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Melanoma: HELP
Articles by Carmen Loquai
Based on 70 articles published since 2010
(Why 70 articles?)
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Between 2010 and 2020, C. Loquai wrote the following 70 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Guideline S3-guideline "diagnosis, therapy and follow-up of melanoma" -- short version. 2013

Pflugfelder, Annette / Kochs, Corinna / Blum, Andreas / Capellaro, Marcus / Czeschik, Christina / Dettenborn, Therese / Dill, Dorothee / Dippel, Edgar / Eigentler, Thomas / Feyer, Petra / Follmann, Markus / Frerich, Bernhard / Ganten, Maria-Katharina / Gärtner, Jan / Gutzmer, Ralf / Hassel, Jessica / Hauschild, Axel / Hohenberger, Peter / Hübner, Jutta / Kaatz, Martin / Kleeberg, Ulrich R / Kölbl, Oliver / Kortmann, Rolf-Dieter / Krause-Bergmann, Albrecht / Kurschat, Peter / Leiter, Ulrike / Link, Hartmut / Loquai, Carmen / Löser, Christoph / Mackensen, Andreas / Meier, Friedegund / Mohr, Peter / Möhrle, Matthias / Nashan, Dorothee / Reske, Sven / Rose, Christian / Sander, Christian / Satzger, Imke / Schiller, Meinhard / Schlemmer, Heinz-Peter / Strittmatter, Gerhard / Sunderkötter, Cord / Swoboda, Lothar / Trefzer, Uwe / Voltz, Raymond / Vordermark, Dirk / Weichenthal, Michael / Werner, Andreas / Wesselmann, Simone / Weyergraf, Ansgar J / Wick, Wolfgang / Garbe, Claus / Schadendorf, Dirk / Anonymous5770759. ·Department of Dermatology, University Hospital Tübingen, Germany. ·J Dtsch Dermatol Ges · Pubmed #23721604.

ABSTRACT: -- No abstract --

2 Review Radiotherapy with BRAF inhibitor therapy for melanoma: progress and possibilities. 2016

Zahnreich, Sebastian / Mayer, Arnulf / Loquai, Carmen / Grabbe, Stephan / Schmidberger, Heinz. ·Department of Radiation Oncology & Radiotherapy, University Medical Center Johannes Gutenberg University Mainz, Germany. · Department of Dermatology, University Medical Center Johannes Gutenberg University Mainz, Germany. ·Future Oncol · Pubmed #26616061.

ABSTRACT: The introduction of small molecule BRAF(V600) kinase inhibitors represents a milestone in the targeted therapy of patients with metastatic melanoma by a significant increase in therapeutic efficacy in terms of overall and progression-free survival compared with conventional chemotherapy. Beside BRAF(V600) inhibitor treatment, radiotherapy is a further mainstay for the therapy of metastatic melanoma and thus a concomitant or sequential application of BRAF(V600) inhibitors and radiotherapy is inevitable. Recent reports show a significant radiosensitization of the irradiated healthy tissue in patients with melanoma after the combination of radiotherapy and BRAF(V600) inhibitors, evoking concern in clinical practice. We review interactions of BRAF(V600) inhibitors and radiation with regard to antitumor effects and an increased radiotoxicity in the healthy tissue.

3 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.

4 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.

5 Clinical Trial Pembrolizumab-induced lichen planus pemphigoides in a patient with metastatic melanoma. 2017

Schmidgen, Maria Isabel / Butsch, Florian / Schadmand-Fischer, Simin / Steinbrink, Kerstin / Grabbe, Stephan / Weidenthaler-Barth, Beate / Loquai, Carmen. ·Department of Dermatology, University Medical Center, Johannes Gutenberg University Mainz, Germany. · Department of Radiology, University Medical Center, Johannes Gutenberg University Mainz, Germany. ·J Dtsch Dermatol Ges · Pubmed #28622432.

ABSTRACT: -- No abstract --

6 Clinical Trial Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. 2017

Ascierto, Paolo A / Del Vecchio, Michele / Robert, Caroline / Mackiewicz, Andrzej / Chiarion-Sileni, Vanna / Arance, Ana / Lebbé, Céleste / Bastholt, Lars / Hamid, Omid / Rutkowski, Piotr / McNeil, Catriona / Garbe, Claus / Loquai, Carmen / Dreno, Brigitte / Thomas, Luc / Grob, Jean-Jacques / Liszkay, Gabriella / Nyakas, Marta / Gutzmer, Ralf / Pikiel, Joanna / Grange, Florent / Hoeller, Christoph / Ferraresi, Virginia / Smylie, Michael / Schadendorf, Dirk / Mortier, Laurent / Svane, Inge Marie / Hennicken, Delphine / Qureshi, Anila / Maio, Michele. ·Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. Electronic address: paolo.ascierto@gmail.com. · Medical Oncology, National Cancer Institute, Milan, Italy. · Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. · Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, Poznan Medical University, Poznan, Poland. · IOV-IRCCS, Melanoma Oncology Unit, Padova, Italy. · Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain. · AP-HP Dermatology CIC Departments, Saint-Louis Hospital, INSERM U976, Université Paris Diderot, Paris, France. · Odense University Hospital, Odense, Denmark. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland. · Chris O'Brien Lifehouse and Royal Prince Alfred Hospital, Camperdown, NSW, Australia; Melanoma Institute Australia, Sydney, NSW, Australia. · Eberhard Karls University, Tübingen, Germany. · University Medical Center, Mainz, Germany. · Department of Oncodermatology, INSERM Research Unit 892, Nantes University Hospital, Nantes, France. · Department of Dermatology, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France. · Hospital de la Timone, Marseille, France. · National Institute of Oncology, Budapest, Hungary. · Oslo University Hospital, Oslo, Norway. · Medizinische Hochschule Hannover, Hannover, Germany. · Wojewodzkie Centrum Oncologii, Gdańsk, Poland. · Department of Dermatology, Reims University Hospital, Reims, France. · Medical University of Vienna, Vienna, Austria. · Istituti Fisioterapici Ospitalieri, Rome, Italy. · Cross Cancer Institute, Edmonton, AB, Canada. · University Hospital Essen, Essen, Germany. · Hôspital Claude Huriez, Lille, France. · Herlev Hospital, University of Copenhagen, Herlev, Denmark. · Bristol-Myers Squibb, Princeton, NJ, USA. · University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. ·Lancet Oncol · Pubmed #28359784.

ABSTRACT: BACKGROUND: A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3-4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit-risk profile of ipilimumab 10 mg/kg versus 3 mg/kg. METHODS: This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov, number NCT01515189. FINDINGS: Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6-42·3) for the ipilimumab 10 mg/kg group and 11·2 months (4·9-29·4) for the ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6-17·8) for ipilimumab 10 mg/kg compared with 11·5 months (9·9-13·3) for ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70-0·99; p=0·04). The most common grade 3-4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (<1%) patients died from treatment-related adverse events. INTERPRETATION: In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment. FUNDING: Bristol-Myers Squibb.

7 Clinical Trial Ipilimumab alone or in combination with nivolumab after progression on anti-PD-1 therapy in advanced melanoma. 2017

Zimmer, Lisa / Apuri, Susmitha / Eroglu, Zeynep / Kottschade, Lisa A / Forschner, Andrea / Gutzmer, Ralf / Schlaak, Max / Heinzerling, Lucie / Krackhardt, Angela M / Loquai, Carmen / Markovic, Svetomir N / Joseph, Richard W / Markey, Kelly / Utikal, Jochen S / Weishaupt, Carsten / Goldinger, Simone M / Sondak, Vernon K / Zager, Jonathan S / Schadendorf, Dirk / Khushalani, Nikhil I. ·Department of Dermatology, University Hospital, University Duisburg-Essen, Germany & German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address: lisa.zimmer@uk-essen.de. · Hematology/Oncology Fellowship Program, H Lee Moffitt Cancer Center and Research Institute/University of South Florida, Tampa, FL, USA. · Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA. · Department of Oncology, Hematology and Immunology, Mayo Clinic, Rochester, MN, USA. · Department of Dermatology, University Hospital Tübingen, Germany. · Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Germany. · Department of Dermatology, University Hospital Cologne, Skin Cancer Center, Center for Integrated Oncology (CIO) Köln Bonn, Germany. · Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Germany. · III. Medical Department, Technische Universität München (TUM) Munich, Germany. · Department of Dermatology, University Hospital Mainz, Germany. · Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany. · Department of Dermatology, University Hospital Münster, Germany. · Department of Dermatology, University Hospital Zurich, Switzerland. · Department of Dermatology, University Hospital, University Duisburg-Essen, Germany & German Cancer Consortium (DKTK), Heidelberg, Germany. ·Eur J Cancer · Pubmed #28214657.

ABSTRACT: BACKGROUND: The anti-programmed cell death-1 (PD-1) inhibitors pembrolizumab and nivolumab alone or in combination with ipilimumab have shown improved objective response rates and progression-free survival compared to ipilimumab only in advanced melanoma patients. Anti-PD-1 therapy demonstrated nearly equal clinical efficacy in patients who had progressed after ipilimumab or were treatment-naïve. However, only limited evidence exists regarding the efficacy of ipilimumab alone or in combination with nivolumab after treatment failure to anti-PD-therapy. PATIENTS AND METHODS: A multicenter retrospective study in advanced melanoma patients who were treated with nivolumab (1 or 3 mg/kg) and ipilimumab (1 mg or 3 mg/kg) or ipilimumab (3 mg/kg) alone after treatment failure to anti-PD-1 therapy was performed. Patient, tumour, pre- and post-treatment characteristics were analysed. RESULTS: In total, 47 patients were treated with ipilimumab (ipi-group) and 37 patients with ipilimumab and nivolumab (combination-group) after treatment failure to anti-PD-1 therapy. Overall response rates for the ipi- and the combination-group were 16% and 21%, respectively. Disease control rate was 42% for the ipi-group and 33% for the combination-group. One-year overall survival rates for the ipi- and the combination-group were 54% and 55%, respectively. CONCLUSIONS: Ipilimumab should be considered as a viable treatment option for patients with failure to prior anti-PD-1 therapy, including those with progressive disease as best response to prior anti-PD-1. In contrast, the combination of ipilimumab and nivolumab appears significantly less effective in this setting compared to treatment-naïve patients.

8 Clinical Trial Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. 2016

Schadendorf, Dirk / Dummer, Reinhard / Hauschild, Axel / Robert, Caroline / Hamid, Omid / Daud, Adil / van den Eertwegh, Alfons / Cranmer, Lee / O'Day, Steven / Puzanov, Igor / Schachter, Jacob / Blank, Christian / Salama, April / Loquai, Carmen / Mehnert, Janice M / Hille, Darcy / Ebbinghaus, Scot / Kang, S Peter / Zhou, Wei / Ribas, Antoni. ·University Hospital Essen, Hufelandstrasse 55, D-45147 Essen, Germany. Electronic address: dirk.schadendorf@uk-essen.de. · Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, 8091 Zurich, Switzerland. Electronic address: Reinhard.Dummer@usz.ch. · Department of Dermatology, Venereology, and Allergology, University Hospital Schleswig-Holstein, Kiel Campus, Arnold-Heller Strasse 3, 24105 Kiel, Germany. Electronic address: ahauschild@dermatology.uni-kiel.de. · Gustave Roussy Cancer Campus and Paris-Sud University, 114 Rue Edouard Vaillant, 94800 Villejuif, France. Electronic address: Caroline.Robert@gustaveroussyr.fr. · The Angeles Clinic and Research Institute, 2001 Santa Monica Blvd, Ste 560W, Santa Monica, CA 90404, USA. Electronic address: ohamid@theangelesclinic.org. · University of California, San Francisco School of Medicine, 1600 Divisadero St, NZ Bldg A, San Francisco, CA 94115, USA. Electronic address: Adil.Daud@ucsf.edu. · Department of Medical Oncology, VU University Medical Center Amsterdam, De Boelelaan 1118, 1081 HZ Amsterdam, The Netherlands. Electronic address: vandeneertwegh@VUMC.nl. · Department of Hematology/Oncology, University of Arizona Cancer Center at UMC North, 3838 N. Campbell Ave, Tucson, AZ 85724, USA. Electronic address: lcranmer@uacc.arizona.edu. · The Los Angeles Skin Cancer Institute, The Beverly Hills Cancer Center, 8900 Wilshire Blvd, Beverly Hills, CA 90211, USA. Electronic address: stevenjoday@gmail.com. · Vanderbilt-Ingram Cancer Center, 2220 Pierce Ave, 777 Preston Research Building, Nashville, TN 37232, USA. Electronic address: igor.puzanov@vanderbilt.edu. · Department of Oncology, Ella Institute for Melanoma, Sheba Medical Center, Derech Sheba 2, Tel-Hashomer, Ramat-Gan, Israel. Electronic address: Jacob.Schachter@sheba.health.gov.il. · Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Electronic address: c.blank@nki.nl. · Division of Medical Oncology, Duke Cancer Institute, Duke University Medical Center, Box 3198, 20 Duke Medicine Circle, Durham, NC 27710, USA. Electronic address: april.salama@duke.edu. · Skin Clinic, Universitätsmedizin Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. Electronic address: carmen.loquai@unimedizin-mainz.de. · Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA. Electronic address: mehnerja@cinj.rutgers.edu. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: darcy_hille@merck.com. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: scot_ebbinghaus@merck.com. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: s.peter.kang@merck.com. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: wei.zhou2@merck.com. · Department of Medicine, Division of Hematology-Oncology, Jonsson Comprehensive Cancer Center (JCCC) at the University of California, Los Angeles (UCLA), 10833 Le Conte Ave, Los Angeles, CA 90095, USA. Electronic address: aribas@mednet.ucla.edu. ·Eur J Cancer · Pubmed #27596353.

ABSTRACT: BACKGROUND: In KEYNOTE-002, pembrolizumab significantly prolonged progression-free survival and was associated with a better safety profile compared with chemotherapy in patients with advanced melanoma that progressed after ipilimumab. We present health-related quality of life (HRQoL) outcomes from KEYNOTE-002. METHODS: Patients were randomly assigned 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or investigator-choice chemotherapy. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 instrument. A constrained longitudinal data analysis model was implemented to assess between-arm differences in HRQoL scores. The study is registered with ClinicalTrials.gov, number NCT01704287. RESULTS: Of the 540 patients enrolled, 520 were included in the HRQoL analysis. Baseline global health status (GHS) was similar across treatment arms. Compliance rates at week 12 were 76.6% (n = 108), 82.3% (n = 121), and 86.4% (n = 133) for the control, pembrolizumab 2 mg/kg Q3W, and pembrolizumab 10 mg/kg Q3W arms, respectively. From baseline to week 12, GHS/HRQoL scores were maintained to a higher degree in the pembrolizumab arms compared with the chemotherapy arm (decrease of -2.6 for each pembrolizumab arm versus -9.1 for chemotherapy; P = 0.01 for each pembrolizumab arm versus chemotherapy). Fewer patients treated with pembrolizumab experienced deterioration in GHS at week 12 (31.8% for pembrolizumab 2 mg/kg, 26.6% for 10 mg/kg, and 38.3% for chemotherapy), with similar trends observed for the individual functioning and symptoms scales. CONCLUSIONS: HRQoL was better maintained with pembrolizumab than with chemotherapy in KEYNOTE-002, supporting the use of pembrolizumab in patients with ipilimumab-refractory melanoma.

9 Clinical Trial Open-label, multicenter, single-arm phase II DeCOG-study of ipilimumab in pretreated patients with different subtypes of metastatic melanoma. 2015

Zimmer, Lisa / Eigentler, Thomas K / Kiecker, Felix / Simon, Jan / Utikal, Jochen / Mohr, Peter / Berking, Carola / Kämpgen, Eckhart / Dippel, Edgar / Stadler, Rudolf / Hauschild, Axel / Fluck, Michael / Terheyden, Patrick / Rompel, Rainer / Loquai, Carmen / Assi, Zeinab / Garbe, Claus / Schadendorf, Dirk. ·Department of Dermatology, University Hospital, University Duisburg-Essen, Essen, Germany. lisa.zimmer@uk-essen.de. · Department of Dermatology, Center for Dermatooncology, University Medical Center Tübingen, Tübingen, Germany. thomas.eigentler@med.uni-tuebingen.de. · Department of Dermatology and Allergy, Skin Cancer Center, Charité-Universitätsmedizin Berlin, Berlin, Germany. felix.kiecker@charite.de. · Department of Dermatology, Venereology and Allergology, University Hospital Leipzig, Leipzig, Germany. Jan.simon@medizin.uni-leipzig.de. · Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany. jochen.utikal@umm.de. · Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany. jochen.utikal@umm.de. · Department of Dermatology, Elbekliniken Stade Buxtehude, Buxtehude, Germany. peter.mohr@elbekliniken.de. · Department of Dermatology and Allergy, Ludwig-Maximilian University, Munich, Germany. carola.berking@med.uni-muenchen.de. · Department of Dermatology, Dermatologikum Berlin, Berlin, Germany. Kaempgen@dermatologikum-berlin.de. · Department of Dermatology, Klinikum Ludwigshafen, Skin Cancer Center Rheinpfalz, Ludwigshafen, Germany. dippele@klilu.de. · Department of Dermatology, Medical Centre Minden, Minden, Germany. rudolf.stadler@muehlenkreiskliniken.de. · University Department of Dermatology, Kiel, Germany. ahauschild@dermatology.uni-kiel.de. · Department of Dermatology Hornheide, Münster, Germany. michael.fluck@fachklinik-hornheide.de. · Department of Dermatology, University of Lübeck, Lübeck, Germany. patrick.terheyden@uksh.de. · Department of Dermatology, Clinical Centre Kassel, Kassel, Germany. rompel@klinikum-kassel.de. · Department of Dermatology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany. Carmen.Loquai@unimedizin-mainz.de. · Department of Dermatology, Center for Dermatooncology, University Medical Center Tübingen, Tübingen, Germany. zeinab.jradi.assi@gmail.com. · Department of Dermatology, Center for Dermatooncology, University Medical Center Tübingen, Tübingen, Germany. claus.garbe@uni-tuebingen.de. · Department of Dermatology, University Hospital, University Duisburg-Essen, Essen, Germany. dirk.schadendorf@uk-essen.de. ·J Transl Med · Pubmed #26541511.

ABSTRACT: BACKGROUND: Ipilimumab is an approved immunotherapy that has shown an overall survival benefit in patients with cutaneous metastatic melanoma in two phase III trials. As results of registrational trials might not answer all questions regarding safety and efficacy of ipilimumab in patients with advanced melanoma seen in daily clinical practice, the Dermatologic Cooperative Oncology Group conducted a phase II study to assess the efficacy and safety of ipilimumab in patients with different subtypes of metastatic melanoma. PATIENTS AND METHODS: We undertook a multicenter phase II study in melanoma patients irrespective of location of the primary melanoma. Here we present data on patients with pretreated metastatic cutaneous, mucosal and occult melanoma who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC) v.4.0. Primary endpoint was the OS rate at 12 months. RESULTS: 103 pretreated patients received at least one dose of ipilimumab, including 83 cutaneous, seven mucosal and 13 occult melanomas. 1-year OS rates for cutaneous, mucosal and occult melanoma were 38 %, 14 % and 27 %, respectively. Median OS was 6.8 months (95 % CI 5.3-9.9) for cutaneous, 9.6 months (95 % CI 1.6-11.1) for mucosal, and 9.9 months (lower 95 % CI 2.3, upper 95 % CI non-existent) for occult melanoma. Overall response rates for cutaneous, mucosal and occult melanoma were 16 %, 17 % and 11 %, respectively. Eleven patients had partial response (16 %) and ten patients experienced stable disease (14 %), none achieved a complete response. Treatment-related AEs were observed in 71 patients (69 %), including 20 grade 3-4 events (19 %). No new and unexpected safety findings were noted. CONCLUSIONS: Ipilimumab is a treatment option for pretreated patients with advanced cutaneous melanoma seen in daily routine. Toxicity was manageable when treated as per protocol-specific guidelines. TRIAL REGISTRATION: Clinical Trials.gov NCT01355120.

10 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.

11 Clinical Trial A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. 2015

Hersh, E M / Del Vecchio, M / Brown, M P / Kefford, R / Loquai, C / Testori, A / Bhatia, S / Gutzmer, R / Conry, R / Haydon, A / Robert, C / Ernst, S / Homsi, J / Grob, J J / Kendra, K / Agarwala, S S / Li, M / Clawson, A / Brachmann, C / Karnoub, M / Elias, I / Renschler, M F / Hauschild, A. ·Department of Medicine, Arizona Cancer Center, Tucson, USA ehersh@azcc.arizona.edu. · Department of Medical Oncology, Fondazione IRCCS National Tumor Institute, Milan, Italy. · Cancer Clinical Trials Unit, Royal Adelaide Hospital and School of Medicine, University of Adelaide, Adelaide. · Sydney West Cancer Trials Centre/Westmead Hospital and Melanoma Institute Australia, University of Sydney, North Sydney, Australia. · Department of Dermatology, University of Mainz, Mainz, Germany. · Melanoma and Muscle Cutaneous Sarcoma Division, European Institute of Oncology, Milan, Italy. · Department of Medicine, Seattle Cancer Care Alliance, Seattle, USA. · Department of Dermatology and Oncology, Hannover Medical School, Hannover, Germany. · Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, USA. · Department of Medical Oncology, Alfred Hospital, Melbourne, Australia. · Demartology Unit, Department of Medicine, The Gustave Roussy Cancer Institute, Villejuif, France. · Department of Medical Oncology, London Health Sciences Center-London Regional Cancer Program, London, Canada. · Department of Medical Oncology, Banner MD Anderson Cancer Center, Gilbert, USA. · Department of Dermatology, Timone Hospital, APHM and Aix-Marseille University, Marseille, France. · Department of Internal Medicine, Division of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus. · Department of Hematology and Oncology, St Luke's Cancer Center and Temple University, Bethlehem. · Biometrics and Data Operations/Translational Medicine/Biometrics and Data Operations/Clinical Research & Development/Global Medical Affairs, Celgene Corporation, Summit, USA. · Department of Dermatology, University Medical Center Schleswig-Holstein, Kiel, Germany. ·Ann Oncol · Pubmed #26410620.

ABSTRACT: BACKGROUND: The efficacy and safety of nab-paclitaxel versus dacarbazine in patients with metastatic melanoma was evaluated in a phase III randomized, controlled trial. PATIENTS AND METHODS: Chemotherapy-naïve patients with stage IV melanoma received nab-paclitaxel 150 mg/m(2) on days 1, 8, and 15 every 4 weeks or dacarbazine 1000 mg/m(2) every 3 weeks. The primary end point was progression-free survival (PFS) by independent radiologic review; the secondary end point was overall survival (OS). RESULTS: A total of 529 patients were randomized to nab-paclitaxel (n = 264) or dacarbazine (n = 265). Baseline characteristics were well balanced. The majority of patients were men (66%), had an Eastern Cooperative Oncology Group status of 0 (71%), and had M1c stage disease (65%). The median PFS (primary end point) was 4.8 months with nab-paclitaxel and 2.5 months with dacarbazine [hazard ratio (HR), 0.792; 95.1% confidence interval (CI) 0.631-0.992; P = 0.044]. The median OS was 12.6 months with nab-paclitaxel and 10.5 months with dacarbazine (HR, 0.897; 95.1% CI 0.738-1.089; P = 0.271). Independently assessed overall response rate was 15% versus 11% (P = 0.239), and disease control rate (DCR) was 39% versus 27% (P = 0.004) for nab-paclitaxel versus dacarbazine, respectively. The most common grade ≥3 treatment-related adverse events were neuropathy (nab-paclitaxel, 25% versus dacarbazine, 0%; P < 0.001), and neutropenia (nab-paclitaxel, 20% versus dacarbazine, 10%; P = 0.004). There was no correlation between secreted protein acidic and rich in cysteine (SPARC) status and PFS in either treatment arm. CONCLUSIONS: nab-Paclitaxel significantly improved PFS and DCR compared with dacarbazine, with a manageable safety profile.

12 Clinical Trial Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. 2015

Ribas, Antoni / Puzanov, Igor / Dummer, Reinhard / Schadendorf, Dirk / Hamid, Omid / Robert, Caroline / Hodi, F Stephen / Schachter, Jacob / Pavlick, Anna C / Lewis, Karl D / Cranmer, Lee D / Blank, Christian U / O'Day, Steven J / Ascierto, Paolo A / Salama, April K S / Margolin, Kim A / Loquai, Carmen / Eigentler, Thomas K / Gangadhar, Tara C / Carlino, Matteo S / Agarwala, Sanjiv S / Moschos, Stergios J / Sosman, Jeffrey A / Goldinger, Simone M / Shapira-Frommer, Ronnie / Gonzalez, Rene / Kirkwood, John M / Wolchok, Jedd D / Eggermont, Alexander / Li, Xiaoyun Nicole / Zhou, Wei / Zernhelt, Adriane M / Lis, Joy / Ebbinghaus, Scot / Kang, S Peter / Daud, Adil. ·University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: aribas@mednet.ucla.edu. · Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. · University of Zürich, Zürich, Switzerland. · University Hospital Essen, Essen, Germany. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Gustave Roussy and Paris-Sud University, Villejuif, France. · Dana-Farber Cancer Institute, Boston, MA, USA. · Sheba Medical Center, Tel Hashomer, Israel. · New York University Cancer Institute, New York, NY, USA. · University of Colorado Denver, Aurora, CO, USA. · University of Arizona Cancer Center, Tucson, AZ, USA. · Netherlands Cancer Institute, Amsterdam, Netherlands. · Beverly Hills Cancer Center, Beverly Hills, CA, USA. · Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, Italy. · Duke Cancer Institute, Durham, NC, USA. · Seattle Cancer Care Alliance/University of Washington, Seattle, WA, USA. · University Medical Center, Mainz, Germany. · Universitätsklinikum Tübingen, Tübingen, Germany. · Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA. · Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, and Melanoma Institute Australia, Westmead, NSW, Australia. · St Luke's Cancer Center, Bethlehem, PA, USA; Temple University, Philadelphia, PA, USA. · University of North Carolina, Chapel Hill, NC, USA. · University of Pittsburgh, Pittsburgh, PA, USA. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Merck & Co, Kenilworth, NJ, USA. · University of California, San Francisco, San Francisco, CA, USA. ·Lancet Oncol · Pubmed #26115796.

ABSTRACT: BACKGROUND: Patients with melanoma that progresses on ipilimumab and, if BRAF(V600) mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma. METHODS: We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF(V600) mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0-1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAF(V600) mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients. FINDINGS: Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45-0·73; p<0·0001) and those assigned to pembrolizumab 10 mg/kg (0·50, 0·39-0·64; p<0·0001) compared with those assigned to chemotherapy. 6-month progression-free survival was 34% (95% CI 27-41) in the pembrolizumab 2 mg/kg group, 38% (31-45) in the 10 mg/kg group, and 16% (10-22) in the chemotherapy group. Treatment-related grade 3-4 adverse events occurred in 20 (11%) patients in the pembrolizumab 2 mg/kg group, 25 (14%) in the pembrolizumab 10 mg/kg group, and 45 (26%) in the chemotherapy group. The most common treatment-related grade 3-4 adverse event in the pembrolizumab groups was fatigue (two [1%] of 178 patients in the 2 mg/kg group and one [<1%] of 179 patients in the 10 mg/kg group, compared with eight [5%] of 171 in the chemotherapy group). Other treatment-related grade 3-4 adverse events include generalised oedema and myalgia (each in two [1%] patients) in those given pembrolizumab 2 mg/kg; hypopituitarism, colitis, diarrhoea, decreased appetite, hyponatremia, and pneumonitis (each in two [1%]) in those given pembrolizumab 10 mg/kg; and anaemia (nine [5%]), fatigue (eight [5%]), neutropenia (six [4%]), and leucopenia (six [4%]) in those assigned to chemotherapy. INTERPRETATION: These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma. FUNDING: Merck Sharp & Dohme.

13 Clinical Trial A randomised, phase II study of intetumumab, an anti-αv-integrin mAb, alone and with dacarbazine in stage IV melanoma. 2011

O'Day, S / Pavlick, A / Loquai, C / Lawson, D / Gutzmer, R / Richards, J / Schadendorf, D / Thompson, J A / Gonzalez, R / Trefzer, U / Mohr, P / Ottensmeier, C / Chao, D / Zhong, B / de Boer, C J / Uhlar, C / Marshall, D / Gore, M E / Lang, Z / Hait, W / Ho, P / Anonymous1080700. ·The Angeles Clinic and Research Institute, 2001 Santa Monica Boulevard, Suite 560W, Santa Monica, CA, USA. soday@theangelesclinic.org ·Br J Cancer · Pubmed #21750555.

ABSTRACT: BACKGROUND: α(v) integrins are involved in angiogenesis and melanoma tumourigenesis. Intetumumab (CNTO 95) is a fully human anti-α(v)-integrin monoclonal antibody. METHODS: In a multicentre, randomised, phase II study, stage IV melanoma patients were randomised 1:1:1:1 to 1000 mg m(-2) dacarbazine+placebo (n=32), 1000 mg m(-2) dacarbazine+10 mg kg(-1) intetumumab (n=32), 10 mg kg(-1) intetumumab (n=33), or 5 mg kg(-1) intetumumab (n=32) q3w. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), adverse events, and pharmacokinetics. RESULTS: No statistically significant differences in efficacy were observed between groups. In the dacarbazine+placebo, dacarbazine+intetumumab, 10 mg kg(-1) intetumumab, and 5 mg kg(-1) intetumumab groups, median PFS was 1.8, 2.5, 1.4, and 1.4 months; median OS was 8, 11, 15, and 9.8 months; and ORR of complete+partial response was 10, 3, 6, and 0%. Nonlinear intetumumab pharmacokinetics and potential intetumumab-dacarbazine interactions were observed. Transient, asymptomatic, nonrecurring, grade 1-2, uveitic reactions that resolved spontaneously or with topical steroids were seen in 22-30% of intetumumab-treated patients. Low-grade infusion-reaction symptoms (headache, fatigue, nausea, vomiting, fever, chills) were observed, as expected, in 16-73% of dacarbazine-treated patients. No intetumumab-related myelosuppression, laboratory/electrocardiogram abnormalities, or deaths occurred. CONCLUSION: With its favourable safety profile and a nonsignificant trend towards improved OS, intetumumab merits further investigation in advanced melanoma.

14 Article Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma. 2020

Ascierto, Paolo A / Dummer, Reinhard / Gogas, Helen J / Flaherty, Keith T / Arance, Ana / Mandala, Mario / Liszkay, Gabriella / Garbe, Claus / Schadendorf, Dirk / Krajsova, Ivana / Gutzmer, Ralf / de Groot, Jan Willem B / Loquai, Carmen / Gollerkeri, Ashwin / Pickard, Michael D / Robert, Caroline. ·Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy. Electronic address: paolo.ascierto@gmail.com. · Department of Dermatology, University Hospital Zürich Skin Cancer Center and University Zürich, Zürich, Switzerland. · Department of Internal Medicine, National and Kapodistrian University of Athens, Laikon Hospital, Athens, Greece. · Cancer Center, Massachusetts General Hospital, Boston, MA, USA. · 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. · Department of Medical Oncology, Isala, Zwolle, Netherlands. · Department of Dermatology, University Medical Center Mainz, Mainz, Germany. · Pfizer Inc., Boulder, CO, USA. · Service of Dermatology, Department of Medicine and Paris-Sud University, Gustave Roussy, Villejuif, France. ·Eur J Cancer · Pubmed #31901705.

ABSTRACT: BACKGROUND: BRAF/MEK inhibitor combinations are established treatments for BRAF V600-mutant melanoma based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). Here, we report an updated analysis of the COLUMBUS (COmbined LGX818 [encorafenib] Used with MEK162 [binimetinib] in BRAF mutant Unresectable Skin cancer) trial with long-term follow-up. METHODS: In part 1 of the COLUMBUS trial, 577 patients with advanced/metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomised 1:1:1 to 450 mg of encorafenib QD + 45 mg of binimetinib BID (COMBO450) vs 960 mg of vemurafenib BID (VEM) or 300 mg of encorafenib ENCO QD (ENCO300). An updated analysis was conducted that included PFS, OS, objective response rate, safety and tolerability and analyses of results by prognostic subgroups. RESULTS: At data cutoff, there were 116, 113 and 138 deaths in the COMBO450, ENCO300 and VEM treatment arms, respectively. The median OS was 33.6 months (95% confidence interval [CI], 24.4-39.2) for COMBO450, 23.5 months (95% CI, 19.6-33.6) for ENCO300 and 16.9 months (95% CI, 14.0-24.5) for VEM. Compared with VEM, COMBO450 decreased the risk of death by 39% (hazard ratio [HR], 0.61; 95% CI, 0.48-0.79). The updated median PFS for COMBO450 was 14.9 months (95% CI, 11.0-20.2), ENCO300 was 9.6 months (95% CI, 7.4-14.8) and VEM was 7.3 months (95% CI, 5.6-7.9). PFS was longer for COMBO450 vs VEM (HR, 0.51; 95% CI, 0.39-0.67). Landmark OS and PFS results show consistent results for each year analysed. Subgroups all favoured COMBO450 vs VEM. CONCLUSIONS: Updated PFS and OS results for COMBO450 from the COLUMBUS trial demonstrate a long-term benefit in patients with advanced BRAF V600-mutated melanoma.

15 Article Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma. 2019

Liu, David / Schilling, Bastian / Liu, Derek / Sucker, Antje / Livingstone, Elisabeth / Jerby-Amon, Livnat / Zimmer, Lisa / Gutzmer, Ralf / Satzger, Imke / Loquai, Carmen / Grabbe, Stephan / Vokes, Natalie / Margolis, Claire A / Conway, Jake / He, Meng Xiao / Elmarakeby, Haitham / Dietlein, Felix / Miao, Diana / Tracy, Adam / Gogas, Helen / Goldinger, Simone M / Utikal, Jochen / Blank, Christian U / Rauschenberg, Ricarda / von Bubnoff, Dagmar / Krackhardt, Angela / Weide, Benjamin / Haferkamp, Sebastian / Kiecker, Felix / Izar, Ben / Garraway, Levi / Regev, Aviv / Flaherty, Keith / Paschen, Annette / Van Allen, Eliezer M / Schadendorf, Dirk. ·Dana-Farber Cancer Institute, Boston, MA, USA. · Broad Institute of Harvard and MIT, Cambridge, MA, USA. · Department of Dermatology, University Hospital Würzburg, Würzburg, Germany. · Department of Dermatology, University Hospital, Essen, Germany. · German Cancer Consortium of Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany. · Harvard Medical School, Boston, MA, USA. · Skin Cancer Center Hannover, Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany. · Department of Dermatology, University Medical Center, Mainz, Germany. · Biophysics Program, Harvard University, Cambridge, MA, USA. · First Department of Medicine, National and Kapodistrian University of Athens, Athens, Greece. · Department of Dermatology, University Hospital Zürich, Zürich, Switzerland. · Department of Dermatology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany. · Skin Cancer Unit, German Cancer Research Center, Heidelberg, Germany. · Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. · Skin Cancer Center at the University Cancer Centre, Department of Dermatology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. · National Center for Tumor Diseases, Dresden, Germany. · German Cancer Research Centre, Heidelberg, Germany. · Department of Dermatology, Medical Center- University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. · Medizinische Klinik III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Department of Dermatology, University Medical Center Tübingen, Tübingen, Germany. · Department of Dermatology, University Hospital Regensburg, Regensburg, Germany. · Department of Dermatology, University Hospital Berlin, Berlin, Germany. · Eli Lilly and Co., Indianapolis, IN, USA. · Massachusetts General Hospital, Boston, MA, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. eliezerm_vanallen@dfci.harvard.edu. · Broad Institute of Harvard and MIT, Cambridge, MA, USA. eliezerm_vanallen@dfci.harvard.edu. · Department of Dermatology, University Hospital, Essen, Germany. dirk.schadendorf@uk-essen.de. · German Cancer Consortium of Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany. dirk.schadendorf@uk-essen.de. ·Nat Med · Pubmed #31792460.

ABSTRACT: Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.

16 Article Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study. 2019

Heppt, Markus V / Amaral, Teresa / Kähler, Katharina C / Heinzerling, Lucie / Hassel, Jessica C / Meissner, Markus / Kreuzberg, Nicole / Loquai, Carmen / Reinhardt, Lydia / Utikal, Jochen / Dabrowski, Evelyn / Gesierich, Anja / Pföhler, Claudia / Terheyden, Patrick / Thoms, Kai-Martin / Zimmer, Lisa / Eigentler, Thomas K / Kirchberger, Michael C / Stege, Henner M / Meier, Friedegund / Schlaak, Max / Berking, Carola. ·Department of Dermatology and Allergy, Munich University Hospital (LMU), Frauenlobstr. 9-11, 80337, Munich, Germany. · Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Ulmenweg 18, 91054, Erlangen, Germany. · Department of Dermatology, Center for Dermatooncology, University Hospital Tübingen, Liebermeisterstr. 25, 72076, Tübingen, Germany. · Portuguese Air Force Health Care Direction, Lisbon, Portugal. · Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Rosalind-Franklin-Str. 7, 24105, Kiel, Germany. · Skin Cancer Center, Department of Dermatology and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany. · Department of Dermatology, Venereology and Allergology, Goethe University, Theodor-Stern Kai 7, 60590, Frankfurt am Main, Germany. · Department of Dermatology and Venereology, Skin Cancer Center at the Center of Integrated Oncology (CIO) Köln Bonn, University Hospital of Cologne, Kerpenerstr. 62, 50937, Cologne, Germany. · Department of Dermatology, University Medical Center Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. · Department of Dermatology, Skin Cancer Center, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, Fetscherstr. 74, 01307, Dresden, Germany. · Skin Cancer Unit, German Cancer Research Center (DKFZ) and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany. · Department of Dermatology, Klinikum Ludwigshafen, Bremserstr. 79, 67063, Ludwigshafen, Germany. · Department of Dermatology, University Hospital Würzburg, Josef-Schneider Straße 2, 97080, Würzburg, Germany. · Department of Dermatology, Saarland University Medical School, Kirrbergerstr, 66421, Homburg/Saar, Germany. · Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany. · Department of Dermatology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany. · Department of Dermatology, University Hospital, University Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany. · Department of Dermatology and Allergy, Munich University Hospital (LMU), Frauenlobstr. 9-11, 80337, Munich, Germany. Carola.Berking@uk-erlangen.de. · Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Ulmenweg 18, 91054, Erlangen, Germany. Carola.Berking@uk-erlangen.de. ·J Immunother Cancer · Pubmed #31722735.

ABSTRACT: BACKGROUND: Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages. The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear. METHODS: Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers. Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety. Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression. RESULTS: The best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively. The median duration of response was 25.5 months (range 9.0-65.0). Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0-65.0). The median PFS was 3.0 months (95% CI 2.4-3.6). The median OS was estimated to 16.1 months (95% CI 12.9-19.3). Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%). The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%). A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007). CONCLUSIONS: The tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma. This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials.

17 Article Adverse events associated with encorafenib plus binimetinib in the COLUMBUS study: incidence, course and management. 2019

Gogas, Helen J / Flaherty, Keith T / Dummer, Reinhard / Ascierto, Paolo A / Arance, Ana / Mandala, Mario / Liszkay, Gabriella / Garbe, Claus / Schadendorf, Dirk / Krajsova, Ivana / Gutzmer, Ralf / Sileni, Vanna Chiarion / Dutriaux, Caroline / de Groot, Jan Willem B / Yamazaki, Naoya / Loquai, Carmen / Gollerkeri, Ashwin / Pickard, Michael D / Robert, Caroline. ·Department of Internal Medicine, National and Kapodistrian University of Athens, Laikon Hospital, Athens, Greece. Electronic address: helgogas@gmail.com. · Cancer Center, Massachusetts General Hospital, Boston, MA, USA. · Department of Dermatology, University Hospital Zürich Skin Cancer Center and University Zürich, Zürich, Switzerland. · Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy. · 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, and 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, 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. · Array BioPharma Inc., Boulder, CO, USA. · Service of Dermatology, Department of Medicine and Paris-Sud University, Gustave Roussy, Villejuif, France. ·Eur J Cancer · Pubmed #31437754.

ABSTRACT: BACKGROUND: Dual inhibition of the mitogen-activated protein kinase pathway with BRAF/MEK inhibitor (BRAFi/MEKi) therapy is a standard treatment for BRAFV600-mutant metastatic melanoma and has historically been associated with grade III pyrexia or photosensitivity depending on the combination used. The objective of this study was to fully describe adverse events from the COLUMBUS study evaluating the most recent BRAF/MEK inhibitor combination encorafenib+binimetinib. PATIENTS AND METHODS: Patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma were randomised to receive encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, encorafenib 300 mg once daily or vemurafenib 960 mg twice daily. Adverse events that represent known effects of available BRAFi and/or MEKi were evaluated. RESULTS: The safety population included a total of 570 patients (encorafenib+binimetinib = 192; encorafenib = 192; vemurafenib = 186). Median duration of exposure was longer with encorafenib+binimetinib (51 weeks) than with encorafenib (31 weeks) or vemurafenib (27 weeks). Common BRAFi/MEKi toxicities with encorafenib+binimetinib were generally manageable, reversible and infrequently associated with discontinuation. Pyrexia was less frequent with encorafenib+binimetinib (18%) and encorafenib (16%) than with vemurafenib (30%) and occurred later in the course of therapy with encorafenib+binimetinib (median time to first onset: 85 days versus 2.5 days and 19 days, respectively). The incidence of photosensitivity was lower with encorafenib+binimetinib (5%) and encorafenib (4%) than with vemurafenib (30%). The incidence of serous retinopathy was higher with encorafenib+binimetinib (20%) than with encorafenib (2%) or vemurafenib (2%), but no patients discontinued encorafenib+binimetinib because of this event. CONCLUSION: Encorafenib+binimetinib is generally well tolerated and has a low discontinuation rate in patients with BRAFV600-mutant melanoma, with a distinct safety profile as compared with other anti-BRAF/MEK targeted therapies. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT01909453) and with EudraCT (number 2013-001176-38).

18 Article Real-World Use of Talimogene Laherparepvec in German Patients with Stage IIIB to IVM1a Melanoma: A Retrospective Chart Review and Physician Survey. 2019

Mohr, Peter / Haferkamp, Sebastian / Pinter, Andreas / Weishaupt, Carsten / Huber, Margit A / Downey, Gerald / Öhrling, Katarina / Loquai, Carmen / Louie, Karly S. ·Department of Dermatology, Elbe-Klinikum Buxtehude, Buxtehude, Germany. peter.mohr@elbekliniken.de. · Department of Dermatology, University Hospital Regensburg, Regensburg, Germany. · Department of Dermatology, Venereology and Allergology, University Hospital Frankfurt, Frankfurt am Main, Germany. · Department of Dermatology, University Hospital of Muenster, Muenster, Germany. · Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany. · Amgen Ltd, Cambridge, UK. · Amgen Europe GmbH, Rotkreuz, Switzerland. · Department of Dermatology, University Medical Center Mainz, Mainz, Germany. · Amgen Ltd, Uxbridge, UK. ·Adv Ther · Pubmed #30536143.

ABSTRACT: INTRODUCTION: Talimogene laherparepvec is a first-in-class oncolytic immunotherapy for intratumoral injection with proven efficacy and tolerability in patients with unresectable early metastatic melanoma (stage IIIB-IVM1a) in the pivotal phase III OPTiM study. The objective was to characterize melanoma patients treated with talimogene laherparepvec in routine clinical practice in Germany. METHODS: A retrospective chart review was conducted in unresectable stage IIIB-IVM1a melanoma patients. Data on demographics, disease and medical history, and use of talimogene laherparepvec were collected. A survey was also conducted to understand physician treatment decisions. RESULTS: Data for 27 patients who initiated talimogene laherparepvec between June 2016 and July 2017 were analyzed (median age 68; stage IIIB/C disease 56%). All patients had prior surgery, and over half had repeated resections for recurrent disease (median 3). Overall, 48% of patients received at least one prior local treatment, mainly radiation therapy or electrochemotherapy. Talimogene laherparepvec was first-line systemic therapy in 63% of patients. The most frequent prior systemic treatment was immunotherapy (7/27 patients). At end of follow-up, 13 patients were still on talimogene laherparepvec and 14 patients had discontinued treatment. Among those who discontinued, 8 (57%) did not receive subsequent systemic therapy. Only one patient receiving first-line talimogene laherparepvec received a subsequent systemic therapy. Three patients stopped treatment because of no remaining injectable lesions. Median treatment duration was 22.1 weeks overall and 27.9 weeks in stage IIIB/C disease patients. Nearly all cutaneous lesions (93%) were injected with talimogene laherparepvec compared to subcutaneous (83%) and nodal lesions (77%). No new safety signals were reported. The main reasons given in the physician survey for treating with talimogene laherparepvec were good tolerability, overall efficacy, and lack of contraindications. CONCLUSION: Talimogene laherparepvec is now included as a routine treatment option for unresectable early metastatic melanoma in Germany. This study characterizes the first patients treated with talimogene laherparepvec in Europe and confirms the good tolerability observed in clinical trials. TRIAL REGISTRATION: EUPAS registry, EUPAS17410. FUNDING: Amgen Inc.

19 Article The efficacy of re-challenge with BRAF inhibitors after previous progression to BRAF inhibitors in melanoma: A retrospective multicenter study. 2018

Tietze, Julia K / Forschner, Andrea / Loquai, Carmen / Mitzel-Rink, Heidrun / Zimmer, Lisa / Meiss, Frank / Rafei-Shamsabadi, David / Utikal, Jochen / Bergmann, Maike / Meier, Friedegund / Kreuzberg, Nicole / Schlaak, Max / Weishaupt, Carsten / Pföhler, Claudia / Ziemer, Mirjana / Fluck, Michael / Rainer, Jessica / Heppt, Markus V / Berking, Carola. ·Department of Dermatology and Allergy, University Hospital Munich (LMU), 80337 Munich, Germany. · Department of Dermatology, Center for Dermatooncology, University Hospital Tübingen, 72076 Tübingen, Germany. · Department of Dermatology, University Medical Center Mainz, 55131 Mainz, Germany. · Department of Dermatology, University Hospital Essen, University of Essen, 45147 Essen, Germany. · Department of Dermatology and Venereology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany. · Skin Cancer Unit, German Cancer Research Center (DKFZ) and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, 68167 Mannheim, Germany. · Department of Dermatology, Skin Cancer Center, National Center for Tumor Diseases, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany. · Department of Dermatology, University of Cologne, 50937 Cologne, Germany. · Department of Dermatology, University of Münster, 48149 Münster, Germany. · Department of Dermatology, Saarland University Medical Center, 66421 Homburg/Saar, Germany. · Department of Dermatology, Venereology, and Allergology, University Hospital Leipzig, 04103 Leipzig, Germany. · Department of Internal Medical Oncology, Clinic Hornheide, 48157 Münster, Germany. · Deparment of Dermatology, Klinikum Süd, 86179 Augsburg, Germany. ·Oncotarget · Pubmed #30344946.

ABSTRACT: BRAF and MEK inhibition is efficient in patients with BRAF V600-mutated metastatic melanoma, but due to acquired resistance the duration of response (DoR) is often only short-lived. In this retrospective multicenter study with 60 patients suffering from inoperable or metastatic melanoma we evaluated the efficacy of re-challenge with a BRAF inhibitor (BRAF2) with or without MEK-inhibition after progressive disease upon previous treatment with a BRAF inhibitor (BRAF1) with or without MEK inhibition. Treatment with BRAF1 led to a disease control rate (DCR) of 90% with 12% complete responses (CR), 58% partial responses (PR) and 20% stable diseases (SD), the median progression-free survival (PFS) was 9.9 and DoR 10.7 months. BRAF2 with (68%) or without (32%) additional MEK inhibition was initiated after a median interval of 3.4 months. DCR after re-challenge with BRAF2 was 57%, 8% CR, 20% PR and 28% SD, median PFS was 5.0 and DoR 14.0 months. The duration of the treatment interval or the treatment in the interval did not influence the DCR or PFS to BRAF2. The only predictive factor for response to BRAF2 was previous response to BRAF1; all patients with CR to BRAF1 achieved disease control with BRAF2, but only 60% of the patients with PR to BRAF1 (p=0.002). Addition of MEK inhibition to BRAF2 after treatment with BRAF1 as monotherapy did not significantly increase the DCR or PFS compared to patients treated solely with mono- or combination therapy. In conclusion re-challenge with a BRAF inhibitor is a meaningful therapeutic option for patients with BRAF V600-mutated metastatic melanoma.

20 Article Long-term survival of patients after ipilimumab and hypofractionated brain radiotherapy for brain metastases of malignant melanoma: sequence matters. 2018

Schmidberger, Heinz / Rapp, Matthias / Ebersberger, Anne / Hey-Koch, Silla / Loquai, Carmen / Grabbe, Stephan / Mayer, Arnulf. ·Department of Radiation Oncology, University Medical Center of the Johannes Gutenberg University, Langenbeckstr. 1, 55131, Mainz, Germany. · Department of Dermatology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany. · Department of Radiation Oncology, University Medical Center of the Johannes Gutenberg University, Langenbeckstr. 1, 55131, Mainz, Germany. arnmayer@uni-mainz.de. ·Strahlenther Onkol · Pubmed #30298365.

ABSTRACT: PURPOSE: Since the introduction of ipilimumab (IPI) for the treatment of patients with metastatic malignant melanoma, we have observed remarkable responses after hypofractionated whole brain irradiation (WBRT) or stereotactic radiotherapy (STX) for brain metastases of malignant melanoma. We sought to investigate the impact of the sequence of these treatment modalities. METHODS: We retrospectively evaluated the survival of melanoma patients with brain metastases who were treated with WBRT or STX and received IPI in close temporal relation between October 2010 and March 2015. Follow-up was obtained until November 2016. A total of 27 patients with advanced melanoma and brain metastases who were treated with WBRT before 2010, and who had not received IPI, served as historical controls. RESULTS: We identified a total of 41 patients of whom 15 were treated with STX, 7 with a combination of STX and WBRT and 19 with WBRT alone. All patients received at least 2 doses of IPI. The median time interval between radiotherapy and IPI was 2 months. Patients treated with IPI after radiotherapy had a censored median survival of 11 months, compared with 3 months for the patients who received IPI prior to radiotherapy. Patients who received IPI before radiotherapy showed a similar survival as historical controls, who had not received IPI. We observed long-term survivors after radiotherapy of brain metastases followed by IPI. CONCLUSIONS: These data suggest that the sequence of RT and immune checkpoint inhibition with IPI may be crucial for the success of combined modality treatment of melanoma brain metastases.

21 Article Fear of cancer progression in patients with stage IA malignant melanoma. 2018

Wagner, Tobias / Augustin, Matthias / Blome, Christine / Forschner, Andrea / Garbe, Claus / Gutzmer, Ralf / Hauschild, Axel / Heinzerling, Lucie / Livingstone, Elisabeth / Loquai, Carmen / Schadendorf, Dirk / Terheyden, Patrick / Mueller-Brenne, Tina / Kähler, Katharina C. ·German Center for Health Services Research in Dermatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Department of Dermatology, Eberhard-Karls University of Tuebingen, Tuebingen, Germany. · Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany. · Department of Dermatology, Skin Cancer Center, University of Kiel, Kiel, Germany. · Department of Dermatology, University Hospital Erlangen, Erlangen, Germany. · Department of Dermatology, University Hospital Essen, Essen, Germany. · Department of Dermatology, University Medical Center Mainz, Mainz, Germany. · Department of Dermatology, University Hospital (UKSH), Luebeck, Germany. ·Eur J Cancer Care (Engl) · Pubmed #30126009.

ABSTRACT: We aimed to determine the prevalence and importance of fear of cancer progression (FoP) in melanoma patients with stage IA tumours to assess psychosocial and demographic factors associated with severity of FoP and to determine the relationship of FoP and quality of life (QoL). One hundred and thirty-six patients with stage IA melanoma completed the short version of the Fear of Progression Questionnaire (FoP-Q-SF), the Hospital Anxiety and Depression Scale (HADS) and the EORTC-QLQ-C30. We found a mean FoP-Q-SF sum score of 30.2 points (±8.4 points SD). In this study, 33% of patients reported high FoP at or above the cutoff-value of 34 points. Higher FoP was found in women (p < 0.01), young (p = 0.03) and employed (p = 0.02) patients. Being confronted with a cancer diagnosis in closely related persons predicted higher FoP (p < 0.01). FoP correlated positively with the HADS anxiety (r = 0.50, p < 0.01) and depression scales (r = 0.26, p < 0.01) and negatively with the EORTC-QLQ-C30 global health state (r = -0.32, p < 0.01). FoP is considerably prevalent in low-risk melanoma patients and associated with reduced QoL, cancer in related persons, women sex and participation in working life. Considerably high levels of FoP, even in patients with low-risk malignancies, underline the need for psychosocial support and psychotherapeutic interventions for melanoma patients.

22 Article The outweigh of toxicity versus risk of recurrence for adjuvant interferon therapy: a survey in German melanoma patients and their treating physicians. 2018

Kähler, Katharina C / Blome, Christine / Forschner, Andrea / Gutzmer, Ralf / Hauschild, Axel / Heinzerling, Lucie / Livingstone, Elisabeth / Loquai, Carmen / Müller-Brenne, Tina / Schadendorf, Dirk / Utikal, Jochen / Wagner, Tobias / Augustin, Matthias. ·Department of Dermatology, Skin Cancer Center, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany. · Institute for Health Services Research in Dermatology and Nursing (IVDP), University Medical Center Hamburg, Hamburg, Germany. · Department of Dermatology, Eberhard-Karls University of Tübingen, Tübingen, Germany. · Department of Dermatology, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany. · Department of Dermatology, University Hospital Erlangen, Erlangen, Germany. · Department of Dermatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. · Department of Dermatology, University of Mainz, Mainz, Germany. · Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Mannheim, Germany. ·Oncotarget · Pubmed #29899854.

ABSTRACT: After more than two decades with interferon alfa-2a and 2b (IFN) as the only approved drugs in the adjuvant setting for melanoma, new treatment approaches like immune checkpoint inhibitors and BRAF-MEK inhibitors improve the progression free survival (PFS) and also the overall survival (OS). We compared physicians' preferences ("utilities") for health states associated with IFN therapy to their patients' preferences. Utilities describe a preference for a specific health state on a scale of 0 (as bad as death) to 1.0 (perfect health). Setting: We assessed utilities for health states associated with adjuvant IFN using the standard gamble technique in 108 physicians and 130 melanoma patients. Four IFN toxicity scenarios and three outcome scenarios were given to the participants. Both groups were asked for the 5-year disease free survival (DFS) they would need to accept the described IFN-related side effects. Results: In both groups, utilities for melanoma relapse were significantly lower than for IFN side effects, showing that toxicity was more acceptable than relapse. Physicians indicated higher utilities for each scenario and needed lower 5-year DFS both in case of mild-to-moderate and severe side effects. Patients were willing to tolerate mild-to-moderate and severe toxicity for a 50% and 75% chance of 5-year DFS, while physicians only required a chance of 40% and 50%, respectively. Conclusion: Both physicians and patients rated melanoma recurrence much lower than even severe IFN side effects. In direct comparison, physicians rated cancer-related scenarios more positively and accepted IFN toxicity for an even lower treatment benefit.

23 Article Willingness to pay for a cure of low-risk melanoma patients in Germany. 2018

Augustin, Matthias / Blome, Christine / Forschner, Andrea / Gutzmer, Ralf / Hauschild, Axel / Heinzerling, Lucie / Livingstone, Elisabeth / Loquai, Carmen / Schadendorf, Dirk / Utikal, Jochen / Wagner, Tobias / Wilden, Sophia / Kähler, Katharina C. ·Institute for Health Services Research in Dermatology and Nursing (IVDP), University Medical Center Hamburg, Germany. · Department of Dermatology, Eberhard-Karls University of Tübingen, Tübingen, Germany. · Skin Cancer Center Hannover, Department of Dermatology, Hannover Medical School, Hannover, Germany. · Skin Cancer Center, Department of Dermatology, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany. · Department of Dermatology, University Hospital Erlangen, Erlangen, Germany. · Department of Dermatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. · Department of Dermatology, University of Mainz, Mainz, Germany. · Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Mannheim, Germany. ·PLoS One · Pubmed #29795621.

ABSTRACT: Malignant melanoma is potentially life-threatening but in most cases curable if detected early. Willingness to pay (WTP) is a preference-based construct that reflects burden of disease by assessment of the monetary value for a hypothetical cure from disease. Since WTP (directly as total amount of money) has not been assessed so far in patients with low risk melanoma, it was interesting to gain insights in this patient population and then, in a second step, compare it directly with the WTP of their treating dermato-oncologists. WTP was assessed in 125 patients with low-risk melanoma and additionally in 105 treating physicians, asking for the one-time and continuous payments they would be willing to make for a sustainable cure, both as absolute sums and as percentages of monthly income. The median WTP based on one-time payment was €10,000 for patients and €100,000 for physicians; relative numbers were 100% versus 300% of monthly income. For continuous monthly payments, WTP was €500 for patients and €1000 for physicians, relative numbers 25% and 50% of income, respectively. Even after controlling for income differences, there was a significantly higher WTP in physicians for all four questions. Compared to patients with chronic skin diseases such as vitiligo, rosacea, atopic eczema and psoriasis, patients with low-risk melanoma showed a significantly higher WTP. Our data suggest that there is a relevant burden of disease even in patients with low-risk tumors. Higher WTP of physicians underlines the prevalence of differences in disease perception.

24 Article Psycho-oncological care of melanoma patients in certified skin cancer centers. 2018

Meiss, Frank / Loquai, Carmen / Weis, Joachim / Giesler, Jürgen M / Reuter, Katrin / Nashan, Dorothée. ·Department of Dermatology and Venereology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. · Department of Dermatology, University Medical Center Mainz, Mainz, Germany. · Chair of Selfhelp Research, Comprehensive Cancer Center, University Medical Center Freiburg, Medical Faculty, University Freiburg, Freiburg, Germany. · Institute of Medical Biometry and Statistics, Section for Health Care Research and Rehabilitation Research, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany. · Group Practice for Psychotherapy and Psychooncology (PPPO), Stadtstraße 11, Freiburg, Germany. · Medical Center Dortmund, Department of Dermatology, Dortmund, Germany. ·J Dtsch Dermatol Ges · Pubmed #29750461.

ABSTRACT: BACKGROUND: The establishment und certification of skin cancer centers (SCCs) in compliance with requirements issued by the German Cancer Society play a key role for quality-assured treatment of skin cancer patients. These requirements also call for the implementation of a qualified psycho-oncology program. When planning the present study, we assumed site-specific differences in the way such programs were implemented at various SCCs. METHODS: In 2014, we conducted a cross-sectional survey of all SCCs certified at the time (n = 43), in which these institutions were asked to provide information on the structural and process quality of their psycho-oncology programs. RESULTS: Overall, 81.4 % of certified SCCs (n = 35) participated in the survey. Thirty-seven percent of SCCs directly employed personnel trained in psycho-oncology. Nearly all facilities offered information/counseling, crisis intervention, one-on-one discussions, and palliative/end-of-life care as part of their psycho-oncology program. Standardized screening tools were commonly used to evaluate patients' need for psycho-oncological support. Eighty-three percent of psycho-oncology programs primarily focused on inpatients. On average, 25.2 % of melanoma patients received psycho-oncological support. Ninety-seven percent of SCCs stated that the certification requirements had actually improved the psycho-oncological care of their patients. Seventy-one percent of SCCs reported to be satisfied with the implementation of the requirements. CONCLUSIONS: The certification of institutions as SCCs has led to the implementation of personnel, structural, and content requirements relating to psycho-oncological care. The majority of SCCs surveyed reported to be satisfied with the quality of care thus achieved.

25 Article Ipilimumab in metastatic melanoma patients with pre-existing autoimmune disorders. 2018

Kähler, Katharina C / Eigentler, Thomas K / Gesierich, Anja / Heinzerling, Lucie / Loquai, Carmen / Meier, Friedegund / Meiss, Frank / Pföhler, Claudia / Schlaak, Max / Terheyden, Patrick / Thoms, Kai M / Ziemer, Mirjana / Zimmer, Lisa / Gutzmer, Ralf / Anonymous2460938. ·Department of Dermatology, Campus Kiel, University Hospital Schleswig-Holstein (UKSH), Rosalind-Franklind-Str. 7, 24105, Kiel, Germany. kkaehler@dermatology.uni-kiel.de. · Department of Dermatology, Eberhard-Karls University of Tübingen, Tübingen, Germany. · Department of Dermatology, University Hospital Würzburg, Würzburg, Germany. · Department of Dermatology, University Hospital Erlangen, Erlangen, Germany. · Department of Dermatology, University Medical Center of Mainz, Mainz, Germany. · Department of Dermatology, University of Dresden, Dresden, Germany. · Department of Dermatology, Medical Center - Faculty of Medicine, University of Freiburg, Freiburg, Germany. · Department of Dermatology, Saarland University Medical School, Homburg/saar, Germany. · Department of Dermatology, Skin Cancer Center at Center of Integrated Oncology (CIO), University Hospital Cologne, Cologne-Bonn, Germany. · Department of Dermatology, Campus LübeckUniversity, Hospital (UKSH), Lübeck, Germany. · Department of Dermatology, University Medical Center Göttingen, Göttingen, Germany. · Department of Dermatology, University Hospital Leipzig, Leipzig, Germany. · Department of Dermatology, Essen, Germany and German Cancer Consortium (DKTK), University Duisburg-Essen, University Hospital Essen, Heidelberg, Germany. · Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hanover, Germany. ·Cancer Immunol Immunother · Pubmed #29487980.

ABSTRACT: BACKGROUND: Ipilimumab and programmed death (PD) 1-antibodies are effective treatment options in metastatic melanoma. The safety and efficacy of ipilimumab in patients with pre-existing autoimmune disorders (AD) has only been evaluated in a selected number of patients. METHODS: We performed a retrospective analysis in 14 German skin cancer centers for patients with metastatic melanoma and pre-existing AD treated with ipilimumab. RESULTS: 41 patients with 44 pre-existing AD were treated with ipilimumab (thyroiditis n = 15, rheumatoid n = 11, dermatologic n = 10, Crohn's disease/ulcerative colitis n = 3, neurological n = 2, sarcoidosis n = 2, pancreatitis n = 1). 3 out of 41 patients had two AD, 11 patients required immunosuppressants at the time of induction of ipilimumab. 12 patients (29.2%) experienced a flare of their pre-existing AD, mainly patients with rheumatoid or dermatologic diseases. Additional immune-related adverse events (irAEs) occurred in 12 patients (29.2%). In 23 patients (56%) neither a change of their AD nor additional irAEs were observed. Objective responses were seen in five patients (one complete remission, four partial remissions, 12.1%). CONCLUSION: This is the largest series of patients with pre-existing AD and treatment with ipilimumab reported. Flares of pre-existing AD were observed but manageable. Response rates and occurrence of new irAEs were comparable to previous trials. Thus, in this patient subgroup, ipilimumab can be a treatment option after a thorough discussion of pros and cons and taking severity and activity of the preexisting AD into account.

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