoma patients following MAGE-A3 immunotherapeutic (PREDICT). 2016

Saiag, P / Gutzmer, R / Ascierto, P A / Maio, M / Grob, J-J / Murawa, P / Dreno, B / Ross, M / Weber, J / Hauschild, A / Rutkowski, P / Testori, A / Levchenko, E / Enk, A / Misery, L / Vanden Abeele, C / Vojtek, I / Peeters, O / Brichard, V G / Therasse, P. ·General Dermatology and Oncology Service, Ambroise-Paré Hospital, AP-HP, University of Versailles-Saint-Quentin-en-Yvelines, Boulogne, France philippe.saiag@uvsq.fr. · Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany. · National Institute for Tumors Foundation 'G. Pascale', Napoli. · Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. · Department of Dermatology and Skin Cancers, La Timone APHM Hospital, Aix-Marseille University, Marseille, France. · Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, Poznań, Poland. · Dermatology Clinic, Hôtel-Dieu Hospital, CHU Nantes, Nantes, France. · Department of Surgical Oncology, UTMD Anderson Cancer Center, Houston. · Moffitt Cancer Center, Tampa, USA. · Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany. · Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Center and Institute of Oncology, Warsaw, Poland. · Melanoma and Soft Tissue Sarcoma Division, European Institute of Oncology, Milan, Italy. · Petrov Research Institute of Oncology, St Petersburg, Russian Federation. · Department of Dermatology, University of Heidelberg, Heidelberg, Germany. · Department of Dermatology, University Hospital of Brest, Brest, France. · GSK Vaccines, Rixensart, Belgium. ·Ann Oncol · Pubmed #27502712.

ABSTRACT: BACKGROUND: Genomic profiling of tumor tissue may aid in identifying predictive or prognostic gene signatures (GS) in some cancers. Retrospective gene expression profiling of melanoma and non-small-cell lung cancer led to the characterization of a GS associated with clinical benefit, including improved overall survival (OS), following immunization with the MAGE-A3 immunotherapeutic. The goal of the present study was to prospectively evaluate the predictive value of the previously characterized GS. PATIENTS AND METHODS: An open-label prospective phase II trial ('PREDICT') in patients with MAGE-A3-positive unresectable stage IIIB-C/IV-M1a melanoma. RESULTS: Of 123 subjects who received the MAGE-A3 immunotherapeutic, 71 (58.7%) displayed the predictive GS (GS+). The 1-year OS rate was 83.1%/83.3% in the GS+/GS- populations. The rate of progression-free survival at 12 months was 5.8%/4.1% in GS+/GS- patients. The median time-to-treatment failure was 2.7/2.4 months (GS+/GS-). There was one complete response (GS-) and two partial responses (GS+). The MAGE-A3 immunotherapeutic was similarly immunogenic in both populations and had a clinically acceptable safety profile. CONCLUSION: Treatment of patients with MAGE-A3-positive unresectable stage IIIB-C/IV-M1a melanoma with the MAGE-A3 immunotherapeutic demonstrated an overall 1-year OS rate of 83.5%. GS- and GS+ patients had similar 1-year OS rates, indicating that in this study, GS was not predictive of outcome. Unexpectedly, the objective response rate was lower in this study than in other studies carried out in the same setting with the MAGE-A3 immunotherapeutic. Investigation of a GS to predict clinical benefit to adjuvant MAGE-A3 immunotherapeutic treatment is ongoing in another melanoma study.This study is registered at www.clinicatrials.gov NCT00942162.

20 Clinical Trial Effect of nivolumab on health-related quality of life in patients with treatment-naïve advanced melanoma: results from the phase III CheckMate 066 study. 2016

Long, G V / Atkinson, V / Ascierto, P A / Robert, C / Hassel, J C / Rutkowski, P / Savage, K J / Taylor, F / Coon, C / Gilloteau, I / Dastani, H B / Waxman, I M / Abernethy, A P. ·Melanoma Institute Australia, The University of Sydney, and Mater Hospital, Sydney, Australia georgina.long@sydney.edu.au. · Gallipoli Medical Research Foundation and Princess Alexandra Hospital, Greenslopes, Australia. · Istituto Nazionale Tumori Fondazione Pascale, Napoli, Italy. · Gustave-Roussy, Paris, France. · University Hospital Heidelberg and National Center for Tumor Diseases, Heidelberg, Germany. · Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. · BC Cancer Agency, University of British Columbia, Vancouver, Canada. · Adelphi Values, Boston, MA, USA. · Bristol-Myers Squibb, Princeton, NJ, USA. · Duke Clinical Research Institute, Durham, NC, USA. ·Ann Oncol · Pubmed #27405322.

ABSTRACT: BACKGROUND: Nivolumab has shown significant survival benefit and a favorable safety profile compared with dacarbazine chemotherapy among treatment-naïve patients with metastatic melanoma in the CheckMate 066 phase III study. Results from the health-related quality of life (HRQoL) analyses from CheckMate 066 are presented. PATIENTS AND METHODS: HRQoL was evaluated at baseline and every 6 weeks while on treatment using the European Organisation for Research and Treatment of Care (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and the EuroQoL Five Dimensions Questionnaire (EQ-5D). Via a multi-step statistical plan, data were analyzed descriptively, cross-sectionally, and longitudinally, adjusting for baseline covariates, in patients having baseline plus ≥1 post-baseline assessment. RESULTS: Baseline-adjusted completion rates for all HRQoL questionnaires across treatment arms were 65% and 70% for dacarbazine and nivolumab, respectively, and remained similar throughout treatment. The mean baseline HRQoL scores were similar for patients treated with nivolumab and dacarbazine. Baseline HRQoL levels with nivolumab were maintained over time. This exploratory analysis showed a between-arm difference in favor of nivolumab on the EQ-5D utility index and clinically meaningful EQ-5D improvements from baseline at several time points for patients receiving nivolumab. Patients treated with nivolumab did not show increased symptom burden as assessed by the EORTC QLQ-C30. No HRQoL change was noted with dacarbazine patients up to week 43, although the high attrition rate after week 13 did not allow any meaningful analyses. Patients receiving nivolumab deteriorated significantly later than those receiving dacarbazine on several EORTC QLQ-C30 scales and the EQ-5D utility index. CONCLUSIONS: In addition to prolonged survival, these exploratory HRQoL results show that nivolumab maintains baseline HRQoL levels to provide long-term quality of survival benefit, compared with dacarbazine in patients with advanced melanoma.

21 Clinical Trial The long-term results and prognostic significance of cutaneous melanoma surgery using sentinel node biopsy with triple technique. 2015

Rutkowski, Piotr / Szydłowski, Konrad / Nowecki, Zbigniew I / Sałamacha, Maciej / Goryń, Tomasz / Mitręga-Korab, Beata / Pieńkowski, Andrzej / Dziewirski, Wirginiusz / Zdzienicki, Marcin. ·Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, 02-781, Warsaw, Poland. · Department of General Surgery, Elblag, Poland. · Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, 02-781, Warsaw, Poland. mzdzienicki@coi.waw.pl. ·World J Surg Oncol · Pubmed #26462471.

ABSTRACT: BACKGROUND: The sentinel lymph node biopsy (SLN) is a basic staging method in all primary cutaneous melanomas ≥pT1b. The standard technique is a triple technique consisting of preoperative lymphoscintigraphy, intraoperative blue-dye lymphography, and gamma-probe assessment. We performed the analysis of long-term results in a very large one-institution series of cutaneous melanoma patients. METHODS: We have analyzed treatment results of a group of 1764 consecutive patients with cutaneous melanoma, who underwent SLN biopsy between 1997 and 2008 in one tertiary center. Additionally, we have analyzed the outcomes of a group of 473 patients with positive SLN biopsy undergoing completion lymph node dissection (CLND). Median follow-up time was 5.3 years. RESULTS: Metastases to SLN (SLN+) were found in 19.9%. Eight-year overall survival (OS) rate in the entire group was 73.5%, 80% without SLN metastases (SLN-) and 50% in group with SLN+ (p < 0.001). Independent prognostic factors for OS were as follows: presence of metastases to SLN, primary tumor ulceration, and higher mitotic index (>5/mm(2)) of primary tumor. The nodal recurrences in the biopsied lymphatic basin were 5.4%. The metastases to non-sentinel lymph nodes (NSLN found in 27% of patients with SLN+) correlated (on multivariable logistic regression analysis) with primary tumor thickness >4 mm, SLN metastatic deposit size >1 mm, and extracapsular involvement of SLN. In an additionally analyzed SLN+ group, the NSLN involvement was related to poorer prognosis (8-year OS rate NSLN- vs NSLN+: 59.6 vs. 34.7%, respectively). The independent prognostic factors for OS in the SLN+ group were a higher Breslow thickness and ulceration of primary tumor, metastases to more than 1 lymph nodes. CONCLUSIONS: The long-term results confirm crucial prognostic significance of SLN biopsy in cutaneous melanoma. We identified factors related to NSLN involvement, which in the future may limit indications for CLND.

22 Clinical Trial Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial. 2015

Grob, Jean Jacques / Amonkar, Mayur M / Karaszewska, Boguslawa / Schachter, Jacob / Dummer, Reinhard / Mackiewicz, Andrzej / Stroyakovskiy, Daniil / Drucis, Kamil / Grange, Florent / Chiarion-Sileni, Vanna / Rutkowski, Piotr / Lichinitser, Mikhail / Levchenko, Evgeny / Wolter, Pascal / Hauschild, Axel / Long, Georgina V / Nathan, Paul / Ribas, Antoni / Flaherty, Keith / Sun, Peng / Legos, Jeffrey J / McDowell, Diane Opatt / Mookerjee, Bijoyesh / Schadendorf, Dirk / Robert, Caroline. ·Service de Dermatologie, Aix Marseille University, and Assistance Publique Hôpitaux de Marseille (APHM), University Hospital Timone, Marseille, France. Electronic address: jean-jacques.grob@ap-hm.fr. · GlaxoSmithKline Oncology Research and Development, Collegeville, PA, USA. · Przychodnia Lekarska Komed, Konin, Poland. · Sheba Medical Center, Ramat Gan, Ramat, Israel. · Department of Dermatology, Universität Zürich, Zurich, Switzerland. · Oncology Division, Poznan University of Medical Sciences, Med-Polonia, Poznan, Poland. · Moscow City Oncology Hospital #62, Stepanovskoye, Moscow, Russia. · Swissmed Centrum Zdrowia and Gdansk Medical University, Gdansk, Poland. · Centre Hospitalier Universitairede Reims-Hôpital Robert Debré, Reims, France. · Istituto Oncologico Veneto Istituto Di Ricovero e Cura a Carattere Scientifico, Padua, Italy. · Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. · N N Blokhin Russian Cancer Research Center, Moscow, Russia. · Petrov Research Institute of Oncology, Saint Petersburg, Russia. · University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium. · Universitätsklinikum Schleswig-Holstein (UKSH), Department of Dermatology, Kiel, Germany. · Melanoma Institute Australia, The University of Sydney and The Mater Hospital, Sydney, Australia. · Mount Vernon Cancer Centre, Northwood, UK. · University of California Los Angeles (UCLA) Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. · Massachusetts General Hospital Cancer Center, Boston, MA, USA. · Department of Dermatology, University Hospital Essen, Essen, Germany. · Gustave Roussy, Département de Médecine oncologique, Service de Dermatologie et Université Paris-Sud, Faculté de Médecine, Villejuif, France. ·Lancet Oncol · Pubmed #26433819.

ABSTRACT: BACKGROUND: In the COMBI-v trial, patients with previously untreated BRAF Val600Glu or Val600Lys mutant unresectable or metastatic melanoma who were treated with the combination of dabrafenib and trametinib had significantly longer overall and progression-free survival than those treated with vemurafenib alone. Here, we present the effects of treatments on health-related quality of life (HRQoL), an exploratory endpoint in the COMBI-v study. METHODS: COMBI-v was an open-label, randomised phase 3 study in which 704 patients with metastatic melanoma with a BRAF Val600 mutation were randomly assigned (1:1) by an interactive voice response system to receive either a combination of dabrafenib (150 mg twice-daily) and trametinib (2 mg once-daily) or vemurafenib monotherapy (960 mg twice-daily) orally as first-line therapy. The primary endpoint was overall survival. In this pre-specified exploratory analysis, we prospectively assessed HRQoL in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer quality of life (EORTC QLQ-C30), EuroQoL-5D (EQ-5D), and Melanoma Subscale of the Functional Assessment of Cancer Therapy-Melanoma (FACT-M), completed at baseline, during study treatment, at disease progression, and after progression. We used a mixed-model, repeated measures ANCOVA to assess differences in mean scores between groups with baseline score as covariate; all p-values are descriptive. The COMBI-v trial is registered with ClinicalTrials.gov, number NCT01597908, and is ongoing for the primary endpoint, but is not recruiting patients. FINDINGS: From June 4, 2012, to Oct 7, 2013, 1645 patients at 193 centres worldwide were screened for eligibility, and 704 patients were randomly assigned to dabrafenib plus trametinib (n=352) or vemurafenib (n=352). Questionnaire completion rates for both groups were high (>95% at baseline, >80% at follow-up assessments, and >70% at disease progression) with similar HRQoL and symptom scores reported at baseline in both treatment groups for all questionnaires. Differences in mean scores between treatment groups were significant and clinically meaningful in favour of the combination compared with vemurafenib monotherapy for most domains across all three questionnaires during study treatment and at disease progression, including EORTC QLQ-C30 global health (7·92, 7·62, 6·86, 7·47, 5·16, 7·56, and 7·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0·001 for all assessments except p=0·005 at week 40), EORTC QLQ-C30 pain (-13·20, -8·05, -8·82, -12·69, -12·46, -11·41, and -10·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0·001), EQ-5D thermometer scores (7·96, 8·05, 6·83, 11·53, 7·41, 9·08, and 10·51 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0·001 for all assessments except p=0·006 at week 32), and FACT-M Melanoma Subscale score (3·62, 2·93, 2·45, 3·39, 2·85, 3·00, and 3·68 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0·001). INTERPRETATION: From the patient's perspective, which integrates not only survival advantage but also disease-associated and adverse-event-associated symptoms, treatment with the combination of a BRAF inhibitor plus a MEK inhibitor (dabrafenib plus trametinib) adds a clear benefit over monotherapy with the BRAF inhibitor vemurafenib and supports the combination therapy as standard of care in this population.

23 Clinical Trial Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. 2015

Larkin, James / Chiarion-Sileni, Vanna / Gonzalez, Rene / Grob, Jean Jacques / Cowey, C Lance / Lao, Christopher D / Schadendorf, Dirk / Dummer, Reinhard / Smylie, Michael / Rutkowski, Piotr / Ferrucci, Pier F / Hill, Andrew / Wagstaff, John / Carlino, Matteo S / Haanen, John B / Maio, Michele / Marquez-Rodas, Ivan / McArthur, Grant A / Ascierto, Paolo A / Long, Georgina V / Callahan, Margaret K / Postow, Michael A / Grossmann, Kenneth / Sznol, Mario / Dreno, Brigitte / Bastholt, Lars / Yang, Arvin / Rollin, Linda M / Horak, Christine / Hodi, F Stephen / Wolchok, Jedd D. ·From the Department of Medical Oncology, Royal Marsden Hospital, London (J.L.), and South West Wales Cancer Institute, Singleton Hospital, Swansea (J.W.) - both in the United Kingdom · Melanoma Oncology Unit, Veneto Region Oncology Research Institute, Padua (V.C.-S.), Oncology of Melanoma Unit, European Institute of Oncology, Milan (P.F.F.), University Hospital of Siena, Siena (M.M.), and Istituto Nazionale Tumori Fondazione Pascale, Naples (P.A.A.) - all in Italy · Division of Medical Oncology, University of Colorado, Denver, Denver (R.G.) · Aix-Marseille University, Hôpital de La Timone, Assitance Publique-Hôpitaux de Marseille, Marseille (J.J.G.), and Hôtel Dieu Place Alexis Ricordeau, Nantes (B.D.) - both in France · Baylor Charles A. Sammons Cancer Center, Dallas (C.L.C.) · Departments of Internal Medicine and Dermatology, University of Michigan, Ann Arbor (C.D.L.) · Department of Dermatology, University of Essen, Essen, Germany (D.S.) · University of Zürich Hospital, Zurich, Switzerland (R.D.) · Cross Cancer Institute, Edmonton, AB, Canada (M. Smylie) · Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland (P.R.) · Tasman Oncology Research, Southport Gold Coast, QLD (A.H.), and Westmead and Blacktown Hospitals (M.S.C.) and Melanoma Institute Australia (M.S.C., G.V.L.), University of Sydney, and the Mater Hospital (G.V.L.), Sydney, and Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (G.A.M.) - all in Australia · Division of Medical Oncology, the Netherlands Cancer Institute, Amsterdam (J.B.H.) · Servicio de Oncología Médica, Hospital General Universitario Gregorio Marañón, Madrid (I.M.-R.) · Ludwig Center, Memorial Sloan Kettering Cancer Center (M.K.C., M.A.P., J.D.W.) and Weill Cornell Medical College (M.K.C., M.A.P., J.D.W.) - both in New York · Huntsman Cancer Institute, University of Utah, Salt Lake City (K.G.) · Yale Cancer Center, Smilow Cancer Hospital of the Yale-New Haven Hospital, Yale University Sc ·N Engl J Med · Pubmed #26027431.

ABSTRACT: BACKGROUND: Nivolumab (a programmed death 1 [PD-1] checkpoint inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] checkpoint inhibitor) have been shown to have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab plus ipilimumab was compared with ipilimumab alone in patients with metastatic melanoma. METHODS: We assigned, in a 1:1:1 ratio, 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone. Progression-free survival and overall survival were coprimary end points. Results regarding progression-free survival are presented here. RESULTS: The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group. CONCLUSIONS: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).

24 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.).

25 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.).

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