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Melanoma: HELP
Articles by John B. A. G. Haanen
Based on 65 articles published since 2008
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Between 2008 and 2019, J. Haanen wrote the following 65 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Review Advanced Melanoma: Current Treatment Options, Biomarkers, and Future Perspectives. 2018

Rozeman, Elisa A / Dekker, Tim J A / Haanen, John B A G / Blank, Christian U. ·Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. · Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. c.blank@nki.nl. ·Am J Clin Dermatol · Pubmed #29164492.

ABSTRACT: Malignant melanoma accounts for the highest number of deaths from skin cancer, and the prognosis of patients with stage IV disease has historically been poor. Novel insights into both mutations driving tumorigenesis and immune escape mechanisms of these tumors have led to effective treatment options that have revolutionized the treatment of this disease. Targeting the MAPK kinase pathway (with BRAF and MEK inhibitors), as well as targeting checkpoints, such as cytotoxic T-lymphocyte associated protein 4 (CTLA-4) or programmed death 1 (PD-1), have improved overall survival in patients with late-stage melanoma, and biomarker research for personalized therapy is ongoing for each of these treatment modalities. In this review, we will discuss current first-line treatment options, discuss biomarkers supporting treatment decisions, and give an outlook on (combination) therapies we expect to become relevant in the near future.

2 Review (Neo)adjuvant systemic therapy for melanoma. 2017

van Zeijl, M C T / van den Eertwegh, A J / Haanen, J B / Wouters, M W J M. ·Dutch Institute for Clinical Auditing, Rijnsburgerweg 10, 2333AA Leiden, The Netherlands; Department of Surgery, Leiden University Medical Centre, Albinusdreef 2, 2333ZA Leiden, The Netherlands. Electronic address: m.vanzeijl@dica.nl. · Department of Medical Oncology, VU University Medical Center, De Boelelaan 1118, 1081HZ Amsterdam, The Netherlands. · Department of Medical Oncology and Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. · Dutch Institute for Clinical Auditing, Rijnsburgerweg 10, 2333AA Leiden, The Netherlands; Department of Surgical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. ·Eur J Surg Oncol · Pubmed #27453302.

ABSTRACT: Surgery still is the cornerstone of treatment for patients with stage II and III melanoma, but despite great efforts to gain or preserve locoregional control with excision of the primary tumour, satellites, intransits, sentinel node biopsy and lymphadenectomy, surgery alone does not seem to improve survival any further. Prognosis for patients with high risk melanoma remains poor with 5-year survival rates of 40 to 80%. Only interferon-2b has been approved as adjuvant therapy since 1995, but clinical integration is low considering the high risk-benefit ratio. In recent years systemic targeted- and immunotherapy have proven to be beneficial in advanced melanoma and could be a promising strategy for (neo)adjuvant treatment of patients with resectable high risk melanomas as well. Randomised, placebo- controlled phase III trials on adjuvant systemic targeted- and immunotherapy are currently being performed using new agents like ipilimumab, pembrolizumab, nivolumab, vemurafenib and dabrafenib plus trametinib. In this article we review the literature on currently known adjuvant therapies and currently ongoing trials of (neo)adjuvant therapies in high risk melanomas.

3 Review [Issues around melanoma]. 2011

Haanen, John. ·Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis, Divisie Immunologie, Amsterdam, the Netherlands. j.haanen@nki.nl ·Ned Tijdschr Geneeskd · Pubmed #22085568.

ABSTRACT: Over the past 30 years little progress has been made in the treatment of patients with a metastatic melanoma. Recently there have been two new developments. One of these is ipilimumab, a monoclonal antibody that blocks the function of the protein cytotoxic T lymphocyte-associated antigen 4 (CTLA4) which inhibits activated T lymphocytes. This gives the immune system a chance to build up an immune response to the melanoma. The other development is vemurafenib, a small molecule that inhibits a mutated protein (BRAF) that occurs in many melanomas. The BRAF mutation leads to uninhibited proliferation.

4 Review Combination of targeted therapy and immunotherapy in melanoma. 2011

Blank, Christian U / Hooijkaas, Anna I / Haanen, John B / Schumacher, Ton N. ·Division of Immunology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Ziekenhuis, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. c.blank@nki.nl ·Cancer Immunol Immunother · Pubmed #21847631.

ABSTRACT: The treatment of human melanoma has progressed markedly in recent years. Building on the observation that immune recognition is a frequent event in melanoma, a series of immunotherapeutic approaches have been evaluated in clinical trials, culminating in the first phase III study improving overall survival of melanoma patients since 20 years. However, the response rates seen upon immunotherapeutic interventions such as anti-CTLA4 treatment are often low. Furthermore, clinical responses can take several weeks to develop, during which time stage IV melanoma patients often deteriorate. Recent advances in our understanding of the genetic lesions in human melanoma now also allow the specific targeting of the signaling pathway alterations in this disease. Such targeted therapies can lead to high response rates, although the duration of these responses is thus far relatively short. We suggest that the combination of immuno and targeted therapy offers potential for synergy for both conceptual and practical reasons. In this review, we will discuss the potential and possible limitations for such combination therapy, and we describe the most promising combinations of targeted therapy and immunotherapy that can be tested in the clinic in the coming years. The concept of induction therapy by small molecule administration and consolidation by immunotherapeutics also has potential for the treatment of other human cancers.

5 Review Immunotherapeutic strategies: the melanoma example. 2009

Jorritsma, Annelies / Schumacher, Ton N M / Haanen, John B A G. ·Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. a.jorritsma@nki.nl ·Immunotherapy · Pubmed #20635992.

ABSTRACT: T-cell-based immunotherapy can be induced by nonspecific activation, by antigen-specific immunization, or by adoptive immunotherapy. In this review, progress in these areas is discussed as based on data from clinical trials for the treatment of metastatic melanoma. Nonspecific immunotherapy has been shown to result in low, but in some cases significant, levels of objective tumor responses, and is often associated with autoimmune reactions. Antigen-specific targeting of tumors via vaccination has only resulted in low to very low levels of objective responses, and these strategies seem to have most value when the T-cell repertoire is not affected by tolerance. Finally, adoptive immunotherapy can be applied by in vitro expansion of autologous lymphocytes that have escaped tolerance or by genetic transfer of allogeneic T-cell receptors (TCRs). Autologous adoptive T-cell transfer has resulted in a very high frequency of clinical responses when combined with chemotherapy and IL-2 administration in single-center studies. Although TCR gene transfer has, until now, only resulted in a low frequency of clinical responses, it does have a broader application potential, and optimization of this strategy is likely to improve its efficacy.

6 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 .).

7 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.

8 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.

9 Clinical Trial Serous Retinopathy Associated with Mitogen-Activated Protein Kinase Kinase Inhibition (Binimetinib) for Metastatic Cutaneous and Uveal Melanoma. 2015

van Dijk, Elon H C / van Herpen, Carla M L / Marinkovic, Marina / Haanen, John B A G / Amundson, Drake / Luyten, Gré P M / Jager, Martine J / Kapiteijn, Ellen H W / Keunen, Jan E E / Adamus, Grazyna / Boon, Camiel J F. ·Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands. · Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands; Department of Ophthalmology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands. · Division of Medical Oncology, The Netherlands Cancer Institute Antoni van Leeuwenhoek, Amsterdam, The Netherlands. · Department of Ophthalmology, Oregon Health and Science University, Portland, Oregon. · Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands. · Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: c.j.f.boon@lumc.nl. ·Ophthalmology · Pubmed #26123090.

ABSTRACT: PURPOSE: To analyze the clinical characteristics of a serous retinopathy associated with mitogen-activated protein kinase kinase (MEK) inhibition with binimetinib treatment for metastatic cutaneous melanoma (CM) and uveal melanoma (UM), and to determine possible pathogenetic mechanisms that may lead to this retinopathy. DESIGN: Prospective observational, cohort-based, cross-sectional study. PARTICIPANTS: Thirty CM patients and 5 UM patients treated with the MEK inhibitor binimetinib (CM) or a combination of binimetinib and the protein kinase C inhibitor sotrastaurin (UM). METHODS: Extensive ophthalmic examination was performed, including Early Treatment of Diabetic Retinopathy Study best-corrected visual acuity, applanation tonometry, slit-lamp examination, indirect ophthalmoscopy, digital color fundus photography, and optical coherence tomography (OCT). In selected cases, additional examinations were performed, including visual field testing and electro-oculography (EOG). Blood samples were obtained from 3 CM patients and 3 UM patients to analyze the presence of autoantibodies against retinal and retinal pigment epithelium (RPE) proteins. MAIN OUTCOME MEASURES: Visual symptoms, visual acuity, fundus appearance, characteristics on OCT, fundus autofluorescence (FAF), and EOG. RESULTS: Six CM patients (20%) and 2 UM patients (40%) reported visual symptoms during the study. The median time to the onset of symptoms, which were all mild and transient, was 3.5 days (range, <1 hour to 3 weeks). On OCT, subretinal fluid (SRF) was detected in 77% of CM patients and 60% of UM patients. In the 26 patients with SRF, the fovea was affected in 85%. After the start of the medication, an EOG was performed in 19 eyes of 11 patients; 16 of these eyes (84%) developed SRF on OCT. Fifteen of these eyes (94%) showed an abnormal Arden ratio (<1.65). A broad pattern of anti-retinal antibodies was found in 3 CM patients and 2 UM patients tested, whereas anti-RPE antibodies were detected in all 6 tested patients. CONCLUSIONS: A time-dependent and reversible serous retinopathy can develop both in patients with metastatic CM and UM treated with binimetinib. A minority of patients develop visual symptoms, which are generally mild and transient. A cause of binimetinib-associated serous retinopathy may be toxicity of medication, but autoantibodies also may be involved.

10 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.

11 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.).

12 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.).

13 Clinical Trial Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. 2014

Kelderman, Sander / Heemskerk, Bianca / van Tinteren, Harm / van den Brom, Rob R H / Hospers, Geke A P / van den Eertwegh, Alfonsus J M / Kapiteijn, Ellen W / de Groot, Jan Willem B / Soetekouw, Patricia / Jansen, Rob L / Fiets, Edward / Furness, Andrew J S / Renn, Alexandra / Krzystanek, Marcin / Szallasi, Zoltan / Lorigan, Paul / Gore, Martin E / Schumacher, Ton N M / Haanen, John B A G / Larkin, James M G / Blank, Christian U. ·Netherlands Cancer Institute NKI-AVL, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands, s.kelderman@nki.nl. ·Cancer Immunol Immunother · Pubmed #24609989.

ABSTRACT: INTRODUCTION: Ipilimumab, a cytotoxic T lymphocyte-associated antigen-4 blocking antibody, has improved overall survival (OS) in metastatic melanoma in phase III trials. However, about 80 % of patients fail to respond, and no predictive markers for benefit from therapy have been identified. We analysed a 'real world' population of patients treated with ipilimumab to identify markers for treatment benefit. METHODS: Patients with advanced cutaneous melanoma were treated in the Netherlands (NL) and the United Kingdom (UK) with ipilimumab at 3 mg/kg. Baseline characteristics and peripheral blood parameters were assessed, and patients were monitored for the occurrence of adverse events and outcomes. RESULTS: A total of 166 patients were treated in the Netherlands. Best overall response and disease control rates were 17 and 35 %, respectively. Median follow-up was 17.9 months, with a median progression-free survival of 2.9 months. Median OS was 7.5 months, and OS at 1 year was 37.8 % and at 2 years was 22.9 %. In a multivariate model, baseline serum lactate dehydrogenase (LDH) was demonstrated to be the strongest predictive factor for OS. These findings were validated in an independent cohort of 64 patients from the UK. CONCLUSION: In both the NL and UK cohorts, long-term benefit of ipilimumab treatment was unlikely for patients with baseline serum LDH greater than twice the upper limit of normal. In the absence of prospective data, clinicians treating melanoma may wish to consider the data presented here to guide patient selection for ipilimumab therapy.

14 Clinical Trial Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. 2014

McArthur, Grant A / Chapman, Paul B / Robert, Caroline / Larkin, James / Haanen, John B / Dummer, Reinhard / Ribas, Antoni / Hogg, David / Hamid, Omid / Ascierto, Paolo A / Garbe, Claus / Testori, Alessandro / Maio, Michele / Lorigan, Paul / Lebbé, Celeste / Jouary, Thomas / Schadendorf, Dirk / O'Day, Stephen J / Kirkwood, John M / Eggermont, Alexander M / Dréno, Brigitte / Sosman, Jeffrey A / Flaherty, Keith T / Yin, Ming / Caro, Ivor / Cheng, Suzanne / Trunzer, Kerstin / Hauschild, Axel. ·Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia. Electronic address: grant.mcarthur@petermac.org. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Institut Gustave Roussy, Paris, France. · Royal Marsden Hospital, London, UK. · The Netherlands Cancer Institute, Amsterdam, Netherlands. · University of Zurich, Zurich, Switzerland. · Jonsson Comprehensive Cancer Center at University of California, Los Angeles, CA, USA. · Princess Margaret Hospital and University Health Network, Toronto, ON, Canada. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. · The University of Tübingen, Tübingen, Germany. · Istituto Europeo di Oncologia, Milan, Italy. · University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. · University of Manchester, Manchester, UK. · APHP Oncodermatology, Hôpital Saint Louis University, Paris, France. · Saint André Hospital, Bordeaux, France. · University Hospital Essen, Essen, Germany. · Beverly Hills Cancer Center, Beverly Hills, CA, USA. · University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. · Gustave-Roussy Cancer Center and University Paris-Sud, Villejuif/Paris Sud, France. · Nantes University Hospital, Nantes, France. · Vanderbilt University School of Medicine, Nashville, TN, USA. · Massachusetts General Hospital, Boston, MA, USA. · Genentech Inc, San Francisco, CA, USA. · Roche Molecular Systems Inc, Pleasanton, CA, USA. · F Hoffmann-La Roche, Basel, Switzerland. · University of Kiel, Kiel, Germany. ·Lancet Oncol · Pubmed #24508103.

ABSTRACT: BACKGROUND: In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAF(V600) mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAF(V600E) and BRAF(V600K) mutation subgroups. METHODS: Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAF(V600) mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m(2) of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980. FINDINGS: 675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5 months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI 0·57-0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI 0·32-0·46]; p<0·0001). For the 598 (91%) patients with BRAF(V600E) disease, median overall survival in the vemurafenib group was 13·3 months (95% CI 11·9-14·9) compared with 10·0 months (8·0-14·0) in the dacarbazine group (HR 0·75 [95% CI 0·60-0·93]; p=0·0085); median progression-free survival was 6·9 months (95% CI 6·2-7·0) and 1·6 months (1·6-2·1), respectively (HR 0·39 [95% CI 0·33-0·47]; p<0·0001). For the 57 (9%) patients with BRAF(V600K) disease, median overall survival in the vemurafenib group was 14·5 months (95% CI 11·2-not estimable) compared with 7·6 months (6·1-16·6) in the dacarbazine group (HR 0·43 [95% CI 0·21-0·90]; p=0·024); median progression-free survival was 5·9 months (95% CI 4·4-9·0) and 1·7 months (1·4-2·9), respectively (HR 0·30 [95% CI 0·16-0·56]; p<0·0001). The most frequent grade 3-4 events were cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of 287 patients) in the dacarbazine group. Eight (2%) patients in the vemurafenib group and seven (2%) in the dacarbazine group had grade 5 events. INTERPRETATION: Inhibition of BRAF with vemurafenib improves survival in patients with the most common BRAF(V600E) mutation and in patients with the less common BRAF(V600K) mutation. FUNDING: F Hoffmann-La Roche-Genentech.

15 Clinical Trial Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). 2013

McDermott, D / Haanen, J / Chen, T-T / Lorigan, P / O'Day, S / Anonymous5350766. ·Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, USA. ·Ann Oncol · Pubmed #23942774.

ABSTRACT: BACKGROUND: In a phase III trial (ClinicalTrials.gov registration ID: NCT00094653), ipilimumab significantly improved survival versus a vaccine control in pretreated patients with metastatic melanoma. Here, we characterize outcomes of those patients who survived ≥ 2 years. METHODS: Patients were randomized (3 : 1 : 1) to receive ipilimumab 3 mg/kg + gp100 vaccine, ipilimumab 3 mg/kg + placebo, or gp100 vaccine alone. Baseline demographic data, duration of survival, responses, and safety among patients with ≥ 2 years' survival were analyzed. RESULTS: Among 676 randomized patients, 474 and 259 patients had at least 2 or 3 years of potential follow-up, respectively, and were eligible for analysis. Among these, 94 (20%) and 42 (16%) survived ≥ 2 and ≥ 3 years, respectively. Survival rates at 2 and 3 years were 25% (24 of 95) and 25% (13 of 53) with ipilimumab alone and 19% (54 of 284) and 15% (24 of 156) with ipilimumab plus gp100. Safety among patients with ≥ 2 years' survival was comparable with the overall study population, with the onset of new ipilimumab-related toxic effect (all grades) reported in 6 of 78 (8%) patients. CONCLUSIONS: Ipilimumab results in survival of ≥ 2 years in one-fifth of pretreated patients with 2 years potential follow-up in a phase III trial. New onset, low-grade events starting after administration of the last dose were infrequent. TRIAL REGISTRATION ID: NCT00094653.

16 Clinical Trial Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. 2013

Ribas, Antoni / Kefford, Richard / Marshall, Margaret A / Punt, Cornelis J A / Haanen, John B / Marmol, Maribel / Garbe, Claus / Gogas, Helen / Schachter, Jacob / Linette, Gerald / Lorigan, Paul / Kendra, Kari L / Maio, Michele / Trefzer, Uwe / Smylie, Michael / McArthur, Grant A / Dreno, Brigitte / Nathan, Paul D / Mackiewicz, Jacek / Kirkwood, John M / Gomez-Navarro, Jesus / Huang, Bo / Pavlov, Dmitri / Hauschild, Axel. ·Division of Hematology-Oncology, 11-934 Factor Building, UCLA Medical Center, 10833 Le Conte Ave, Los Angeles, CA 90095-1782, USA. aribas@mednet.ucla.edu ·J Clin Oncol · Pubmed #23295794.

ABSTRACT: PURPOSE: In phase I/II trials, the cytotoxic T lymphocyte-associated antigen-4-blocking monoclonal antibody tremelimumab induced durable responses in a subset of patients with advanced melanoma. This phase III study evaluated overall survival (OS) and other safety and efficacy end points in patients with advanced melanoma treated with tremelimumab or standard-of-care chemotherapy. PATIENTS AND METHODS: Patients with treatment-naive, unresectable stage IIIc or IV melanoma were randomly assigned at a ratio of one to one to tremelimumab (15 mg/kg once every 90 days) or physician's choice of standard-of-care chemotherapy (temozolomide or dacarbazine). RESULTS: In all, 655 patients were enrolled and randomly assigned. The test statistic crossed the prespecified futility boundary at second interim analysis after 340 deaths, but survival follow-up continued. At final analysis with 534 events, median OS by intent to treat was 12.6 months (95% CI, 10.8 to 14.3) for tremelimumab and 10.7 months (95% CI, 9.36 to 11.96) for chemotherapy (hazard ratio, 0.88; P = .127). Objective response rates were similar in the two arms: 10.7% in the tremelimumab arm and 9.8% in the chemotherapy arm. However, response duration (measured from date of random assignment) was significantly longer after tremelimumab (35.8 v 13.7 months; P = .0011). Diarrhea, pruritus, and rash were the most common treatment-related adverse events in the tremelimumab arm; 7.4% had endocrine toxicities. Seven deaths in the tremelimumab arm and one in the chemotherapy arm were considered treatment related by either investigators or sponsor. CONCLUSION: This study failed to demonstrate a statistically significant survival advantage of treatment with tremelimumab over standard-of-care chemotherapy in first-line treatment of patients with metastatic melanoma.

17 Clinical Trial Targeting CD4(+) T-helper cells improves the induction of antitumor responses in dendritic cell-based vaccination. 2013

Aarntzen, Erik H J G / De Vries, I Jolanda M / Lesterhuis, W Joost / Schuurhuis, Danita / Jacobs, Joannes F M / Bol, Kalijn / Schreibelt, Gerty / Mus, Roel / De Wilt, Johannes H W / Haanen, John B A G / Schadendorf, Dirk / Croockewit, Alexandra / Blokx, Willeke A M / Van Rossum, Michelle M / Kwok, William W / Adema, Gosse J / Punt, Cornelis J A / Figdor, Carl G. ·Department of Tumor Immunology, Radboud University Nijmegen Medical Centre (RUNMC), Nijmegen, The Netherlands. ·Cancer Res · Pubmed #23087058.

ABSTRACT: To evaluate the relevance of directing antigen-specific CD4(+) T helper cells as part of effective anticancer immunotherapy, we investigated the immunologic and clinical responses to vaccination with dendritic cells (DC) pulsed with either MHC class I (MHC-I)-restricted epitopes alone or both MHC class I and II (MHC-I/II)-restricted epitopes. We enrolled 33 stage III and IV HLA-A*02:01-positive patients with melanoma in this study, of whom 29 were evaluable for immunologic response. Patients received intranodal vaccinations with cytokine-matured DCs loaded with keyhole limpet hemocyanin and MHC-I alone or MHC-I/II-restricted tumor-associated antigens (TAA) of tyrosinase and gp100, depending on their HLA-DR4 status. In 4 of 15 patients vaccinated with MHC-I/II-loaded DCs and 1 of 14 patients vaccinated with MHC-I-loaded DCs, we detected TAA-specific CD8(+) T cells with maintained IFN-γ production in skin test infiltrating lymphocyte (SKIL) cultures and circulating TAA-specific CD8(+) T cells. If TAA-specific CD4(+) T-cell responses were detected in SKIL cultures, it coincided with TAA-specific CD8(+) T-cell responses. In 3 of 13 patients tested, we detected TAA-specific CD4(+)CD25(+)FoxP3(-) T cells with high proliferative capacity and IFN-γ production, indicating that these were not regulatory T cells. Vaccination with MHC-I/II-loaded DCs resulted in improved clinical outcome compared with matched control patients treated with dacarbazine (DTIC), median overall survival of 15.0 versus 8.3 months (P = 0.089), and median progression-free survival of 5.0 versus 2.8 months (P = 0.0089). In conclusion, coactivating TAA-specific CD4(+) T-helper cells with DCs pulsed with both MHC class I and II-restricted epitopes augments TAA-specific CD8(+) T-cell responses, contributing to improved clinical responses.

18 Clinical Trial Improved survival with vemurafenib in melanoma with BRAF V600E mutation. 2011

Chapman, Paul B / Hauschild, Axel / Robert, Caroline / Haanen, John B / Ascierto, Paolo / Larkin, James / Dummer, Reinhard / Garbe, Claus / Testori, Alessandro / Maio, Michele / Hogg, David / Lorigan, Paul / Lebbe, Celeste / Jouary, Thomas / Schadendorf, Dirk / Ribas, Antoni / O'Day, Steven J / Sosman, Jeffrey A / Kirkwood, John M / Eggermont, Alexander M M / Dreno, Brigitte / Nolop, Keith / Li, Jiang / Nelson, Betty / Hou, Jeannie / Lee, Richard J / Flaherty, Keith T / McArthur, Grant A / Anonymous4380696. ·Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. chapmanp@mskcc.org ·N Engl J Med · Pubmed #21639808.

ABSTRACT: BACKGROUND: Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation. METHODS: We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths. RESULTS: At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. CONCLUSIONS: Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann-La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.).

19 Clinical Trial Successful treatment of metastatic melanoma by adoptive transfer of blood-derived polyclonal tumor-specific CD4+ and CD8+ T cells in combination with low-dose interferon-alpha. 2011

Verdegaal, Els M E / Visser, Marten / Ramwadhdoebé, Tamara H / van der Minne, Caroline E / van Steijn, Jeanne A Q M J / Kapiteijn, Ellen / Haanen, John B A G / van der Burg, Sjoerd H / Nortier, Johan W R / Osanto, Susanne. ·Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands. e.verdegaal@lumc.nl ·Cancer Immunol Immunother · Pubmed #21431917.

ABSTRACT: A phase I/II study was conducted to test the feasibility and safety of the adoptive transfer of tumor-reactive T cells and daily injections of interferon-alpha (IFNα) in metastatic melanoma patients with progressive disease. Autologous melanoma cell lines were established to generate tumor-specific T cells by autologous mixed lymphocyte tumor cell cultures using peripheral blood lymphocytes. Ten patients were treated with on average 259 (range 38-474) million T cells per infusion to a maximum of six infusions, and clinical response was evaluated according to the response evaluation criteria in solid tumors (RECIST). Five patients showed clinical benefit from this treatment, including one complete regression, one partial response, and three patients with stable disease. No treatment-related serious adverse events were observed, except for the appearance of necrotic-like fingertips in one patient. An IFNα-related transient leucopenia was detected in 6 patients, including all responders. One responding patient displayed vitiligo. The infused T-cell batches consisted of tumor-reactive polyclonal CD8+ and/or CD4+ T cells. Clinical reactivity correlated with the functional properties of the infused tumor-specific T cells, including their in vitro expansion rate and the secretion of mainly Th1 cytokines as opposed to Th2 cytokines. Our study shows that relatively low doses of T cells and low-dose IFNα can lead to successful treatment of metastatic melanoma and reveals a number of parameters potentially associated with this success.

20 Clinical Trial Improved survival with ipilimumab in patients with metastatic melanoma. 2010

Hodi, F Stephen / O'Day, Steven J / McDermott, David F / Weber, Robert W / Sosman, Jeffrey A / Haanen, John B / Gonzalez, Rene / Robert, Caroline / Schadendorf, Dirk / Hassel, Jessica C / Akerley, Wallace / van den Eertwegh, Alfons J M / Lutzky, Jose / Lorigan, Paul / Vaubel, Julia M / Linette, Gerald P / Hogg, David / Ottensmeier, Christian H / Lebbé, Celeste / Peschel, Christian / Quirt, Ian / Clark, Joseph I / Wolchok, Jedd D / Weber, Jeffrey S / Tian, Jason / Yellin, Michael J / Nichol, Geoffrey M / Hoos, Axel / Urba, Walter J. ·Dana-Farber Cancer Institute, Boston, MA 02115, USA. stephen_hodi@dfci.harvard.edu ·N Engl J Med · Pubmed #20525992.

ABSTRACT: BACKGROUND: An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. METHODS: A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. RESULTS: The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. CONCLUSIONS: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

21 Clinical Trial Local administration of PF-3512676 CpG-B instigates tumor-specific CD8+ T-cell reactivity in melanoma patients. 2008

Molenkamp, Barbara G / Sluijter, Berbel J R / van Leeuwen, Paul A M / Santegoets, Saskia J A M / Meijer, Sybren / Wijnands, Pepijn G J T B / Haanen, John B A G / van den Eertwegh, Alfons J M / Scheper, Rik J / de Gruijl, Tanja D. ·Department of Surgical Oncology, Medical Oncology, and Pathology, VU University Medical Center, Amsterdam, The Netherlands. ·Clin Cancer Res · Pubmed #18628468.

ABSTRACT: PURPOSE: Impaired immune effector functions in the melanoma sentinel lymph node (SLN) may allow for early metastatic events. Local administration of PF-3512676 (formerly known as CpG 7909) has shown immunostimulatory effects of both dendritic cell and T-cell subsets in the melanoma SLN. Here, we set out to ascertain whether these PF-3512676-induced immunostimulatory effects translate into higher frequencies of melanoma-specific CD8(+) T cells. EXPERIMENTAL DESIGN: Twenty-four stage I to III melanoma patients were randomized to preoperative local administration of either PF-3512676 or saline. CD8(+) T cells from SLN and peripheral blood were tested for reactivity by IFN-gamma ELISPOT assay against several HLA-A1/A2/A3-restricted epitopes derived from various melanoma-associated antigens (MAA) in 21 of 24 enrolled patients. Frequencies of natural killer (NK) cells and frequencies and maturation state of dendritic cell subsets in the SLN were determined by flow cytometry. RESULTS: Melanoma-specific CD8(+) T-cell response rates against >1 MAA epitope in the SLN were 0 of 11 for the saline group versus 5 of 10 for the PF-3512676-administered group (P = 0.012). Of these 5 responding patients, 4 also had a measurable response to >1 MAA epitope in the blood. Increased frequencies in the SLN of both MAA-specific CD8(+) T cells and NK cells correlated to CpG-induced plasmacytoid dendritic cell maturation. CONCLUSIONS: These data show an increase in melanoma-specific CD8(+) T-cell frequencies as well as an increased effector NK cell rate after a single dose of PF-3512676 and thus support the utility of local PF-3512676 administration as adjuvant treatment in early-stage melanoma to try and halt metastatic spread.

22 Clinical Trial GMP production of pDERMATT for vaccination against melanoma in a phase I clinical trial. 2008

Quaak, S G L / van den Berg, J H / Toebes, M / Schumacher, T N M / Haanen, J B A G / Beijnen, J H / Nuijen, B. ·Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands. Susanne.Quaak@slz.nl ·Eur J Pharm Biopharm · Pubmed #18606527.

ABSTRACT: For the treatment of melanoma DNA vaccines are a promising therapeutic approach. In our institute a plasmid encoding a melanoma-associated epitope (MART-1) and an immunostimulatory sequence (tetanus toxin fragment-c) termed pDERMATT was developed. In a phase I study the plasmid will be administered intradermally using a newly developed tattoo strategy to assess the toxicity and efficacy of inducing tumor-specific T-cell immunity. To facilitate this study a Good Manufacturing Practice (GMP)-compliant plasmid manufacturing process was set up and a pharmaceutical dosage form was developed. Each batch resulted in approximately 200mg plasmid DNA of a high purity >90% supercoiled DNA, an A260/280 ratio 1.80-1.95, undetectable or extremely low residual endotoxins, Escherichia coli host cell protein, RNA, and DNA. In the manufacturing process no animal derived enzymes like RNase or potentially harmful organic solvents are used. After sterile filtration the concentration of the plasmid solution is approximately 1.1mg/mL. For the scheduled phase I study a concentration of 5mg/mL is desired, and further concentration of the solution is achieved by lyophilisation. The formulation solution is composed of 1mg/mL pDERMATT and 20mg/mL sucrose in Water for Injections. Upon reconstitution with a five times smaller volume an isotonic sucrose solution containing 5mg/mL pDERMATT is obtained. Lyophilised pDERMATT is sterile with >90% supercoiled DNA, an A260-280 ratio 1.80-1.95, content 90-110% of labeled, and residual water content <2% (w/w). The product yields the predicted profile upon restriction-enzyme digestion, is highly immunogenic as confirmed in an in vivo mouse model, and stable for at least six months at 5 degrees C. We have not only developed a reproducible process to manufacture pharmaceutical grade plasmid DNA but also a stable dosage form for the use in clinical trials.

23 Article Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. 2018

Blank, Christian U / Rozeman, Elisa A / Fanchi, Lorenzo F / Sikorska, Karolina / van de Wiel, Bart / Kvistborg, Pia / Krijgsman, Oscar / van den Braber, Marlous / Philips, Daisy / Broeks, Annegien / van Thienen, Johannes V / Mallo, Henk A / Adriaansz, Sandra / Ter Meulen, Sylvia / Pronk, Loes M / Grijpink-Ongering, Lindsay G / Bruining, Annemarie / Gittelman, Rachel M / Warren, Sarah / van Tinteren, Harm / Peeper, Daniel S / Haanen, John B A G / van Akkooi, Alexander C J / Schumacher, Ton N. ·Medical Oncology Department, Netherlands Cancer Institute, Amsterdam, The Netherlands. c.blank@nki.nl. · Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands. c.blank@nki.nl. · Medical Oncology Department, Netherlands Cancer Institute, Amsterdam, The Netherlands. · Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands. · Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands. · Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands. · Surgical Oncology Department, Netherlands Cancer Institute, Amsterdam, The Netherlands. · Department of Radiology, Netherlands Cancer Institute, Amsterdam, The Netherlands. · Adaptive Biotechnologies, Seattle, WA, USA. · NanoString Technologies, Inc., Seattle, WA, USA. · Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands. t.schumacher@nki.nl. ·Nat Med · Pubmed #30297911.

ABSTRACT: Adjuvant ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) both improve relapse-free survival of stage III melanoma patients

24 Article Early cost-effectiveness of tumor infiltrating lymphocytes (TIL) for second line treatment in advanced melanoma: a model-based economic evaluation. 2018

Retèl, Valesca P / Steuten, Lotte M G / Geukes Foppen, Marnix H / Mewes, Janne C / Lindenberg, Melanie A / Haanen, John B A G / van Harten, Wim H. ·Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital (NKI-AVL), Plesmanlaan 121, 1066, CX, Amsterdam, the Netherlands. V.retel@nki.nl. · Department of Health Technology and Services Research, University of Twente, Postbus 217, 7500, AE, Enschede, the Netherlands. V.retel@nki.nl. · Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, P.O. Box 19024, Seattle, WA, 98109-1024, USA. · Department of Medical Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital (NKI-AVL), Plesmanlaan 121, 1066, CX, Amsterdam, the Netherlands. · Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital (NKI-AVL), Plesmanlaan 121, 1066, CX, Amsterdam, the Netherlands. · Department of Health Technology and Services Research, University of Twente, Postbus 217, 7500, AE, Enschede, the Netherlands. ·BMC Cancer · Pubmed #30219040.

ABSTRACT: BACKGROUND: An emerging immunotherapy is infusion of tumor infiltrating Lymphocytes (TIL), with objective response rates of around 50% versus 19% for ipilimumab. As an Advanced Therapeutic Medicinal Products (ATMP), TIL is highly personalized and complex therapy. It requests substantial upfront investments from the hospital in: expensive lab-equipment, staff expertise and training, as well as extremely tight hospital logistics. Therefore, an early health economic modelling study, as part of a Coverage with Evidence Development (CED) program, was performed. METHODS: We used a Markov decision model to estimate the expected costs and outcomes (quality-adjusted life years; QALYs) for TIL versus ipilimumab for second line treatment in metastatic melanoma patients from a Dutch health care perspective over a life long time horizon. Three mutually exclusive health states (stable disease (responders)), progressive disease and death) were modelled. To inform further research prioritization, Value of Information (VOI) analysis was performed. RESULTS: TIL is expected to generate more QALYs compared to ipilimumab (0.45 versus 0.38 respectively) at lower incremental cost (presently €81,140 versus €94,705 respectively) resulting in a dominant ICER (less costly and more effective). Based on current information TIL is dominating ipilimumab and has a probability of 86% for being cost effective at a cost/QALY threshold of €80,000. The Expected Value of Perfect Information (EVPI) amounted to €3 M. CONCLUSIONS: TIL is expected to have the highest probability of being cost-effective in second line treatment for advanced melanoma compared to ipilimumab. To reduce decision uncertainty, a clinical trial investigating e.g. costs and survival seems most valuable. This is currently being undertaken as part of a CED program in the Netherlands Cancer Institute, Amsterdam, the Netherlands, in collaboration with Denmark.

25 Article [Recent treatment results for metastatic melanoma: data from the Dutch Melanoma Treatment Registry]. 2018

van Zeijl, Michiel C T / van den Eertwegh, Alfons J M / Wouters, Michel W J M / Jochems, Anouk / Schouwenburg, Maartje G / Haanen, John B A G / Aarts, Maureen J / van den Berkmortel, Franchette W P J / de Groot, Jan W B / Hospers, Geke A P / Kapiteijn, Ellen / Koornstra, Rutger H / Piersma, Djura / van Rijn, Rozemarijn S / Suijkerbuijk, Karijn P M / Ten Tije, Albert J / van der Veldt, Astrid A M / Vreugdenhil, Gerard / van der Hoeven, Koos J M. ·LUMC, afd. Heelkunde, Leiden. · Contact: M.C.T. van Zeijl (m.vanzeijl@dica.nl). · VUmc, afd. Medische oncologie, Amsterdam. · NKI-AVL, afd. Chirurgische Oncologie, Amsterdam. · DICA, Leiden. · NKI-AVL, afd. Medische oncologie en afd. Immunologie, Amsterdam. · MUMC+, afd. Medische Oncologie, Maastricht. · Zuyderland MC, afd. Medische oncologie, Heerlen. · Isala, afd. Medische oncologie, Zwolle. · UMCG, afd. Medische Oncologie, Groningen. · LUMC, afd. Medische Oncologie, Leiden. · Radboudumc, afd. Medische Oncologie, Nijmegen. · Medisch Spectrum Twente, afd. Medische oncologie, Enschede. · Medisch Centrum Leeuwarden, afd. Medische oncologie, Leeuwarden. · UMC Utrecht, afd. Medische Oncologie, Utrecht. · Amphia Ziekenhuis, afd. Medische oncologie, Breda. · Erasmus MC, afd. Medische Oncologie, Rotterdam. · Máxima Medisch Centrum, afd. Medische oncologie, Eindhoven. ·Ned Tijdschr Geneeskd · Pubmed #30040270.

ABSTRACT: OBJECTIVE: To evaluate treatment strategies and survival of patients with unresectable stage IIIc or IV melanoma since the 2012 introduction of new drugs in the Netherlands. DESIGN: Prospective cohort study. METHOD: We analysed data from the Dutch Melanoma Treatment Registry (DMTR) regarding patients diagnosed with unresectable stage IIIc or IV melanoma in the period of 1 July 2012 to 31 December 2015. We estimated survival times using the Kaplan-Meier method. The relationship between year of diagnosis and survival was estimated using Cox regression analysis, adjusted for age, WHO performance status, lactate dehydrogenase values, stage, brain metastases and distant metastases. RESULTS: Out of 2,768 registered patients, approximately three-quarters received systemic therapy. This treatment was subject to change every year. Median survival was 10.7 months (95% CI: 9.6-13.2) in 2012 and 13.8 months (95% CI: 11.8-15.6) in 2015. Median survival for patients receiving systemic therapy was 17.1 months in 2015. 2-year survival in this period increased from 23% to 40%. Patients diagnosed in 2015 had better survival than patients of 2014 (hazard ratio (HR) 0.82; 95% CI: 0.73-0.93). This was also true for patients receiving systemic therapy (HR: 0.79; 95% CI: 0.69-0.91). CONCLUSION: Fast availability of new drugs, initiated by the then minister of VWS (health, welfare and sport) and the professional organisation, has thoroughly changed treatment of unresectable stage IIIc and IV melanoma. Data from the DMTR indicate safe use of these new drugs in daily practice and improved survival of advanced-melanoma patients in recent years.

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