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Clinical trials

Peer-reviewed articles on Melanoma related clinical trials

  • Nivolumab in Previously Untreated Melanoma without BRAF Mutation

    Caroline Robert, M.D., Ph.D., Georgina V. Long, M.D., Ph.D., Benjamin Brady, M.D., Et al

    N Engl J Med 2014, E-pub November 16, 2014,

    Editor's comments: Prof Paolo A. Ascierto
    Nivolumab is a fully human IgG4 anti PD-1 antibody that selectively blocks the interaction of the PD-1 receptor with its two ligands, PD-L1 and PD-L2, disrupting the negative signal which regulates T-cell activation and proliferation. In a phase I study nivolumab was associated with promising antitumor activity in patients with solid tumors, including advanced melanoma. In this manuscript were reported data of a randomized phase 3 double-blind study where nivolumab was compared to dacarbazine to verify whether it’s able to improve overall survival of previously untreated patients with advanced melanoma BRAF wild type. The study was largely positive showing a significant improvement of ORR (40 % vs 13.9%), PFS (5.1 vs 22 months) and 1-year OS (72.95 vs 42.1%) for the group of patients treated with nivolumab respect to those treated with dacarbazine. In addition to an high response rate, it was also found a long duration of responses (median DOR in the patients treated with nivolumab was not found yet), and a rapid time to response (2.1 months) with a good toxicity profile. Nivolumab treated patients had improved ORR as compared with dacarbazine treated patients both in PD-L1 positive and PD-L1 negative groups. In the subgroup with PD-L1 positive, the ORR was 52.7% in the nivolumab group versus 10.8% in the dacarbazine group. In the subgroup with PD-L1 negative, the ORR was 33.1% in the nivolumab group versus 15.7% in the dacarbazine group. The 1-year OS rate for the nivolumab PD-L1 positive, nivolumab PD-L1 negative, dacarbazine PD-L1 positive, and dacarbazine PD-L1 negative was of 82.1%, 67.8, 52.7, and 37.4 respectively. These data evidenced that PD-L1 positive status is related with a better survival but also PD-L1 negative patients had an higher OS respect to the control arm.

    When this study was planning ipilimumab wasn't still approved as first-line of treatment. Currently is ongoing a three-arms phase III study which is evaluating the combination of ipilimumab and nivolumab with nivolumab and ipilimumab monotherapy in previously untreated advanced melanoma patients.

  • Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib

    Caroline Robert, M.D., Ph.D., Boguslawa Karaszewska, M.D., Jacob Schachter, M.D., Et al.

    N Engl J Med 2015; 372:30-39 January 1, 2015

    Editor's comments: Prof Paolo A. Ascierto
    The advent of BRAF inhibitors for the treatment of metastatic melanoma harboring the BRAF V600 mutation has allowed to achieve significant results in terms of PFS and OS compared to standard chemotherapy. Unfortunately, the principal limitation of these treatments is the occurrence of acquired resistance due to the reactivation of the MAPK pathway. In addition, it is known that the use of BRAF inhibitors may result in the development of secondary skin tumors, due to a paradoxical activation of the MAPK pathway in cells with without a BRAF mutation but with NRAS mutated. The combination of a BRAF inhibitor with a MEK inhibitor could reduce both of these limitations of BRAF inhibitors monotherapy. The study presented in this manuscript is an open-label, randomized, phase 3 study enrolling 704 patients with unresectable stage IIIC or IV melanoma with BRAF V600E or V600K mutations, designed to evaluate the effect on overall survival of the combination therapy with dabrafenib plus trametinib versus vemurafenib monotherapy. The median overall survival was 17.2 months in the vemurafenib group while was not reached in the combination-therapy group; the risk reduction for progression or death was of 31%. A significant improvements were found also in terms of ORR and PFS. Skin adverse events were less frequent in the combination-therapy group: cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% in the vemurafenib group. This finding confirms that the addition of MEK inhibitors may delay the treatment resistance and reduce the occurrence of skin cancers.

  • Bevacizumab plus Ipilimumab in Patients with Metastatic Melanoma

    Hodi FS, Lawrence D, Lezcano C, Wu X, Zhou J, Sasada T, Zeng W, Giobbie-Hurder A, Atkins MB, Ibrahim N, Friedlander P, Flaherty KT, Murphy GF, Rodig S, Velazquez EF, Mihm MC Jr, Russell S, DiPiro PJ, Yap JT, Ramaiya N, Van den Abbeele AD, Gargano M, McDer

    Cancer Immunol Res. 2014 Apr 21. [Epub ahead of print]

    Editors' comments:
    This is a study evaluating the combination of ipilimumab with bevacizumab in the treatment of metastatic melanoma. It shows that bevacizumab, blocking VEGF-A, is able to modify the immune responses triggered by the administration of ipilimumab, influencing the inflammation, the traffic of lymphocytes and immune regulation, with an acceptable toxicity profile. This study provides the basis for further research on the influences of antiangiogenic drugs in the immune response and the possibility of new associations with immune checkpoint blockade.

  • Final trial report of sentinel-node biopsy versus nodal observation in melanoma.

    Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Nieweg OE, Roses DF, Hoekstra HJ, Karakousis CP, Puleo CA, Coventry BJ, Kashani-Sabet M, Smithers BM, Paul E, Kraybill WG, McKinnon JG, Wang HJ, Elashoff R, Faries MB; MSLT Group.

    N Engl J Med. 2014 Feb 13;370(7):599-609
  • Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic melanoma: a phase 2 double-blind randomised study

    Dr Caroline Robert MD, Prof Reinhard Dummer MD, Prof Ralf Gutzmer MD, Paul Lorigan MB, Kevin B Kim MD, Marta Nyakas MD, Ana Arance MD, Prof Gabriella Liszkay MD, Prof Dirk Schadendorf MD, Mireille Cantarini MBChB, Stuart Spencer MSc, Prof Mark R Middleton

    The Lancet Oncology
  • Intracerebral metastases of malignant melanoma and their recurrences—A clinical analysis

    Dorothea Miller, Valeria Zappala, Nicolai El Hindy, Elisabeth Livingstone, Dirk Schadendorf, Ulrich Sure, Ibrahim Erol Sandalcioglu

    Clinical Neurology and Neurosurgery, 9, 115, pages 1721 - 1728

  • Overcoming Intrinsic Multidrug Resistance in Melanoma by Blocking the Mitochondrial Respiratory Chain of Slow-Cycling JARID1Bhigh Cells

    Alexander Roesch, Adina Vultur, Ivan Bogeski, Huan Wang, Katharina M. Zimmermann, David Speicher, Christina Körbel, Matthias W. Laschke, Phyllis A. Gimotty, Stephan E. Philipp, Elmar Krause, Sylvie Pätzold, Jessie Villanueva, Clemens Krepler, Mizuho Fukunaga-Kalabis, Markus Hoth, Boris C. Bastian, Thomas Vogt, Meenhard Herlyn

    Cancer Cell, 6, 23, pages 811 - 825

  • Final results of the EORTC 18871/DKG 80-1 randomised phase III trial: rIFN-α2b versus rIFN-γ versus ISCADOR M® versus observation after surgery in melanoma patients with either high-risk primary (thickness >3 mm) or regional lymph node metastasis

    U.R. Kleeberg, S. Suciu, E.B. Bröcker, D.J. Ruiter, C. Chartier, D. Liénard, J. Marsden, D. Schadendorf, A.M.M. Eggermont, for the EORTC Melanoma Group in cooperation with the German Cancer Society (DKG) 1 2 .

    European Journal of Cancer, 3, 40, pages 390 - 402

  • Low level of education is associated with later stage at diagnosis and reduced survival in cutaneous malignant melanoma: A nationwide population-based study in Sweden

    H. Eriksson, J. Lyth, E. Månsson-Brahme, M. Frohm-Nilsson, C. Ingvar, C. Lindholm, P. Naredi, U. Stierner, G. Wagenius, J. Carstensen, J. Hansson

    European Journal of Cancer, Volume 49, Issue 12 , Pages 2705-2716, August 2013
  • MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study

    Paolo A Ascierto, Dirk Schadendorf, Carola Berking, Sanjiv S Agarwala, Carla M L van Herpen, Paola Queirolo, Christian U Blank, Axel Hauschild, J Thaddeus Beck, Annie St-Pierre, Faiz Niazi, Simon Wandel, Malte Peters, Angela Zubel, Reinhard Dummer

    The Lancet Oncology, 2013; 14: 249–56






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