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Melanoma: HELP
Articles by Helen J. Gogas
Based on 63 articles published since 2009
(Why 63 articles?)
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Between 2009 and 2019, H. Gogas wrote the following 63 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Review Mucosal melanoma of the head and neck. 2017

Ascierto, Paolo Antonio / Accorona, Remo / Botti, Gerardo / Farina, Davide / Fossati, Piero / Gatta, Gemma / Gogas, Helen / Lombardi, Davide / Maroldi, Roberto / Nicolai, Piero / Ravanelli, Marco / Vanella, Vito. ·Department Melanoma, Soft Tissues, Musculoskeletal and Head & Neck, Italian National Cancer Institute - IRCCS Pascale Foundation, Naples, Italy. Electronic address: paolo.ascierto@gmail.com. · Department of Otorhinolaryngology, University of Brescia, Italy. · Department of Pathology and Cytopathology, Italian National Cancer Institute - IRCCS Pascale Foundation, Naples, Italy. · Department of Radiology, University of Brescia, Italy. · Particle Therapy Cancer Research Institute, CNAO Foundation, Milan, Italy. · Evaluative Epidemiology Unit, Fondazione IRCCS "Istituto Nazionale dei Tumori", Milan, Italy. · First Department of Medicine, Laiko General Hospital, Athens, Greece. · Department Melanoma, Soft Tissues, Musculoskeletal and Head & Neck, Italian National Cancer Institute - IRCCS Pascale Foundation, Naples, Italy. ·Crit Rev Oncol Hematol · Pubmed #28325255.

ABSTRACT: Mucosal melanoma of the head and neck is a very rare and aggressive malignancy with a very poor prognosis. The nasal cavity, paranasal sinuses, and oral cavity are the most common locations. One-, 3- and 5-year survival rates between 2000 and 2007 were 63%, 30% and 20%, respectively. Cigarette smoking seems to be a risk factor even though the evidence for this is very low. Clinical signs and symptoms are usually nonspecific. While surgery is considered the mainstay of treatment for most mucosal melanomas of the head and neck region, radiotherapy has a role in local control of the disease after surgery. Many new treatment options in the last years, in particular targeted therapies (i.e. inhibitors of c-KIT, NRAS/MEK or BRAF) and immunotherapies (anti CTLA-4 and anti PD-1/PD-L1 antibodies), have changed the history of cutaneous melanoma. Despite the different biology, mucosal melanoma is currently treated in the same way as cutaneous melanoma; however, patients with mucosal melanoma were excluded from the majority of recent clinical trials. Recent molecular findings offer new hope for the development of more effective systemic therapy.

2 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.

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

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

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

4 Review Advances in adjuvant therapy: potential for prognostic and predictive biomarkers. 2014

Davar, Diwakar / Tarhini, Ahmad A / Gogas, Helen / Kirkwood, John M. ·Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. ·Methods Mol Biol · Pubmed #24258973.

ABSTRACT: Melanoma is the third most common skin cancer but accounts for the majority of skin cancer-related mortality. The rapidly rising incidence and younger age at diagnosis has made melanoma a leading cause of lost productive years of life and has increased the urgency of finding improved adjuvant therapy for melanoma. Interferon-α was approved for the adjuvant treatment of resected high-risk melanoma following studies that demonstrated improvements in relapse-free survival and overall survival that were commenced nearly 30 years ago. The clinical benefits associated with this agent have been consistently observed across multiple studies and meta-analyses in terms of relapse rate, and to a smaller and less-consistent degree, mortality. However, significant toxicity and lack of prognostic and/or predictive biomarkers that would allow greater risk-benefit ratio have limited the more widespread adoption of this modality.Recent success with targeted agents directed against components of the MAP-kinase pathway and checkpoint inhibitors have transformed the treatment landscape in metastatic disease. Current research efforts are centered around discovering predictive/prognostic biomarkers and exploring the options for more effective regimens, either singly or in combination.

5 Review Immunotherapy for advanced melanoma: fulfilling the promise. 2013

Gogas, Helen / Polyzos, Aristidis / Kirkwood, John. ·1st Department of Medicine, University of Athens, Medical School, Laikon General Hospital, Athens, Greece. Electronic address: hgogas@hol.gr. ·Cancer Treat Rev · Pubmed #23725878.

ABSTRACT: The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with median survival between 6 and 9 months. Over the past thirty years and despite extensive clinical research, the treatment options for metastatic disease were limited and melanoma is still considered as one of the most therapy-resistant malignancies. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimes failed to show significant improvement in overall survival. Recent advances and in-depth understanding of the biology of melanoma, have contributed in the development of new agents. Based on the molecular and immunological background of the disease, the new drugs have shown benefit in overall and progression free survival. As the picture of the disease begins to change, oncologists need to alter their approach to melanoma treatment and consider disease biology together with targeted individualized treatment. In this review the authors attempt to offer an insight in present and past melanoma treatment options, with a focus on the recently approved immunotherapeutic agents and the clinical perspectives of these new weapons against metastatic melanoma.

6 Review Adjuvant interferon alfa in malignant melanoma: an interdisciplinary and multinational expert review. 2013

Ascierto, Paolo A / Gogas, Helen J / Grob, Jean Jacques / Algarra, Salvador Martín / Mohr, Peter / Hansson, Johan / Hauschild, Axel. ·Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale," Naples, Italy. paolo.ascierto@gmail.com ·Crit Rev Oncol Hematol · Pubmed #22874771.

ABSTRACT: Interferon alfa (IFNα) and pegylated IFNα2b (PegIFNα2b) are the only agents currently approved for the adjuvant treatment of resected melanoma at high risk of recurrence. Meta-analyses showed statistically significant disease-free survival (DFS) and overall survival (OS) benefits versus controls but did not clarify optimal dose/duration. We review data from all recent clinical trials to provide the latest information on dose, duration, and potential predictive factors of treatment success. Recent data largely confirm DFS and OS benefits but optimal dose/duration is not clarified. The data suggest greater responses in patients with stage III micro-metastatic versus macro-metastatic disease, and ulceration may also predict greater sensitivity to therapy, although further investigation is needed. Presently, IFNα and PegIFNα2b remain valid adjuvant therapies following resection of high-risk melanoma; the most appropriate treatment regimen should be determined on an individual patient basis according to patient lifestyle and approach, potential for toxicity, and the available clinical evidence.

7 Review IFN-α in the treatment of melanoma. 2012

Tarhini, Ahmad A / Gogas, Helen / Kirkwood, John M. ·Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA. tarhiniaa@upmc.edu ·J Immunol · Pubmed #23042723.

ABSTRACT: Among the IFNs, IFN-α2 has been the most broadly evaluated clinically. At the molecular level, IFN-α has multiple effects in a variety of malignancies that range from antiangiogenic to potent immunoregulatory, differentiation-inducing, antiproliferative, and proapoptotic effects. A multitude of IFN-α2 regimens that may be classified as low dose, intermediate dose, and high dose have been evaluated as adjuvant therapy in melanoma. A durable impact on both relapse-free and overall survival was seen only with the regimen utilizing high-dose IFN-α2b tested in the Eastern Cooperative Oncology Group and intergroup trials E1684, E1690, and E1694 as adjuvant therapy for high-risk surgically resected melanoma (stage IIB or III). Adjuvant pegylated IFN-α2b has also been evaluated at maximally tolerable doses compared with the observation group in the European Organization for Research and Treatment of Cancer trial 18991 and has shown relapse-free survival benefits in patients with microscopic nodal disease.

8 Review Prognostic significance of autoimmunity during treatment of melanoma with interferon. 2011

Krauze, Michal T / Tarhini, Ahmad / Gogas, Helen / Kirkwood, John M. ·University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. ·Semin Immunopathol · Pubmed #21279809.

ABSTRACT: Since the pivotal cooperative group trials in the 1980's-90's,, high-dose interferon (HDI) has been the standard of adjuvant therapy. Despite multiple other trials evaluating potential new therapies in melanoma, HDI remains the only FDA-approved therapy for stage IIB and III melanoma. Initial reports from the more recent phase III international trials of modifications of the original HDI regimen linked the appearance of autoimmunity with improved outcomes of disease. Trials of high-dose interleukin-2, many years earlier, reported anecdotal observations that were consistent with the hypothesis that autoimmunity and clinical benefit of immunotherapies of melanoma are linked with one another. The only prospectively conducted study examining the appearance of clinical and laboratory evidence of autoimmunity during HDI therapy was published by Gogas and colleagues, demonstrating statistically significant impact on relapse-free survival and overall survival. Retrospectively conducted studies of different intermediate dosage regimens of interferon (IFN) have not fully confirmed the linkage of serological evidence of autoimmunity and improved survival outcomes. With the emergence of new immunotherapies in treatment of melanoma, this review highlights the importance of autoimmunity for future applications in melanoma and reviews significant differences of past studies evaluating the appearance of autoimmunity during IFN therapy in high-risk melanoma.

9 Review Melanoma: the radiotherapeutic point of view; review of the current literature. 2011

Zygogianni, A / Kyrgias, G / Kouvaris, J / Mystakidou, K / Gogas, H / Kouloulias, V. ·Kapodistrian University of Athens, Medical School, Radiation Oncology, Greece. annazygo1@yahoo.gr ·Rev Recent Clin Trials · Pubmed #21241230.

ABSTRACT: Surgery remains the mainstay of melanoma therapy at all sites. Melanoma is widely believed to be a radioresistant tumor, a misconception that has historically led to the limited use of RT for its treatment. We searched pubmed from 1978 until 2010 by means of prospective randomized trials. The aim was to assess the potential impact of radiotherapy (RT) on local control, quality of life and overall survival. Radiotherapy should be considered in lentigo maligna, especially in elderly patients with extensive or unresectable disease in difficult areas on the face, with adequate tumor control with good cosmetic and functional results. In addition, radiation therapy provides effective palliation in patients with metastatic malignant melanoma. Doses up to 30 Gy or BED > 39.0Gy were found to be associated with prolonged palliation. These findings should be viewed with caution because the lack of data regarding performance status as well as other unknown confounding factors limits the applicability of retrospectives studies. We recommend that higher doses of RT be considered when using RT for the palliation of patients with metastatic melanoma and a performance status that could tolerate such therapy. In the future, the combination of radiation therapy with hyperthermia may be a reasonable therapeutic option.

10 Review Methods of detection of circulating melanoma cells: a comparative overview. 2011

Nezos, Andrianos / Msaouel, Pavlos / Pissimissis, Nikolaos / Lembessis, Peter / Sourla, Antigone / Armakolas, Athanasios / Gogas, Helen / Stratigos, Alexandros J / Katsambas, Andreas D / Koutsilieris, Michael. ·Department of Experimental Physiology, Medical School, National and Kapodistrian University of Athens, 75 Micras Asias str., Goudi-Athens 115 27, Greece. anezos@med.uoa.gr ·Cancer Treat Rev · Pubmed #21106295.

ABSTRACT: Disease dissemination is the major cause of melanoma-related death. A crucial step in the metastatic process is the intravascular invasion and circulation of melanoma cells in the bloodstream with subsequent development of distant micrometastases that is initially clinically undetectable and will eventually progress into clinically apparent metastasis. Therefore, the use of molecular methods to detect circulating melanoma cells may be of value in risk stratification and clinical management of such patients. Herein, we review the currently applied techniques for the detection, isolation, enrichment and further characterization of circulating melanoma cells from peripheral blood samples in melanoma patients. Furthermore, we provide a brief overview of the various molecular markers currently being evaluated as prognostic indicators of melanoma progression.

11 Review Biomarkers in melanoma. 2009

Gogas, H / Eggermont, A M M / Hauschild, A / Hersey, P / Mohr, P / Schadendorf, D / Spatz, A / Dummer, R. ·First Department of Medicine, Medical School, University of Athens, Greece. hgogas@hol.gr ·Ann Oncol · Pubmed #19617299.

ABSTRACT: Biomarkers are tumour- or host-related factors that correlate with tumour biological behaviour and patient prognosis. High-throughput analytical techniques--DNA and RNA microarrays--have identified numerous possible biomarkers, but their relevance to melanoma progression, clinical outcome and the selection of optimal treatment strategies still needs to be established. The review discusses a possible molecular basis for predictive tissue biomarkers such as melanoma thickness, ulceration and mitotic activity, and provides a list of promising new biomarkers identified from tissue microarrays that needs confirmation by independent, prospectively collected clinical data sets. In addition, common predictive serum biomarkers--lactate dehydrogenase, S100B and melanoma-inhibiting activity--as well as selected investigational serum biomarkers such as TA90IC and YKL-40 are also reviewed. A more accurate, therapeutically predictive classification of human melanomas and selection of patient populations that would profit from therapeutic interventions are among the major challenges expected to be addressed in the future.

12 Review Utility of adjuvant systemic therapy in melanoma. 2009

Eggermont, A M M / Testori, A / Marsden, J / Hersey, P / Quirt, I / Petrella, T / Gogas, H / MacKie, R M / Hauschild, A. ·Department of Surgical Oncology, Erasmus University Medical Center-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. ·Ann Oncol · Pubmed #19617295.

ABSTRACT: The lack of effective drugs in stage IV melanoma has impacted the effectiveness of adjuvant therapies in stage II/III disease. To date, chemotherapy, immunostimulants and vaccines have been used with minimal success. Interferon (IFN) has shown an effect on relapse-free survival (RFS) in several clinical trials; however, without a clinically significant effect on overall survival (OS). A recently conducted meta-analysis demonstrated prolongation of disease-free survival (DFS) in 7% and OS benefit in 3% of IFN-treated patients when compared with observation-only patients. There were no clear differences for the dose and duration of treatment observed. Observation is still an appropriate control arm in adjuvant clinical trials. Regional differences exist in Europe in the adjuvant use of IFN. In Northwest Europe, IFN is infrequently prescribed. In Central and Mediterranean Europe, dermatologists commonly prescribe low-dose IFN therapy for AJCC stage II and III disease. High-dose IFN regimens are not commonly used. The population of patients that may benefit from IFN needs to be further characterised, potentially by finding biomarkers that can predict response. Such studies are ongoing.

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

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

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

14 Clinical Trial Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. 2018

Dummer, Reinhard / Ascierto, Paolo A / Gogas, Helen J / Arance, Ana / Mandala, Mario / Liszkay, Gabriella / Garbe, Claus / Schadendorf, Dirk / Krajsova, Ivana / Gutzmer, Ralf / Chiarion Sileni, Vanna / Dutriaux, Caroline / de Groot, Jan Willem B / Yamazaki, Naoya / Loquai, Carmen / Moutouh-de Parseval, Laure A / Pickard, Michael D / Sandor, Victor / Robert, Caroline / Flaherty, Keith T. ·Department of Dermatology, University Hospital Zürich Skin Cancer Center, Zürich, Switzerland. Electronic address: reinhard.dummer@usz.ch. · Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy. · Department of Internal Medicine, National and Kapodistrian University of Athens, Laikon Hospital, Athens, Greece. · Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain. · Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy. · Department of Dermatology, National Institute of Oncology, Budapest, Hungary. · Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany. · Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. · Department of Dermato-oncology, University Hospital Prague and Charles University First Medical Faculty, Prague, Czech Republic. · Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany. · Melanoma Cancer Unit, Oncology Institute of Veneto IRCCS, Padua, Italy. · Department of Oncologic Dermatology, Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux Cédex, France. · Department of Medical Oncology, Isala, Zwolle, Netherlands. · Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Department of Dermatology, University Medical Center Mainz, Mainz, Germany. · Translational Clinical Oncology, Novartis Pharma AG, Basel, Switzerland. · Array BioPharma, Boulder, CO, USA. · Service of Dermatology, Department of Medicine and Paris-Sud University, Gustave Roussy, Villejuif Cedex, France. · Cancer Center, Massachusetts General Hospital, Boston, MA, USA. ·Lancet Oncol · Pubmed #30219628.

ABSTRACT: BACKGROUND: Encorafenib plus binimetinib and encorafenib alone improved progression-free survival compared with vemurafenib in patients with BRAF METHODS: COLUMBUS was a two-part, randomised, open-label, phase 3 study done at 162 hospitals in 28 countries. Eligible patients were aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, BRAF FINDINGS: Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). Median follow-up for overall survival was 36·8 months (95% CI 35·9-37·5). Median overall survival was 33·6 months (95% CI 24·4-39·2) with encorafenib plus binimetinib and 16·9 months (14·0-24·5) with vemurafenib (hazard ratio 0·61 [95% CI 0·47-0·79]; two-sided p<0·0001). The most common grade 3 or 4 adverse events did not change substantially from the first report; those seen in more than 5% of patients treated with encorafenib plus binimetinib were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased blood creatine phosphokinase (14 [7%]), and hypertension (12 [6%]); those seen with encorafenib alone were palmar-plantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and with vemurafenib the most common grade 3 or 4 adverse event was arthralgia (11 [6%] of 186 patients). One death in the combination treatment group was considered by the investigator to be possibly related to treatment. INTERPRETATION: The combination of encorafenib plus binimetinib provided clinically meaningful efficacy with good tolerability as shown by improvements in both progression-free survival and overall survival compared with vemurafenib. These data suggest that the combination of encorafenib plus binimetinib is likely to become an important therapeutic option in patients with BRAF FUNDING: Array BioPharma, Novartis.

15 Clinical Trial Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. 2018

Dummer, Reinhard / Ascierto, Paolo A / Gogas, Helen J / Arance, Ana / Mandala, Mario / Liszkay, Gabriella / Garbe, Claus / Schadendorf, Dirk / Krajsova, Ivana / Gutzmer, Ralf / Chiarion-Sileni, Vanna / Dutriaux, Caroline / de Groot, Jan Willem B / Yamazaki, Naoya / Loquai, Carmen / Moutouh-de Parseval, Laure A / Pickard, Michael D / Sandor, Victor / Robert, Caroline / Flaherty, Keith T. ·Department of Dermatology, University Hospital Zürich Skin Cancer Center, Zürich, Switzerland. Electronic address: reinhard.dummer@usz.ch. · Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy. · Department of Internal Medicine, National and Kapodistrian University of Athens, Laikon Hospital, Athens, Greece. · Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain. · Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy. · Department of Dermatology, National Institute of Oncology, Budapest, Hungary. · Department of Dermatology, University Hospital Tüebingen, Tüebingen, Germany. · Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. · Department of Dermato-oncology, University Hospital Prague, Charles University First Medical Faculty, Prague, Czech Republic. · Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany. · Melanoma Cancer Unit, Oncology Institute of Veneto IRCCS, Padua, Italy. · Department of Oncologic Dermatology, Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux, France. · Department of Medical Oncology, Isala, Zwolle, Netherlands. · Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Department of Dermatology, University Medical Center Mainz, Mainz, Germany. · Translational Clinical Oncology, Novartis Pharma AG, Basel, Switzerland. · Array BioPharma, Boulder, CO, USA. · Service of Dermatology, Department of Medicine, Paris-Sud University, Gustave Roussy, Villejuif, France. · Cancer Center, Massachusetts General Hospital, Boston, MA, USA. ·Lancet Oncol · Pubmed #29573941.

ABSTRACT: BACKGROUND: Combined BRAF-MEK inhibitor therapy is the standard of care for BRAF METHODS: COLUMBUS was conducted as a two-part, randomised, open-label phase 3 study at 162 hospitals in 28 countries. Eligible patients were aged 18 years or older and had histologically confirmed locally advanced (American Joint Committee on Cancer [AJCC] stage IIIB, IIIC, or IV), unresectable or metastatic cutaneous melanoma, or unknown primary melanoma; a BRAF FINDINGS: Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to either the encorafenib plus binimetinib group (n=192), the encorafenib group (n=194), or the vemurafenib group (n=191). With a median follow-up of 16·6 months (95% CI 14·8-16·9), median progression-free survival was 14·9 months (95% CI 11·0-18·5) in the encorafenib plus binimetinib group and 7·3 months (5·6-8·2) in the vemurafenib group (hazard ratio [HR] 0·54, 95% CI 0·41-0·71; two-sided p<0·0001). The most common grade 3-4 adverse events seen in more than 5% of patients in the encorafenib plus binimetinib group were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased creatine phosphokinase (13 [7%]), and hypertension (11 [6%]); in the encorafenib group they were palmoplantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and in the vemurafenib group it was arthralgia (11 [6%] of 186 patients). There were no treatment-related deaths except for one death in the combination group, which was considered possibly related to treatment by the investigator. INTERPRETATION: Encorafenib plus binimetinib and encorafenib monotherapy showed favourable efficacy compared with vemurafenib. Overall, encorafenib plus binimetinib appears to have an improved tolerability profile compared with encorafenib or vemurafenib. Encorafenib plus binimetinib could represent a new treatment option for patients with BRAF-mutant melanoma. FUNDING: Array BioPharma, Novartis.

16 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 .).

17 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.

18 Clinical Trial Open-label, multicentre safety study of vemurafenib in 3219 patients with BRAF 2017

Blank, Christian U / Larkin, James / Arance, Ana M / Hauschild, Axel / Queirolo, Paola / Del Vecchio, Michele / Ascierto, Paolo A / Krajsova, Ivana / Schachter, Jacob / Neyns, Bart / Garbe, Claus / Chiarion Sileni, Vanna / Mandalà, Mario / Gogas, Helen / Espinosa, Enrique / Hospers, Geke A P / Miller, Wilson H / Robson, Susan / Makrutzki, Martina / Antic, Vladan / Brown, Michael P. ·The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066CX, The Netherlands. Electronic address: c.blank@nki.nl. · The Royal Marsden NHS Foundation Trust, London, UK. Electronic address: James.Larkin@rmh.nhs.uk. · Department of Medical Oncology, Hospital Clínic Barcelona, Barcelona, Spain. Electronic address: AMARANCE@clinic.ub.es. · Department of Dermatology, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany. Electronic address: ahauschild@dermatology.uni-kiel.de. · IRCCS San Martino-IST, Genova, Italy. Electronic address: paola.queirolo@hsanmartino.it. · Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: Michele.delvecchio@istitutotumori.mi.it. · Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. Electronic address: paolo.ascierto@gmail.com. · General University Hospital, Dermatooncology U, Prague, Czech Republic. Electronic address: Ivana.Krajsova@vfn.cz. · Chaim Sheba Medical Centre, Oncology Institute, Ramat-Gan, Israel. Electronic address: Jacob.schachter@sheba.health.gov.il. · Afdelingshoofd, Medische Oncologie, Brussels, Belgium. Electronic address: bart.neyns@uzbrussel.be. · Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany. Electronic address: claus.garbe@med.uni-tuebingen.de. · Oncology Institute of Veneto-IRCCS, Padova, Italy. Electronic address: vanna.chiarion@ioveneto.it. · Papa Giovanni XIII Hospital, Bergamo, Italy. Electronic address: mariomandala@tin.it. · University of Athens, Athens, Greece. Electronic address: hgogas@hol.gr. · Hospital La Paz, Madrid, Spain. Electronic address: eespinosa00@hotmail.com. · University Medical Centre Groningen, Groningen, The Netherlands. Electronic address: g.a.p.hospers@umcg.nl. · McGill University, Segal Cancer Centre, Montreal, Quebec, Canada. Electronic address: wilsonmiller@gmail.com. · F. Hoffmann-La Roche Ltd, Basel, Switzerland. Electronic address: susan.robson@roche.com. · F. Hoffmann-La Roche Ltd, Basel, Switzerland. Electronic address: martina.makrutzki@roche.com. · F. Hoffmann-La Roche Ltd, Basel, Switzerland. Electronic address: vladan.antic@roche.com. · Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, Australia; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia; Discipline of Medicine, University of Adelaide, Adelaide, Australia. Electronic address: MichaelP.brown@sa.gov.au. ·Eur J Cancer · Pubmed #28501764.

ABSTRACT: BACKGROUND: The orally available BRAF kinase inhibitor vemurafenib is an effective and tolerable treatment option for patients with metastatic melanoma harbouring BRAF METHODS: This was an open-label, multicentre study of vemurafenib (960 mg bid) in patients with previously treated or untreated BRAF mutation-positive metastatic melanoma (cobas RESULTS: After a median follow-up of 32.2 months (95% CI, 31.1-33.2 months), 3079/3219 patients (96%) had discontinued treatment. Adverse events (AEs) were largely consistent with previous reports; the most common all-grade treatment-related AEs were arthralgia (37%), alopecia (25%) and hyperkeratosis (23%); the most common grade 3/4 treatment-related AEs were squamous cell carcinoma of the skin (8%) and keratoacanthoma (8%). In the exploratory analysis, patients with DOR ≥12 months (n = 287) or ≥24 months (n = 133) were more likely to experience grade 3/4 AEs than the overall population. No new specific safety signals were observed with longer vemurafenib exposure. CONCLUSIONS: After 2 years' follow-up, safety was maintained in this large group of patients with BRAF

19 Clinical Trial Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. 2017

Long, G V / Flaherty, K T / Stroyakovskiy, D / Gogas, H / Levchenko, E / de Braud, F / Larkin, J / Garbe, C / Jouary, T / Hauschild, A / Chiarion-Sileni, V / Lebbe, C / Mandalà, M / Millward, M / Arance, A / Bondarenko, I / Haanen, J B A G / Hansson, J / Utikal, J / Ferraresi, V / Mohr, P / Probachai, V / Schadendorf, D / Nathan, P / Robert, C / Ribas, A / Davies, M A / Lane, S R / Legos, J J / Mookerjee, B / Grob, J-J. ·Melanoma Institute Australia, The University of Sydney, and Royal North Shore and Mater Hospitals, North Sydney, Australia. · Developmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, Boston, USA. · Moscow City Oncology Hospital #62, Moscow, Russia. · First Department of Medicine, "Laiko" General Hospital, National and Kapodistrian University of Athens, Athens, Greece. · Petrov Research Institute of Oncology, Saint Petersburg, Russia. · Dipartimento di Medicina Oncologica, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · Royal Marsden NHS Foundation Trust, London, UK. · Department of Dermatology, University of Tübingen, Tübingen, Germany. · Service D'oncologie Médicale, Hopital Francois Mitterrand, Pau, France. · Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany. · Melanoma and Oesophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Padova, Italy. · APHP Dermatology and CIC Departments, INSERM U976, University Paris Diderot, Paris, France. · Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. · Medical Oncology Department, Sir Charles Gairdner Hospital, Perth, Australia. · Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain. · Dnipropetrovsk State Medical Academy, Clinical Hospital #4, Dnipropetrovsk, Ukraine. · Netherlands Cancer Institute, Amsterdam, The Netherlands. · Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. · Skin Cancer Unit, German Cancer Research Center (DKFZ) and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim and Heidelberg, Germany. · Department of Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy. · Dermatologisches Zentrum Buxtehude, Elbe Kliniken Buxtehude, Buxtehude, Germany. · Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council, Dnipropetrovsk, Ukraine. · Department of Dermatology, University Hospital Essen, Essen, Germany. · German Cancer Consortium, Heidelberg, Germany. · Mount Vernon Cancer Centre, Northwood, UK. · Gustave Roussy, Département de Médecine Oncologique, Service de Dermatologie et Université Paris-Sud, Faculté de Médecine, Villejuif, France. · Department of Medicine, Hematology/Oncology, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, USA. · Melanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Novartis Pharmaceuticals Corporation, East Hanover, USA. · Service de Dermatologie, Centre Hospitalo-Universitaire Timone, Aix-Marseille Université, Marseille, France. ·Ann Oncol · Pubmed #28475671.

ABSTRACT: Background: Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients. Patients and methods: This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics. Results: Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and <3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use. Conclusions: These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.

20 Clinical Trial Intermittent High-Dose Intravenous Interferon Alfa-2b for Adjuvant Treatment of Stage III Melanoma: Final Analysis of a Randomized Phase III Dermatologic Cooperative Oncology Group Trial. 2015

Mohr, Peter / Hauschild, Axel / Trefzer, Uwe / Enk, Alexander / Tilgen, Wolfgang / Loquai, Carmen / Gogas, Helen / Haalck, Thomas / Koller, Josef / Dummer, Reinhard / Gutzmer, Ralf / Brockmeyer, Norbert / Hölzle, Erhard / Sunderkötter, Cord / Mauch, Cornelia / Stein, Annette / Schneider, Lars A / Podda, Maurizio / Göppner, Daniela / Schadendorf, Dirk / Weichenthal, Michael. ·Peter Mohr, Elbe-Klinikum Buxtehude, Buxtehude · Axel Hauschild and Michael Weichenthal, University Hospital Schleswig-Holstein, Kiel · Uwe Trefzer, Charité-Universitätsmedizin Berlin, Berlin · Alexander Enk, University Hospital Heidelberg, Heidelberg · Wolfgang Tilgen, University Hospital, Homburg/Saarland · Carmen Loquai, University of Mainz, Mainz · Thomas Haalck, Universitätsklinikum Hamburg-Eppendorf, Hamburg · Ralf Gutzmer, Hannover Medical School, Hannover · Norbert Brockmeyer, Ruhr-Universität Bochum, Bochum · Erhard Hölzle, Oldenburg Hospital, Oldenburg · Cord Sunderkötter, University of Münster, Münster · Cornelia Mauch, University of Cologne, Cologne · Annette Stein, Universitätsklinikum Carl Gustav Carus, Dresden · Lars A. Schneider, University of Ulm, Ulm · Maurizio Podda, Darmstadt Hospital, Darmstadt · Daniela G[uml]oppner, University Hospital Magdeburg, Magdeburg · Dirk Schadendorf, University Hospital Essen, Essen, Germany · Helen Gogas, Hellenic Cooperative Oncology Group, Athens, Greece · Josef Koller, Paracelsus Medical University, Salzburg, Austria · and Reinhard Dummer, University Hospital of Zurich, Zurich, Switzerland. ·J Clin Oncol · Pubmed #26503196.

ABSTRACT: PURPOSE: To evaluate the efficacy, safety, tolerability, and quality of life (QoL) in patients receiving intravenous, intermittent high-dose interferon alfa-2b (IFN-α-2b [iHDI]) compared with standard high-dose IFN-α-2b (HDI). PATIENT AND METHODS: Patients with stage III resected lymph node or in-transit metastasis from cutaneous malignant melanoma were randomly assigned to receive either a standard HDI regimen or three courses of IFN-α-2b 20 MIU/m(2) administered intravenously 5 days a week for 4 weeks then repeated every 4 months. Distant metastasis-free survival was the primary end point for efficacy analysis. In addition, relapse-free survival, overall survival, safety as determined by Common Terminology Criteria for Adverse Events criteria, and QoL were secondary end points. RESULTS: Of 649 patients enrolled, 22 patients were excluded from the intent-to-treat analysis. The remaining 627 patients were well balanced between the arms according to sex, age, and stage. After a median follow-up of 55 months, a multivariable Cox model revealed no significant differences for distant metastasis-free survival (hazard ratio [HR], 1.21; P = .12) or overall survival (HR, 1.01; P = .85). In contrast, the difference for relapse-free survival was significant (HR, 1.27; P = .03), favoring standard HDI. Early termination of treatment because of adverse events or QoL occurred significantly more often with HDI than with iHDI (26.0% v 14.8%; P < .001). CONCLUSION: Although the safety and QoL profiles for the intermittent regimen were favorable, no significant difference was observed for survival while the HR for relapse with iHDI was increased. Therefore, an iHDI regimen, as tested here, cannot be recommended as adjuvant treatment for high-risk melanoma.

21 Clinical Trial Pro-Inflammatory Cytokines Predict Relapse-Free Survival after One Month of Interferon-α but Not Observation in Intermediate Risk Melanoma Patients. 2015

Tarhini, Ahmad A / Lin, Yan / Zahoor, Haris / Shuai, Yongli / Butterfield, Lisa H / Ringquist, Steven / Gogas, Helen / Sander, Cindy / Lee, Sandra / Agarwala, Sanjiv S / Kirwood, John M. ·University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. · University of Pittsburgh Cancer Institute Biostatistics Facility, Pittsburgh, Pennsylvania, United States of America. · Hellenic Cooperative Oncology Group, Athens, Greece. · Dana Farber Cancer Institute, Boston, Massachusetts, United States of America. · St. Luke's Cancer Center, Bethlehem, Pennsylvania, United States of America; Temple University, Philadelphia, Pennsylvania, United States of America. ·PLoS One · Pubmed #26192408.

ABSTRACT: BACKGROUND: E1697 was a phase III trial of adjuvant interferon (IFN)-α2b for one month (Arm B) versus observation (Arm A) in patients with resected melanoma at intermediate risk. We evaluated the levels of candidate serum cytokines, the HLA genotype, polymorphisms of CTLA4 and FOXP3 genes and the development of autoantibodies for their association with relapse free survival (RFS) in Arm A and Arm B among 268 patients with banked biospecimens. METHODS: ELISA was used to test 5 autoantibodies. Luminex/One Lambda LABTypeRSSO was used for HLA Genotyping. Selected CTLA4 and FOXP3 Single nucleotide polymorphisms (SNPs) and microsatellites were tested for by polymerase chain reaction (PCR). Sixteen serum cytokines were tested at baseline and one month by Luminex xMAP multiplex technology. Cox Proportional Hazards model was applied and the Wald test was used to test the marginal association of each individual marker and RFS. We used the Lasso approach to select the markers to be included in a multi-marker Cox Proportional Hazards model. The ability of the resulting models to predict one year RFS was evaluated by the time-dependent ROC curve. The leave-one-out method of cross validation (LOOCV) was used to avoid over-fitting of the data. RESULTS: In the multi-marker modeling analysis conducted in Arm B, one month serum IL2Rα, IL-12p40 and IFNα levels predicted one year RFS with LOOCV AUC = 82%. Among the three markers selected, IL2Rα and IFNα were the most stable (selected in all the cross validation cycles). The risk score (linear combination of the 3 markers) separated the RFS curves of low and high risk groups well (p = 0.05). This model did not hold for Arm A, indicating a differential marker profile in Arm B linked to the intervention (adjuvant therapy). CONCLUSIONS: Early on-treatment proinflammatory serum markers (IL2Rα, IL-12p40, IFNα) significantly predict RFS in our cohort of patients treated with adjuvant IFN-α2b and warrant further study.

22 Clinical Trial Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. 2015

Long, Georgina V / Stroyakovskiy, Daniil / Gogas, Helen / Levchenko, Evgeny / de Braud, Filippo / Larkin, James / Garbe, Claus / Jouary, Thomas / Hauschild, Axel / Grob, Jean-Jacques / Chiarion-Sileni, Vanna / Lebbe, Celeste / Mandalà, Mario / Millward, Michael / Arance, Ana / Bondarenko, Igor / Haanen, John B A G / Hansson, Johan / Utikal, Jochen / Ferraresi, Virginia / Kovalenko, Nadezhda / Mohr, Peter / Probachai, Volodymr / Schadendorf, Dirk / Nathan, Paul / Robert, Caroline / Ribas, Antoni / DeMarini, Douglas J / Irani, Jhangir G / Swann, Suzanne / Legos, Jeffrey J / Jin, Fan / Mookerjee, Bijoyesh / Flaherty, Keith. ·Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Mater Hospital, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au. · Moscow City Oncology Hospital, Moscow, Russia. · Department of Medicine, University of Athens, Medical School, Athens, Greece. · Petrov Research Institute of Oncology, Saint Petersburg, Russia. · Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. · Royal Marsden Hospital, London, UK. · Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany. · Department of Dermatology, Hôpital Saint André, CHU Bordeaux, Bordeaux, France. · University Hospital Schleswig-Holstein, Kiel, Germany. · Aix-Marseille University and APHM Hospital CHU Timone, Marseille, France. · Melanoma and Oesophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Padua, Italy. · APHP Dermatology CIC Hôpital Saint Louis, University Paris Diderot, INSERM U976, Paris, France. · Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy. · Sir Charles Gairdner Hospital, Hospital Avenue, Perth, WA, Australia. · Department of Medical Oncology, Hospital Clinic and Translational Genomics and Targeted Therapeutics in Solid Tumors, Barcelona, Spain. · Dnepropetrovsk State Medical Academy, Dnepropetrovsk, Ukraine. · Netherlands Cancer Institute, Amsterdam, Netherlands. · Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden. · University Medical Center Mannheim, Heidelberg University, Mannheim, Germany; German Cancer Research Center, Heidelberg, Germany. · Istituto Nazionale Tumori Regina Elena, Rome, Italy. · Volograd Regional Oncology Dispensary #3, Volzhsky, Russia. · Elbe Klinikum Stade, Stade, Germany. · Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council, Dnipropetrovsk, Ukraine. · University Hospital Essen, Essen, Germany. · Mount Vernon Cancer Centre, Northwood, UK. · Gustave Roussy, Villejuif-Paris-Sud, France; Paris Sud University, Le Kremlin Bicêtre, France. · David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. · Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. · Merck & Co, Kenilworth, NJ, USA. · Massachusetts General Hospital Cancer Center, Boston MA, USA. ·Lancet · Pubmed #26037941.

ABSTRACT: BACKGROUND: Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article. METHODS: We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648. FINDINGS: Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2-not reached) in the dabrafenib and trametinib group versus 18·7 months (15·2-23·7) in the dabrafenib only group (hazard ratio [HR] 0·71, 95% CI 0·55-0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0-13·9) in the dabrafenib and trametinib group and 8·8 months (5·9-9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53-0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group. INTERPRETATION: The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing. FUNDING: GlaxoSmithKline.

23 Clinical Trial Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma. 2015

Schadendorf, Dirk / Amonkar, Mayur M / Stroyakovskiy, Daniil / Levchenko, Evgeny / Gogas, Helen / de Braud, Filippo / Grob, Jean-Jacques / Bondarenko, Igor / Garbe, Claus / Lebbe, Celeste / Larkin, James / Chiarion-Sileni, Vanna / Millward, Michael / Arance, Ana / Mandalà, Mario / Flaherty, Keith T / Nathan, Paul / Ribas, Antoni / Robert, Caroline / Casey, Michelle / DeMarini, Douglas J / Irani, Jhangir G / Aktan, Gursel / Long, Georgina V. ·Universitätsklinikum Essen, Hufelandstr. 55, Essen 45147, Germany. Electronic address: Dirk.Schadendorf@uk-essen.de. · GlaxoSmithKline, 1250 S Collegeville Rd, Collegeville, PA 19426, United States. Electronic address: mayur.m.amonkar@gsk.com. · Moscow City Oncology Hospital #62, Moscow 143423, Russia. Electronic address: sdaniel@mail.ru. · Petrov Research Institute of Oncology, 68 Leningradskaya Street, Saint Petersburg 197758, Russia. Electronic address: levchenko@newmail.ru. · University of Athens, Aghiou Thoma 17, Athens 11527, Greece. Electronic address: hgogas@hol.gr. · Fondazione IRCCS Istituto Nazionale Tumori, via Giacomo Venezian, 1, Milan, Italy. Electronic address: filippo.debraud@istitutotumori.mi.it. · Service de Dermatologie, Centre Hospitalo-Universitaire Sainte-Marguerite, 270 Boulevard de Sainte-Marguerite, Marseille 13009, France. Electronic address: jean-jacques.grob@ap-hm.fr. · Dnepropetrovsk State Medical Academy, Dzerzhyns'koho Street 9, Dnepropetrovsk 49044, Ukraine. Electronic address: oncology@dsma.dp.ua. · Department of Dermatology, University Hospital Tuebingen, Liebermeisterstraße 25, Tuebingen 72076, Germany. Electronic address: claus.garbe@med.uni-tuebingen.de. · APHP Dermatology CIC Hôpital Saint Louis, University Paris Diderot, INSERM U976, Avenue Claude Vellefaux, Paris 75010, France. Electronic address: celeste.lebbe@sls.aphp.fr. · Royal Marsden Hospital, Fulham Road, London SW3 6JJ, United Kingdom. Electronic address: james.larkin@rmh.nhs.uk. · Melanoma and Esophageal Oncology Unit, Veneto Oncology Institute-IRCCS, via Gattamelata, 64, Padua 35128, Italy. Electronic address: mgaliz@tiscali.it. · Sir Charles Gairdner Hospital, Hospital Avenue, Perth, WA 6009, Australia. Electronic address: michael.millward@uwa.edu.au. · Hospital Clinic, Carrer Villarroel 170, Barcelona 08036, Spain. Electronic address: amarance@clinic.ub.es. · Papa Giovanni XIII Hospital, Piazza OMS 1, Bergamo 24127, Italy. Electronic address: mmandala@hpg23.it. · Massachusetts General Hospital Cancer Center, 55 Fruit St, Boston 02114, MA, United States. Electronic address: kflaherty@partners.org. · Mount Vernon Cancer Centre, Rickmansworth Road, Northwood HA6 2RN, United Kingdom. Electronic address: p.nathan@nhs.net. · David Geffen School of Medicine, UCLA, 10833 Le Conte Avenue, Los Angeles 90095, CA, United States. Electronic address: aribas@mednet.ucla.edu. · Gustave Roussy and Paris 11 University, 114 Rue Edouard Vaillant, Villejuif-Paris-Sud 94805, France. Electronic address: Caroline.Robert@igr.fr. · GlaxoSmithKline, 1250 S Collegeville Rd, Collegeville, PA 19426, United States. Electronic address: meshellcasey@yahoo.com. · GlaxoSmithKline, 1250 S Collegeville Rd, Collegeville, PA 19426, United States. Electronic address: douglas.j.demarini@gsk.com. · GlaxoSmithKline, 1250 S Collegeville Rd, Collegeville, PA 19426, United States. Electronic address: jhangir.g.irani@gsk.com. · GlaxoSmithKline, 1250 S Collegeville Rd, Collegeville, PA 19426, United States. Electronic address: gursel.aktan@gmail.com. · Melanoma Institute Australia & The University of Sydney, 40 Rocklands Road, Sydney 2060, Australia. Electronic address: georgina.long@sydney.edu.au. ·Eur J Cancer · Pubmed #25794603.

ABSTRACT: AIM: To present the impact of treatments on health-related quality of life (HRQoL) from the double-blind, randomised phase III COMBI-d study that investigated the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600E/K-mutant metastatic melanoma. COMBI-d showed significantly prolonged progression-free survival for the combination. METHODS: HRQoL was evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30, a generic cancer questionnaire (completed at baseline, during study treatment, at progression and post progression) assessing various dimensions (global health/QoL, functional status, and symptom impact). A mixed-model, repeated-measures analyses of covariance evaluated differences between arms. RESULTS: Questionnaire completion rates were >95% at baseline, >85% to week 40 and >70% at disease progression. Baseline scores across both arms were comparable for all dimensions. Global health dimension scores were significantly better at weeks 8, 16 and 24 for patients receiving the combination during treatment and at progression. The majority of functional dimension scores (physical, social, role, emotional and cognitive functioning) trended in favour of the combination. Pain scores were significantly improved and clinically meaningful (6-13 point difference) for patients receiving the combination for all follow-up assessments versus those receiving dabrafenib monotherapy. For other symptom dimensions (nausea and vomiting, diarrhoea, dyspnoea, and constipation), scores trended in favour of dabrafenib monotherapy. CONCLUSION: This analysis demonstrates that the combination of dabrafenib and trametinib provides better preservation of HRQoL and pain improvements versus dabrafenib monotherapy while also delaying progression. (Clinicaltrials.gov registration number: NCT01584648).

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 Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. 2014

Long, Georgina V / Stroyakovskiy, Daniil / Gogas, Helen / Levchenko, Evgeny / de Braud, Filippo / Larkin, James / Garbe, Claus / Jouary, Thomas / Hauschild, Axel / Grob, Jean Jacques / Chiarion Sileni, Vanna / Lebbe, Celeste / Mandalà, Mario / Millward, Michael / Arance, Ana / Bondarenko, Igor / Haanen, John B A G / Hansson, Johan / Utikal, Jochen / Ferraresi, Virginia / Kovalenko, Nadezhda / Mohr, Peter / Probachai, Volodymyr / Schadendorf, Dirk / Nathan, Paul / Robert, Caroline / Ribas, Antoni / DeMarini, Douglas J / Irani, Jhangir G / Casey, Michelle / Ouellet, Daniele / Martin, Anne-Marie / Le, Ngocdiep / Patel, Kiran / Flaherty, Keith. ·The authors' affiliations are listed in the Appendix. ·N Engl J Med · Pubmed #25265492.

ABSTRACT: BACKGROUND: Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations. METHODS: In this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) or dabrafenib and placebo. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, response duration, and safety. A preplanned interim overall survival analysis was conducted. RESULTS: The median progression-free survival was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib-trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P=0.03). The overall response rate was 67% in the dabrafenib-trametinib group and 51% in the dabrafenib-only group (P=0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P=0.02). However, a specified efficacy-stopping boundary (two-sided P=0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib-trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib-trametinib group. CONCLUSIONS: A combination of dabrafenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations. (Funded by GlaxoSmithKline; Clinical Trials.gov number, NCT01584648.).

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