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Melanoma: HELP
Articles by Luc Thomas
Based on 66 articles published since 2008
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Between 2008 and 2019, Luc Thomas wrote the following 66 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Review Cobimetinib and vemurafenib for the treatment of melanoma. 2016

Boespflug, Amélie / Thomas, Luc. ·a Dermatology Unit , Hospices Civils de Lyon , Lyon , France. · b INSERM U1052 , Cancer Research Center of Lyon , Lyon , France. · c CNRS UMR 5286 , Cancer Research Center of Lyon , Lyon , France. · d Université Lyon1 , Department of Medecine , Lyon , France. ·Expert Opin Pharmacother · Pubmed #26999478.

ABSTRACT: INTRODUCTION: Cobimetinib combined with vemurafenib is a new approved MEK inhibitor for first line treatment of metastatic melanoma patients with BRAF V600 mutations. It improves tumor response rates and progression free survival compared to vemurafenib alone, while decreasing toxicities due to the paradoxical activation of the MAPK signaling pathway. AREAS COVERED: This review covers the pharmacology, efficacy, and toxicity data derived from clinical and preclinical studies on cobimetinib. It also reports ongoing trials evaluating cobimetinib to better understand future developments for this drug. EXPERT OPINION: The combination of cobimetinib and vemurafenib seems to be more toxic than the combination therapy dabrafenib and trametinib even if these four drugs have never been compared in a randomized trial. The future of this combination depends on its capacity to be combined simultaneously or sequentially with immune based therapies to improve the durability of responses.

2 Review [Prevention, early detection and monitoring of cutaneous melanoma]. 2016

Thomas, Luc. ·Service de dermatologie, Centre hospitalier Lyon Sud, Université Claude Bernard Lyon 1, Centre de recherche en cancérologie de Lyon INSERM U1052, CNRS UMR5286, 69495 Pierre Bénite Cedex, France. Electronic address: luc.thomas@chu-lyon.fr. ·Rev Infirm · Pubmed #26944640.

ABSTRACT: In parallel to the development of new treatments, considerable work remains to be done with regard on the one hand to early detection, and on the other, to the prevention of the main extrinsic risk factor, namely ultraviolet rays. Caregivers have an important educational role to play with patients and their families concerning these different aspects.

3 Review Special locations dermoscopy: facial, acral, and nail. 2013

Thomas, Luc / Phan, Alice / Pralong, Pauline / Poulalhon, Nicolas / Debarbieux, Sébastien / Dalle, Stéphane. ·Department of Dermatology, Centre Hospitalier Lyon Sud, Université Claude Bernard Lyon 1, Piere Bénite Cedex 69495, France. Electronic address: luc.thomas@chu-lyon.fr. ·Dermatol Clin · Pubmed #24075549.

ABSTRACT: Although dermoscopy reflects the anatomy, skin anatomy is different on facial and acral skin as well as in the nail unit. Malignant patterns on acral sites include the parallel ridge pattern and irregular diffuse pigmentation, whose presence should lead to a biopsy. Malignant patterns on the face include features of follicular invasion (signet-ring images, annular granular images, and rhomboidal structures) and atypical vessels. Malignant patterns on the nail unit include the micro-Hutchinson sign and irregular longitudinal lines.

4 Review A clinico-dermoscopic approach for skin cancer screening: recommendations involving a survey of the International Dermoscopy Society. 2013

Argenziano, Giuseppe / Giacomel, Jason / Zalaudek, Iris / Blum, Andreas / Braun, Ralph P / Cabo, Horacio / Halpern, Allan / Hofmann-Wellenhof, Rainer / Malvehy, Josep / Marghoob, Ashfaq A / Menzies, Scott / Moscarella, Elvira / Pellacani, Giovanni / Puig, Susana / Rabinovitz, Harold / Saida, Toshiaki / Seidenari, Stefania / Soyer, H Peter / Stolz, Wilhelm / Thomas, Luc / Kittler, Harald. ·Dermatology and Skin Cancer Unit, Arcispedale Santa Maria Nuova IRCCS, Viale Risorgimento 80, Reggio Emilia 42100, Italy. Electronic address: g.argenziano@gmail.com. ·Dermatol Clin · Pubmed #24075542.

ABSTRACT: Dermoscopy is useful for skin cancer screening, but a detailed approach is required that integrates this tool into a rational clinical work flow. To investigate clinician perceptions and behavior in approaching patients with skin tumors, a survey was launched by electronic mail through the International Dermoscopy Society. After 4 months, the responses were analyzed and significant findings calculated. Considering the current approach of study participants in examining patients for skin cancer, an up-to-date system of triage is presented in this review, which aims to promote an improved diagnostic accuracy and more timely management of skin malignancy.

5 Review Targeted therapies in metastatic melanoma: toward a clinical breakthrough? 2010

Julia, Fanny / Thomas, Luc / Dumontet, Charles / Dalle, Stéphane. ·Centre de Recherche en Cancérologie de Lyon,Faculté de Médecine Rockefeller, 8 Avenue Rockefeller, 69008 Lyon, France. ·Anticancer Agents Med Chem · Pubmed #21235437.

ABSTRACT: Metastatic melanoma is a very aggressive cancer. Dacarbazine has been considered as the standard therapy for decades. Due to a better understanding of melanoma cells signalling and immunological response, new targeted therapies are now proposed. The efficency of these new drugs needs to be confirmed by on larger clinical trials. Ipilimumab (anti-CTLA4 monoclonal antibody) and V600-E-B-raf inhibitor have shown encouraging results, while c-KIT and MEK inhibitors are currently under evaluation. These recently published data shed the light on melanoma management. We review here the latest development of these molecules and the current perspectives in the treatment of metastatic melanoma.

6 Clinical Trial Health-related quality of life impact of cobimetinib in combination with vemurafenib in patients with advanced or metastatic BRAF 2018

Dréno, Brigitte / Ascierto, Paolo A / Atkinson, Victoria / Liszkay, Gabriella / Maio, Michele / Mandalà, Mario / Demidov, Lev / Stroyakovskiy, Daniil / Thomas, Luc / de la Cruz-Merino, Luis / Dutriaux, Caroline / Garbe, Claus / Bartley, Karen / Karagiannis, Thomas / Chang, Ilsung / Rooney, Isabelle / Koralek, Daniel O / Larkin, James / McArthur, Grant A / Ribas, Antoni. ·Department of Dermato Cancerology, Nantes University, Nantes 44093, France. · Istituto Nazionale Tumori Fondazione G. Pascale, Naples 80131, Italy. · Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia. · National Institute of Oncology, Budapest 1122, Hungary. · Azienda Ospedaliera Universitaria Senese, Siena 53100, Italy. · Department of Oncology and Haematology, Papa Giovanni XXIII Hospital, Bergamo 24127, Italy. · N. N. Blokhin Russian Cancer Research Center, Moscow 115478, Russia. · Moscow City Oncology Hospital 62, Krasnogorsk 14301, Russia. · Service de Dermatologie, Centre Hospitalier Lyon Sud, Pierre-Bénite 69495, France. · Hospital Universitario Virgen Macarena, Seville 41009, Spain. · Hôpital Saint André, Bordeaux 33075, France. · Department of Dermatology, University of Tübingen, Tübingen 72074, Germany. · Genentech, Inc., South San Francisco, CA 94080, USA. · The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. · Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia. · University of Melbourne, Parkville, VIC 3052, Australia. · Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA. ·Br J Cancer · Pubmed #29438370.

ABSTRACT: BACKGROUND: In the coBRIM study, cobimetinib plus vemurafenib (C+V) significantly improved survival outcomes vs placebo and vemurafenib (P+V) in patients with advanced/metastatic BRAF METHODS: Patients completing the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline and ⩾1 time point thereafter constituted the analysis population. Change from baseline ⩾10 points was considered clinically meaningful. RESULTS: Mean baseline scores for all QLQ-C30 domains were similar between arms. Most on-treatment scores for QLQ-C30 domains were also comparable between arms. A transient deterioration in role function in cycle 1 day 15 (C1D15; -14.7 points) in the P+V arm and improvement in insomnia in the C+V arm at C2D15 (-12.4 points) was observed. Among patients who experienced a ⩾10-point change from baseline (responders), between-group differences were greatest for insomnia (16%), social functioning (10%), fatigue (9%) and pain (7%), all favouring C+V. Diarrhoea, photosensitivity reaction, pyrexia, and rash did not meaningfully affect global health status (GHS). Serous retinopathy was associated with a transient decrease in GHS at C1D15 assessment. CONCLUSIONS: In patients with advanced/metastatic BRAF

7 Clinical Trial Dabrafenib plus trametinib in patients with BRAF 2017

Davies, Michael A / Saiag, Philippe / Robert, Caroline / Grob, Jean-Jacques / Flaherty, Keith T / Arance, Ana / Chiarion-Sileni, Vanna / Thomas, Luc / Lesimple, Thierry / Mortier, Laurent / Moschos, Stergios J / Hogg, David / Márquez-Rodas, Iván / Del Vecchio, Michele / Lebbé, Céleste / Meyer, Nicolas / Zhang, Ying / Huang, Yingjie / Mookerjee, Bijoyesh / Long, Georgina V. ·Melanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: mdavies@mdanderson.org. · Service de Dermatologie Générale et Oncologique, Hôpital A Paré, Assistance Publique-Hôpitaux de Paris, Boulogne Billancourt, France; EA 4340, Université Versailles Saint-Quentin-en-Yvelines, Boulogne Billancourt, France. · Gustave Roussy, Département de Médecine Oncologique, Service de Dermatologie et Université Paris-Sud, Faculté de Médecine, Villejuif, France. · Service de Dermatologie, Centre Hospitalo-Universitaire Timone, Aix Marseille University, Marseille, France. · Developmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, Boston, MA, USA. · Department of Medical Oncology, Hospital Clinic of Barcelona, Carrer de Villarroel, Barcelona, Spain. · Melanoma and Oesophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Padova, Italy. · Service de Dermatologie, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France. · Oncologie Dermatologique, Centre Eugène Marquis, Rennes, France. · Clinique de Dermatologie, Unité d'Onco-Dermatologie, Le Centre Hospitalier Régional Universitaire de Lille, University Lille 2, Lille, France. · Melanoma Program, Medical Oncology, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA. · Clinical Cancer Research Unit, Princess Margaret Cancer Centre, Toronto, ON, Canada. · Servicio de Oncología Médica; Hospital General Universitario Gregorio Marañon, Madrid, Spain. · Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · APHP Dermatology and CIC Departments, INSERM U976, University Paris Diderot, Hôpital Saint Louis Paris, Paris, France. · Medical Oncology, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France. · Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. · Melanoma Institute Australia, The University of Sydney, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. ·Lancet Oncol · Pubmed #28592387.

ABSTRACT: BACKGROUND: Dabrafenib plus trametinib improves clinical outcomes in BRAF METHODS: This ongoing, multicentre, multicohort, open-label, phase 2 study evaluated oral dabrafenib (150 mg twice per day) plus oral trametinib (2 mg once per day) in four patient cohorts with melanoma brain metastases enrolled from 32 hospitals and institutions in Europe, North America, and Australia: (A) BRAF FINDINGS: Between Feb 28, 2014, and Aug 5, 2016, 125 patients were enrolled in the study: 76 patients in cohort A; 16 patients in cohort B; 16 patients in cohort C; and 17 patients in cohort D. At the data cutoff (Nov 28, 2016) after a median follow-up of 8·5 months (IQR 5·5-14·0), 44 (58%; 95% CI 46-69) of 76 patients in cohort A achieved an intracranial response. Intracranial response by investigator assessment was also achieved in nine (56%; 95% CI 30-80) of 16 patients in cohort B, seven (44%; 20-70) of 16 patients in cohort C, and ten (59%; 33-82) of 17 patients in cohort D. The most common serious adverse events related to study treatment were pyrexia for dabrafenib (eight [6%] of 125 patients) and decreased ejection fraction (five [4%]) for trametinib. The most common grade 3 or worse adverse events, regardless of study drug relationship, were pyrexia (four [3%] of 125) and headache (three [2%]). INTERPRETATION: Dabrafenib plus trametinib was active with a manageable safety profile in this melanoma population that was consistent with previous dabrafenib plus trametinib studies in patients with BRAF FUNDING: Novartis.

8 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.

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

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

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

10 Clinical Trial Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. 2016

Eggermont, Alexander M M / Chiarion-Sileni, Vanna / Grob, Jean-Jacques / Dummer, Reinhard / Wolchok, Jedd D / Schmidt, Henrik / Hamid, Omid / Robert, Caroline / Ascierto, Paolo A / Richards, Jon M / Lebbé, Céleste / Ferraresi, Virginia / Smylie, Michael / Weber, Jeffrey S / Maio, Michele / Bastholt, Lars / Mortier, Laurent / Thomas, Luc / Tahir, Saad / Hauschild, Axel / Hassel, Jessica C / Hodi, F Stephen / Taitt, Corina / de Pril, Veerle / de Schaetzen, Gaetan / Suciu, Stefan / Testori, Alessandro. ·From Gustave Roussy Cancer Campus Grand Paris, Villejuif (A.M.M.E., C.R.), Aix-Marseille University, Hôpital de La Timone, Marseille (J.-J.G.), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris (C.L.), University Lille, INSERM Unité-1189, Centre Hospitalier Universitaire (CHU) Lille, Service de Dermatologie, Lille (L.M.), and CHU Lyon, Lyon (L.T.) - all in France · the Oncology Institute of Veneto-Istituto di Ricovero e Cura a Carattere Scientifico, Padua (V.C.-S.), Istituto Nazionale Tumori Fondazione G. Pascale, Naples (P.A.A.), Istituti Fisioterapici Ospitalieri, Rome (V.F.), University Hospital of Siena, Istituto Toscano Tumori, Siena (M.M.), and the European Institute of Oncology, Milan (A.T.) - all in Italy · University of Zurich Hospital, Zurich, Switzerland (R.D.) · Memorial Sloan Kettering Cancer Center, New York (J.D.W.) · Aarhus University Hospital, Aarhus (H.S.), and Odense University Hospital, Odense (L.B.) - both in Denmark · the Angeles Clinic and Research Institute, Los Angeles (O.H.) · Oncology Specialists, Park Ridge, IL (J.M.R.) · Cross Cancer Institute, Edmonton, AB, Canada (M.S.) · H. Lee Moffitt Cancer Center, Tampa, FL (J.S.W.) · Broomfield Hospital, Chelmsford, United Kingdom (S.T.) · Universitätsklinikum Schleswig-Holstein, Kiel (A.H.), and University Hospital Heidelberg, Heidelberg (J.C.H.) - both in Germany · Dana-Farber Cancer Institute, Boston (F.S.H.) · Bristol-Myers Squibb, Princeton, NJ (C.T., V.P.) · and the European Organization for Research and Treatment of Cancer, Brussels (G.S., S.S.). ·N Engl J Med · Pubmed #27717298.

ABSTRACT: BACKGROUND: On the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma. METHODS: After patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred. Recurrence-free survival was the primary end point. Secondary end points included overall survival, distant metastasis-free survival, and safety. RESULTS: At a median follow-up of 5.3 years, the 5-year rate of recurrence-free survival was 40.8% in the ipilimumab group, as compared with 30.3% in the placebo group (hazard ratio for recurrence or death, 0.76; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). The rate of overall survival at 5 years was 65.4% in the ipilimumab group, as compared with 54.4% in the placebo group (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P=0.001). The rate of distant metastasis-free survival at 5 years was 48.3% in the ipilimumab group, as compared with 38.9% in the placebo group (hazard ratio for death or distant metastasis, 0.76; 95.8% CI, 0.64 to 0.92; P=0.002). Adverse events of grade 3 or 4 occurred in 54.1% of the patients in the ipilimumab group and in 26.2% of those in the placebo group. Immune-related adverse events of grade 3 or 4 occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. In the ipilimumab group, 5 patients (1.1%) died owing to immune-related adverse events. CONCLUSIONS: As adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis-free survival than placebo. There were more immune-related adverse events with ipilimumab than with placebo. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00636168 , and EudraCT number, 2007-001974-10 .).

11 Clinical Trial Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. 2016

Ascierto, Paolo A / McArthur, Grant A / Dréno, Brigitte / Atkinson, Victoria / Liszkay, Gabrielle / Di Giacomo, Anna Maria / Mandalà, Mario / Demidov, Lev / Stroyakovskiy, Daniil / Thomas, Luc / de la Cruz-Merino, Luis / Dutriaux, Caroline / Garbe, Claus / Yan, Yibing / Wongchenko, Matthew / Chang, Ilsung / Hsu, Jessie J / Koralek, Daniel O / Rooney, Isabelle / Ribas, Antoni / Larkin, James. ·Istituto Nazionale Tumori Fondazione G Pascale, Naples, Italy. · Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; University of Melbourne, Parkville, VIC, Australia. Electronic address: grant.mcarthur@petermac.org. · Nantes University, Nantes, France. · Princess Alexandra Hospital, Woolloongabba, QLD, Australia. · National Institute of Oncology, Budapest, Hungary. · Azienda Ospedaliera Universitaria Senese, Siena, Italy. · Papa Giovanni XXIII Hospital, Bergamo, Italy. · N N Blokhin Russian Cancer Research Center, Moscow, Russia. · Moscow City Oncology Hospital 62, Krasnogorsk, Russia. · Centre Hospitalier Lyon Sud, Lyon 1 University, Lyon, France; Lyons Cancer Research Center, Lyon, France. · Hospital Universitario Virgen Macarena, Seville, Spain. · Hôpital Saint André, Bordeaux, France. · University of Tübingen, Tübingen, Germany. · Genentech Inc, South San Francisco, CA, USA. · Jonsson Comprehensive Cancer Center at University of California, Los Angeles, Los Angeles, CA, USA. · Royal Marsden NHS Foundation Trust, London, UK. ·Lancet Oncol · Pubmed #27480103.

ABSTRACT: BACKGROUND: The combination of cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAF(V600)-mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies. METHODS: In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAF(V600) mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01689519, and is ongoing but no longer recruiting participants. FINDINGS: Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14·2 months (IQR 8·5-17·3), the updated investigator-assessed median progression-free survival was 12·3 months (95% CI 9·5-13·4) for cobimetinib and vemurafenib versus 7·2 months (5·6-7·5) for placebo and vemurafenib (HR 0·58 [95% CI 0·46-0·72], p<0·0001). The final analysis for overall survival occurred when 255 (52%) patients had died (Aug 28, 2015). Median overall survival was 22·3 months (95% CI 20·3-not estimable) for cobimetinib and vemurafenib versus 17·4 months (95% CI 15·0-19·8) for placebo and vemurafenib (HR 0·70, 95% CI 0·55-0·90; p=0·005). The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. The most common grade 3-4 adverse events occurring at a higher frequency in patients in the cobimetinib and vemurafenib group compared with the vemurafenib group were γ-glutamyl transferase increase (36 [15%] in the cobimetinib and vemurafenib group vs 25 [10%] in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 [12%] vs one [<1%]), and alanine transaminase increase (28 [11%] vs 15 [6%]). Serious adverse events occurred in 92 patients (37%) in the cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients [2%]) and dehydration (five patients [2%]) were the most common serious adverse events reported in the cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group. INTERPRETATION: These data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAF(V600)-mutant melanoma. FUNDING: F Hoffmann-La Roche-Genentech.

12 Clinical Trial Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. 2015

Weber, Jeffrey S / D'Angelo, Sandra P / Minor, David / Hodi, F Stephen / Gutzmer, Ralf / Neyns, Bart / Hoeller, Christoph / Khushalani, Nikhil I / Miller, Wilson H / Lao, Christopher D / Linette, Gerald P / Thomas, Luc / Lorigan, Paul / Grossmann, Kenneth F / Hassel, Jessica C / Maio, Michele / Sznol, Mario / Ascierto, Paolo A / Mohr, Peter / Chmielowski, Bartosz / Bryce, Alan / Svane, Inge M / Grob, Jean-Jacques / Krackhardt, Angela M / Horak, Christine / Lambert, Alexandre / Yang, Arvin S / Larkin, James. ·Moffitt Cancer Center, Tampa, FL, USA. Electronic address: jeffrey.weber@moffitt.org. · Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. · California Pacific Center for Melanoma Research, San Francisco, CA, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Medizinische Hochschule Hannover, Hannover, Germany. · Universitair Ziekenhuis Brussel, Brussels, Belgium. · Medical University of Vienna, Vienna, Austria. · Roswell Park Cancer Institute, Buffalo, NY, USA. · Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada. · University of Michigan, Ann Arbor, MI, USA. · Washington University, St Louis, MO, USA. · Centre Hospitalier Universitaire de Lyon, Lyon, France. · Christie Hospital, Manchester, UK. · Huntsman Cancer Institute, Salt Lake City, UT, USA. · German Cancer Research Centre University Hospital, Heidelberg, Germany. · Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. · Yale Cancer Center, New Haven, CT, USA. · Istituto Nazionale Tumori Fondazione G Pascale, Naples, Italy. · Elbe Kliniken Buxtehude, Buxtehude, Germany. · Department of Medicine, University of California, Los Angeles, CA, USA. · Department of Medicine, Mayo Clinic, Scottsdale, AZ, USA. · Department of Oncology, Herlev Hospital, Copenhagen, Denmark. · Aix-Marseille University, Hopital de la Timone, Marseille, France. · Technische Universität München School of Medicine, II Medical Department, Munich, Germany. · Bristol-Myers Squibb, Princeton, NJ, USA. · Bristol-Myers Squibb, Braine-I'Alleud, Belgium. · Royal Marsden Hospital, London, UK. ·Lancet Oncol · Pubmed #25795410.

ABSTRACT: BACKGROUND: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries. Eligible patients were 18 years or older, had unresectable or metastatic melanoma, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAF(V 600) mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m(2) every 3 weeks or paclitaxel 175 mg/m(2) combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used permuted blocks (block size of six) within each stratum. Primary endpoints were the proportion of patients who had an objective response and overall survival. Treatment was given open-label, but those doing tumour assessments were masked to treatment assignment. We assessed objective responses per-protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. The trial is closed and this is the first interim analysis, reporting the objective response primary endpoint. This study is registered with ClinicalTrials.gov, number NCT01721746. FINDINGS: Between Dec 21, 2012, and Jan 10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab and 133 to ICC. Confirmed objective responses were reported in 38 (31·7%, 95% CI 23·5-40·8) of the first 120 patients in the nivolumab group versus five (10·6%, 3·5-23·1) of 47 patients in the ICC group. Grade 3-4 adverse events related to nivolumab included increased lipase (three [1%] of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two [1%] each); for ICC, these included neutropenia (14 [14%] of 102), thrombocytopenia (six [6%]), and anaemia (five [5%]). We noted grade 3-4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths occurred. INTERPRETATION: Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need. FUNDING: Bristol-Myers Squibb.

13 Clinical Trial Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. 2015

Maio, Michele / Grob, Jean-Jacques / Aamdal, Steinar / Bondarenko, Igor / Robert, Caroline / Thomas, Luc / Garbe, Claus / Chiarion-Sileni, Vanna / Testori, Alessandro / Chen, Tai-Tsang / Tschaika, Marina / Wolchok, Jedd D. ·Michele Maio, University Hospital of Siena, Siena · Vanna Chiarion-Sileni, Veneto Oncology Institute-Istituto Di Ricovero e Cura a Carattere Scientifico, Padova · Alessandro Testori, Istituto Europeo di Oncologia, Milan, Italy · Jean-Jacques Grob, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Hôpital Timone, Marseille · Luc Thomas, Lyon 1 University, Centre Hospitalier Lyon Sud, Pierre Bénite · Caroline Robert, Institute Gustave Roussy, Villejuif, France · Steinar Aamdal, Oslo University Hospital and Radium Hospital, Oslo, Norway · Igor Bondarenko, Dnepropetrovsk State Medical Academy, Dnepropetrovsk, Ukraine · Claus Garbe, University Medical Center, Tübingen, Germany · Tai-Tsang Chen and Marina Tschaika, Bristol-Myers Squibb, Wallingford, CT · and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY. ·J Clin Oncol · Pubmed #25713437.

ABSTRACT: PURPOSE: There is evidence from nonrandomized studies that a proportion of ipilimumab-treated patients with advanced melanoma experience long-term survival. To demonstrate a long-term survival benefit with ipilimumab, we evaluated the 5-year survival rates of patients treated in a randomized, controlled phase III trial. PATIENTS AND METHODS: A milestone survival analysis was conducted to capture the 5-year survival rate of treatment-naive patients with advanced melanoma who received ipilimumab in a phase III trial. Patients were randomly assigned 1:1 to receive ipilimumab at 10 mg/kg plus dacarbazine (n = 250) or placebo plus dacarbazine (n = 252) at weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22. Eligible patients could receive maintenance ipilimumab or placebo every 12 weeks beginning at week 24. A safety analysis was conducted on patients who survived at least 5 years and continued to receive ipilimumab as maintenance therapy. RESULTS: The 5-year survival rate was 18.2% (95% CI, 13.6% to 23.4%) for patients treated with ipilimumab plus dacarbazine versus 8.8% (95% CI, 5.7% to 12.8%) for patients treated with placebo plus dacarbazine (P = .002). A plateau in the survival curve began at approximately 3 years. In patients who survived at least 5 years and continued to receive ipilimumab, grade 3 or 4 immune-related adverse events were observed exclusively in the skin. CONCLUSION: The additional survival benefit of ipilimumab plus dacarbazine is maintained with twice as many patients alive at 5 years compared with those who initially received placebo plus dacarbazine. These results demonstrate a durable survival benefit with ipilimumab in advanced melanoma.

14 Clinical Trial Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. 2014

Larkin, James / Ascierto, Paolo A / Dréno, Brigitte / Atkinson, Victoria / Liszkay, Gabriella / Maio, Michele / Mandalà, Mario / Demidov, Lev / Stroyakovskiy, Daniil / Thomas, Luc / de la Cruz-Merino, Luis / Dutriaux, Caroline / Garbe, Claus / Sovak, Mika A / Chang, Ilsung / Choong, Nicholas / Hack, Stephen P / McArthur, Grant A / Ribas, Antoni. ·From Royal Marsden Hospital, London (J.L.) · Istituto Nazionale Tumori Fondazione G. Pascale, Naples (P.A.A.), Azienda Ospedaliera Universitaria Senese, Siena (M. Maio), and Papa Giovanni XXIII Hospital, Bergamo (M. Mandalà) - all in Italy · Hôtel Dieu Place Alexis Ricordeau, Nantes (B.D.), Centre Hospitalier Lyon Sud, Pierre-Bénite (L.T.), and Hôpital Saint André, Bordeaux (C.D.) - all in France · Princess Alexandra Hospital, Woolloongabba, QLD (V.A.), and Peter MacCallum Cancer Centre, Melbourne, VIC (G.A.M.) - both in Australia · National Institute of Oncology, Budapest, Hungary (G.L.) · N.N. Blokhin Russian Cancer Research Center, Moscow (L.D.), and Moscow City Oncology Hospital 62, Krasnogorsk (D.S.) - both in Russia · Hospital Universitario Virgen Macarena, Seville, Spain (L.C.-M.) · University of Tübingen, Tübingen, Germany (C.G.) · Genentech, South San Francisco, CA (M.A.S., I.C., N.C., S.P.H.) · and Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, Los Angeles (A.R.). ·N Engl J Med · Pubmed #25265494.

ABSTRACT: BACKGROUND: The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. METHODS: We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. RESULTS: The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. CONCLUSIONS: The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).

15 Clinical Trial Melanoma patients under vemurafenib: prospective follow-up of melanocytic lesions by digital dermoscopy. 2014

Perier-Muzet, Marie / Thomas, Luc / Poulalhon, Nicolas / Debarbieux, Sébastien / Bringuier, Pierre-Paul / Duru, Gerard / Depaepe, Lauriane / Balme, Brigitte / Dalle, Stephane. ·Department of Dermatology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Lyon, France; Université Claude Bernard Lyon 1, Lyon, France. · Department of Dermatology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Lyon, France. · Université Claude Bernard Lyon 1, Lyon, France; Cancer Research Center of Lyon, Lyon, France; Unit of Pathology, Centre Hospitalier Lyon-Sud, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France. · Université Claude Bernard Lyon 1, Lyon, France. · Unit of Pathology, Centre Hospitalier Lyon-Sud, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France. · Department of Dermatology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Lyon, France; Université Claude Bernard Lyon 1, Lyon, France; Cancer Research Center of Lyon, Lyon, France. Electronic address: stephane.dalle@chu-lyon.fr. ·J Invest Dermatol · Pubmed #24304815.

ABSTRACT: Second primary melanomas (SPMs) induced by vemurafenib have been recently described. The aim of this study was to define the dermoscopical signs of melanoma in this context. Patients underwent a total body examination before receiving vemurafenib. Each single melanocytic lesion was registered before therapy by digital dermoscopy (DD), and then repeated monthly until therapy disruption. Forty-two patients were included, the mean duration of follow-up was 6.7 months, and a mean number of 51 lesions per patients were captured and followed. A total number of 2,155 lesions were recorded, of which 56.1% presented at least one change during the study. More common changes concerned the color of the lesions (up to 15%) and appearance or disappearance of globules (14.6%). Thirty-six of the melanocytic lesions were surgically excised, 21 were classified as a nevus, 1 was a lentigo, and 14 as a second new primary melanoma (occurring in 21% of our patients). DD allowed us to excise only 36/2,155 (1.6%) of the lesions and permitted us to detect 14 SPM in the 42 patients with a highly efficient malignant/benign ratio of 63.6%. Although vemurafenib is now tested in an adjuvant setting DD should be systematically used in order to accurately detect SPM and reduce the number of unnecessary excisions.

16 Clinical Trial Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. 2011

Robert, Caroline / Thomas, Luc / Bondarenko, Igor / O'Day, Steven / Weber, Jeffrey / Garbe, Claus / Lebbe, Celeste / Baurain, Jean-François / Testori, Alessandro / Grob, Jean-Jacques / Davidson, Neville / Richards, Jon / Maio, Michele / Hauschild, Axel / Miller, Wilson H / Gascon, Pere / Lotem, Michal / Harmankaya, Kaan / Ibrahim, Ramy / Francis, Stephen / Chen, Tai-Tsang / Humphrey, Rachel / Hoos, Axel / Wolchok, Jedd D. ·Institute Gustave, Roussy, Villejuif, France. ·N Engl J Med · Pubmed #21639810.

ABSTRACT: BACKGROUND: Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma. METHODS: We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival. RESULTS: Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab-dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab-dacarbazine group. CONCLUSIONS: Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.).

17 Clinical Trial Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. 2010

Wolchok, Jedd D / Neyns, Bart / Linette, Gerald / Negrier, Sylvie / Lutzky, Jose / Thomas, Luc / Waterfield, William / Schadendorf, Dirk / Smylie, Michael / Guthrie, Troy / Grob, Jean-Jacques / Chesney, Jason / Chin, Kevin / Chen, Kun / Hoos, Axel / O'Day, Steven J / Lebbé, Celeste. ·Ludwig Center for Cancer Immunotherapy, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. wolchokj@mskcc.org ·Lancet Oncol · Pubmed #20004617.

ABSTRACT: BACKGROUND: Ipilimumab is a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 and has shown promising activity in advanced melanoma. We aimed to ascertain the antitumour efficacy of ipilimumab in patients with advanced melanoma. METHODS: We undertook a randomised, double-blind, phase 2 trial in 66 centres from 12 countries. 217 patients with previously treated stage III (unresectable) or stage IV melanoma were randomly assigned a fixed dose of ipilimumab of either 10 mg/kg (n=73), 3 mg/kg (n=72), or 0.3 mg/kg (n=72) every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. Randomisation was done with a permuted block procedure, stratified on the basis of type of previous treatment. The primary endpoint was best overall response rate (the proportion of patients with a complete or partial response, according to modified WHO criteria). Efficacy analyses were done by intention to treat, whereas safety analyses included patients who received at least one dose of ipilimumab. This study is registered with ClinicalTrials.gov, number NCT00289640. FINDINGS: The best overall response rate was 11.1% (95% CI 4.9-20.7) for 10 mg/kg, 4.2% (0.9-11.7) for 3 mg/kg, and 0% (0.0-4.9) for 0.3 mg/kg (p=0.0015; trend test). Immune-related adverse events of any grade arose in 50 of 71, 46 of 71, and 19 of 72 patients at doses of 10 mg/kg, 3 mg/kg, and 0.3 mg/kg, respectively; the most common grade 3-4 adverse events were gastrointestinal immune-related events (11 in the 10 mg/kg group, two in the 3 mg/kg group, none in the 0.3 mg/kg group) and diarrhoea (ten in the 10 mg/kg group, one in the 3 mg/kg group, none in the 0.3 mg/kg group). INTERPRETATION: Ipilimumab elicited a dose-dependent effect on efficacy and safety measures in pretreated patients with advanced melanoma, lending support to further studies at a dose of 10 mg/kg. FUNDING: Bristol-Myers Squibb.

18 Article The impact of patient characteristics and disease-specific factors on first-line treatment decisions for BRAF-mutated melanoma: results from a European expert panel study. 2018

Ascierto, Paolo A / Bastholt, Lars / Ferrucci, Pier F / Hansson, Johan / Márquez Rodas, Iván / Payne, Miranda / Robert, Caroline / Thomas, Luc / Utikal, Jochen S / Wolter, Pascal / Kudlac, Amber / Tuson, Harriet / McKendrick, Jan. ·Istituto Nazionale Tumori Fondazione G. Pascale, Naples. · Odense University Hospital, Odense, Denmark. · European Institute of Oncology, Milan, Italy. · Karolinska Institutet, Stockholm, Sweden. · Hospital General Universitario Gregorio Marañon, Madrid, Spain. · Oxford University Hospitals NHS Foundation Trust, Oxford. · Gustave-Roussy and Paris-Sud University, Villejuif. · Lyon 1 University, Lyon Cancer Research Center, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France. · German Cancer Research Center (DKFZ) and Heidelberg University, Mannheim, Germany. · CHR Verviers East Belgium, Verviers, Belgium. · PRMA Consulting Ltd, Fleet, UK. ·Melanoma Res · Pubmed #29750751.

ABSTRACT: Treatment decisions for advanced melanoma are increasingly complex and guidelines provide limited advice on how to choose between immunotherapy and targeted therapy for first-line treatment. A Delphi study was carried out to understand which patient characteristics and disease-related factors inform clinicians' choices of first-line treatment for BRAF-mutated melanoma. Twelve European melanoma specialists experienced in using immunotherapies and targeted agents participated in a double-blind two-phase Delphi study. In phase 1, participants completed a questionnaire developed after reviewing patient characteristics and disease-related factors reported in trials, clinical guidelines, and health technology assessments. Phase 2 was an expert panel meeting to explore outstanding issues from phase 1 and seek consensus, defined as 80% agreement. Twenty patient-related and disease-related characteristics were considered. There was consensus that tumor burden (83% of clinicians) and disease tempo (83%) are very or extremely important factors when selecting first-line treatment. Several components were deemed important when assessing tumor burden: brain metastases (82% of clinicians) and location of metastases (89%). There was consensus that disease tempo can be quantified in clinical practice, but not on a formal classification applicable to all patients. Lactate dehydrogenase level is a component of both tumor burden and disease tempo; all clinicians considered lactate dehydrogenase important when choosing first-line treatment. The majority (92%) did not routinely test programmed death ligand-1 status in patients with melanoma. Clinicians agreed that choosing a first-line treatment for advanced melanoma is a complex, multifactorial process and that clinical judgment remains the most important element of decision-making until research can provide clinicians with better scientific parameters and tools for first-line decision-making.

19 Article Truncating mutations of TP53AIP1 gene predispose to cutaneous melanoma. 2018

Benfodda, Meriem / Gazal, Steven / Descamps, Vincent / Basset-Seguin, Nicole / Deschamps, Lydia / Thomas, Luc / Lebbe, Celeste / Saiag, Philippe / Zanetti, Roberto / Sacchetto, Lidia / Chiorino, Giovanna / Scatolini, Maria / Grandchamp, Bernard / Bensussan, Armand / Soufir, Nadem. ·INSERM U976, Centre de Recherche sur la Peau, Hôpital Saint Louis, 75010, Paris, France. · Département de Génétique, Hôpital Bichat Claude Bernard, APHP, 75018, Paris, France. · Université Paris Diderot, Sorbonne Paris Cité, 75005, Paris, France. · UMR S 738, Faculté de Médecine Xavier Bichat, 75018, Paris, France. · Département de Dermatologie, Hôpital Bichat Claude Bernard, APHP, 75018, Paris, France. · Département de Dermatologie, Hôpital Saint Louis, APHP, 75010, Paris, France. · Département d'Anatomie Pathologique, Hôpital Bichat Claude Bernard, APHP, 75018, Paris, France. · Département de Dermatologie, Hôpital de l'Hôtel-Dieu, 69002, Lyon, France. · Département de Dermatologie, Hôpital Ambroise Paré, APHP, 92100, Boulogne Billancourt, France. · Centre for Cancer Prevention, Piedmont Cancer Registry-CPO, Torino, Italy. · Politecnico di Torino, Torino, Italy. · Università degli Studi di Torino, Torino, Italy. · Department of Mathematical Sciences, Politecnico di Torino, Torino, Italy. · Laboratory of Molecular Oncology, Fondazione Edo ed Elvo Tempia, Biella, Italy. ·Genes Chromosomes Cancer · Pubmed #29359367.

ABSTRACT: Genetic predisposition to cutaneous malignant melanoma (CMM) involves highly penetrant predisposing genes and low and intermediate penetrant predisposing alleles. However, the missing heritability in (CMM) is still high. For such and in order to identify new genetic factors for CMM, we conducted an exome sequencing study in high-risk CMM patients. Two rounds of exome sequencing were successively performed in 33 and 27 high-risk patients. We focused on genes carrying rare nonsense, frameshift, and splice variants (allelic frequency <1%) that were present in both series of exomes. An extension study was then conducted in a large cohort (1 079 CMM patients and 1 230 Caucasian ethnically matched healthy controls), and the inactivating variants frequency was compared between groups using two-sided Fisher exact test. Two TP53AIP1 truncating mutations were identified in four patients: a frameshift c.63_64insG, p.Q22Afs*81 in two patients from the same family and in the proband of a second family; and a nonsense mutation c.95 C > A, p.Ser32Stop in a patient with multiple CMMs. In all patients, TP53AIP1 truncating variants were strongly associated with CMM risk (two-sided Fisher exact test = 0.004, OR = 3.3[1.3-8.5]). Additionally, we showed that TP53AIP1 mRNA was strongly down-regulated throughout different phases of melanoma progression. TP53AIP1 gene is a TP53 target which plays a key role by inducting apoptosis in response to UV-induced DNA damage. Constitutional mutations of TP53AIP1 had previously been involved in susceptibility to prostate cancer. Our results show that constitutional truncating TP53AIP1 mutations predispose to CMM in the French population. Replication studies in other populations should be performed.

20 Article Association of Immunotherapy With Overall Survival in Elderly Patients With Melanoma. 2018

Perier-Muzet, Marie / Gatt, Elodie / Péron, Julien / Falandry, Claire / Amini-Adlé, Mona / Thomas, Luc / Dalle, Stephane / Boespflug, Amelie. ·Dermatology Unit, Lyon Sud University Hospital, Pierre Bénite, France. · Cancer Research Center of Lyon, Claude Bernard Lyon-1 University, INSERM 1052, CNRS 5286, Centre Leon Berard, Lyon, France. · Medical Oncology Department, Lyon Sud University Hospital, Pierre Bénite, France. · ImmuCare (Immunology Cancer Research) Institut de Cancérologie des Hospices Civils de Lyon, Lyon, France. · Evolutionary Biology and Biometry Laboratory, Université Lyon 1, CNRS UMR 5558, Villeurbanne, France. · Geriatrics Unit, Lyon Sud University Hospital, Pierre Bénite, France. · Laboratoire CarMeN INSERM U.1060/Université Lyon1/INRA 1397/INSA Lyon/Hospices Civils de Lyon, Faculté de Médecine Lyon Sud, Oullins, France. ·JAMA Dermatol · Pubmed #29214290.

ABSTRACT: Importance: Melanoma treatment has been revolutionized with the development of immune-based therapies that offer durable clinical responses in a subset of patients. Clinical outcomes after treatment by immunotherapy can be influenced by the host's immune system. The immune system is modified with age by age-related immune dysfunction. Objective: To evaluate if age influences clinical outcome and immune adverse events in patients treated by immunotherapy for metastatic melanoma. Design, Setting, and Participants: This was a single-center cohort analysis in patients treated with immunotherapy for metastatic melanoma between January 2007 and February 2016, in the Lyon Sud Hospital, France. A total of 92 patients with metastatic melanoma treated with ipilimumab, nivolumab, or pembrolizumab were retrospectively analyzed. Main Outcomes and Measures: Overall survival, progression-free survival, and immune-related adverse events were evaluated for each treatment line according to the patients' age. Results: A total of 92 patients were eligible and included in this study for a total of 120 lines of treatment. Fifty-four patients were included in the cohort that was 65 years or younger (24 [44%] were female; mean [SD] age, 48.1 [12.5] years), and 38 patients were included in the cohort that was older than 65 years (12 [34%] were female; mean [SD] age, 74.8 [6.9] years). Mean follow-up duration starting at treatment initiation was 12.5 months. Patients older than 65 years treated with immunotherapy had a better mean progression-free survival (4.8 vs 3.4 months; P = .04) and overall survival (not reached vs 10.1 months; P = .009) than younger patients in univariate analysis, and after adjusting on prognosis covariates. This was particularly true with patients treated with anti-programmed cell death protein 1. Common immune-related adverse effects were similar in both cohorts. Conclusions and Relevance: Age might be associated with a better clinical outcome after treatment with immunotherapy in the real-life setting. In our cohort, older patients did not have more immune-related adverse events. Further studies are warranted to confirm our results and describe the underlying mechanisms involved.

21 Article Association of subungual melanoma and subungual squamous cell carcinoma: A case series. 2018

Boespflug, Amélie / Debarbieux, Sébastien / Depaepe, Lauriane / Chouvet, Brigitte / Maucort-Boulch, Delphine / Dalle, Stéphane / Balme, Brigitte / Thomas, Luc. ·Dermatology Unit, Hospices Civils de Lyon, Lyon, France; Department of Medicine, Hospices Civils de Lyon, Lyon, France; Cancer Research Center of Lyon INSERM1052, Lyon, France. · Dermatology Unit, Hospices Civils de Lyon, Lyon, France. · Pathology Unit, Hospices Civils de Lyon, Lyon, France. · Biostatistique-Santé Team, Laboratoire de Biométrie et Biologie Evolutive, CNRS UMR 5558, Claude Bernard Lyon-1 University, Villeurbanne, France. · Dermatology Unit, Hospices Civils de Lyon, Lyon, France; Department of Medicine, Hospices Civils de Lyon, Lyon, France; Cancer Research Center of Lyon INSERM1052, Lyon, France. Electronic address: luc.thomas@chu-lyon.fr. ·J Am Acad Dermatol · Pubmed #28947295.

ABSTRACT: BACKGROUND: Subungual squamous cell carcinoma (SSCC) and subungual melanoma (SUM) are rare tumors. Several case reports of association of SSCC with SUM (SSCC-SUM) have been published. OBJECTIVE: We sought to document the clinical, dermoscopic, and histologic features in a case series of SSCC-SUMs and describe their relative frequency compared with those of SSCC and SUM. METHODS: All patients who underwent surgical exploration of the nail apparatus with a dermatopathologic examination from 2012 to 2015 were reviewed retrospectively to identify all cases of SSCC, SUM, and SSCC-SUM. For patients with SSCC-SUM, clinical characteristics were obtained from electronic medical records. All histologic specimens were reviewed by 3 dermatopathologists. RESULTS: The medical records of 456 patients were reviewed. SSCC was diagnosed in 78 (17%), SUM was diagnosed in 63 (14%), and SSCC-SUM was diagnosed in 9. Patients with SSCC-SUM accounted for 11% of those with a diagnosis of SSCC (9 of 78) and 14% of those with a diagnosis of SUM (9 of 63). LIMITATIONS: This was a single-institution retrospective study. CONCLUSION: The association of SSCC and SUM is relatively frequent in patients with SUM and warrants further consideration to understand the underlying mechanisms involved.

22 Article Dermoscopy Improves the Diagnostic Accuracy of Melanomas Clinically Resembling Seborrheic Keratosis: Cross-Sectional Study of the Ability to Detect Seborrheic Keratosis-Like Melanomas by a Group of Dermatologists with Varying Degrees of Experience. 2017

Carrera, Cristina / Segura, Sonia / Aguilera, Paula / Takigami, Carol Midori / Gomes, Antonio / Barreiro, Alicia / Scalvenzi, Massimiliano / Longo, Caterina / Cavicchini, Stefano / Thomas, Luc / Malvehy, Josep / Puig, Susana / Zalaudek, Iris. ·Melanoma Unit, Department of Dermatology, Hospital Clínic de Barcelona, IDIBAPS, Barcelona University, Barcelona, Spain. · Centre for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain. · Department of Dermatology, Hospital del Mar, Institut Hospital del Mar d'Investigacions Mèdiques, Universitat Autònoma de Barcelona, Barcelona, Spain. · Department of Dermatology, University of Naples Federico II, Naples, Italy. · Dermatology and Skin Cancer Unit, Arcispedale Santa Maria Nuova IRCCS, Department of Dermatology, University of Modena and Reggio Emilia, Modena, Italy. · UO Dermatologia, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy. · Department of Dermatology, Lyons Cancer Research Center, INSERM U1052, CNRS UMR5286, Centre Hospitalier Lyon-Sud, Lyon 1 University, Lyon, France. · Dermatology Clinic, Hospital Maggiore, University of Trieste, Trieste, Italy. ·Dermatology · Pubmed #29502116.

ABSTRACT: BACKGROUND: Malignant melanomas mimicking seborrheic keratosis (SK-like MMs) carry the risk of delayed diagnosis and inadequate treatment. The value of dermoscopy to improve the correct detection of these mimickers has not been previously studied. OBJECTIVE: To evaluate the diagnostic accuracy of clinically SK-like MMs with and without dermoscopy. METHODS: Clinical and dermoscopic images of histopathologically proven SK-like MMs (n = 134) intermingled with other melanomas and benign tumors were randomly presented to clinicians with different levels of experience, blinded to the diagnosis and goal of the study. Each participant classified each lesion as melanoma or benign tumor. The clinical and clinical-dermoscopic diagnostic accuracies were measured separately. RESULTS: Overall, 54 participants with a mean clinical experience of 15.8 years (SD 11.8) evaluated 231 tumors. Almost 40% of SK-like melanomas were clinically misclassified as benign tumor. Dermoscopy improved diagnostic accuracy for all participants, independently of experience, from 60.9 to 68.1% (p < 0.001), mostly due to a significant increase in the sensitivity (clinical 61.9% vs. dermoscopic 74.5%) (p < 0.001). Dermoscopy did not significantly affect specificity among the experienced participants (≥6 years of experience) compared to clinical examination (61.1 vs. 59.6%, respectively); in contrast, dermoscopy was associated with a decrease in specificity compared to clinical diagnosis among novice participants (< 6 years) (45.6 vs. 61.1%, respectively; p = 0.02). CONCLUSION: Melanomas can be clinically indistinguishable from SKs despite being evaluated by expert dermatologists. Dermoscopy, even in nonexpert hands, significantly improves their recognition.

23 Article Pooled Analysis Safety Profile of Nivolumab and Ipilimumab Combination Therapy in Patients With Advanced Melanoma. 2017

Sznol, Mario / Ferrucci, Pier Francesco / Hogg, David / Atkins, Michael B / Wolter, Pascal / Guidoboni, Massimo / Lebbé, Celeste / Kirkwood, John M / Schachter, Jacob / Daniels, Gregory A / Hassel, Jessica / Cebon, Jonathan / Gerritsen, Winald / Atkinson, Victoria / Thomas, Luc / McCaffrey, John / Power, Derek / Walker, Dana / Bhore, Rafia / Jiang, Joel / Hodi, F Stephen / Wolchok, Jedd D. ·Mario Sznol, Yale Comprehensive Cancer Center, New Haven, CT · Pier Francesco Ferrucci, Istituto Europeo di Oncologia, Milan · Massimo Guidoboni, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy · David Hogg, Princess Margaret Cancer Centre, Toronto, Ontario, Canada · Michael B. Atkins, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC · Pascal Wolter, University Hospitals Leuven, Leuven, Belgium · Celeste Lebbé, Université Paris Diderot, Paris · Luc Thomas, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France · John M. Kirkwood, Hillman Cancer Center, Pittsburgh, PA · Jacob Schachter, Sheba Medical Center, Ramat Gan, Israel · Gregory A. Daniels, University of California San Diego, Moores Cancer Center, La Jolla, CA · Jessica Hassel, University Hospital, Heidelberg, Germany · Jonathan Cebon, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria · Winald Gerritsen, University of Queensland, St Lucia · Victoria Atkinson, Gallipoli Medical Research Foundation, Greenslopes · Victoria Atkinson, Princess Alexandra Hospital, Brisbane, Queensland, Australia · Winald Gerritsen, Radboud University Medical Center, Nijmegen, the Netherlands · John McCaffrey, Irish Clinical Oncology Research Group, Dublin · Derek Power, Irish Clinical Oncology Research Group, Cork, Ireland · Dana Walker, Rafia Bhore, and Joel Jiang, Bristol-Myers Squibb, Princeton, NJ · F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA · and Jedd D. Wolchok, Parker Institute and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY. ·J Clin Oncol · Pubmed #28915085.

ABSTRACT: Purpose The addition of nivolumab (anti-programmed death-1 antibody) to ipilimumab (anti-cytotoxic T-cell lymphocyte-associated 4 antibody) in patients with advanced melanoma improves antitumor response and progression-free survival but with a higher frequency of adverse events (AEs). This cross-melanoma study describes the safety profile of the approved nivolumab plus ipilimumab regimen. Methods This retrospective safety review on data from three trials (phase I, II, and III) included patients with advanced melanoma who received at least one dose of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks × 4 and then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity while following established guidelines for AE management. Analyses were of all treatment-related AEs, select (immune-related) AEs, time to onset and resolution, and use of immune-modulating agents and their effects on outcome. Results Among 448 patients, median duration of follow-up was 13.2 months. Treatment-related grade 3/4 AEs occurred in 55.5% of patients; 35.7% had treatment-related AEs that led to discontinuation. The most frequent treatment-related select AEs of any grade were skin (64.3%) and GI (46.7%) and of grade 3/4, hepatic (17.0%) and GI (16.3%); 30.1% developed a grade 2 to 4 select AE in more than one organ category. Median time to onset of grade 3/4 treatment-related select AEs ranged from 3.1 (skin) to 16.3 (renal) weeks, and with the exclusion of endocrine AEs, median time to resolution from onset ranged from 1.9 (renal) to 4.5 (pulmonary) weeks, with resolution rates between 79% and 100% while using immune-modulating agents. Four (< 1%) on-study deaths were attributed to therapy. Conclusion Frequency of grade 3/4 treatment-related AEs was higher with nivolumab plus ipilimumab and occurred earlier than historical experience with either agent alone, but resolution rates were similar.

24 Article Improvement of Genetic Testing for Cutaneous Melanoma in Countries With Low to Moderate Incidence: The Rule of 2 vs the Rule of 3. 2017

Delaunay, Juliette / Martin, Ludovic / Bressac-de Paillerets, Brigitte / Duru, Gerard / Ingster, Olivier / Thomas, Luc. ·Service de Dermatologie Centre Hospitalier, Lyon Sud, France. · Service de Dermatologie, CHU d'Angers, Angers CEDEX, France. · Gustave Roussy, Université Paris-Saclay, Département de Biologie et Pathologie Médicales, Villejuif, France. · INSERM U1186, Université Paris-Saclay, Villejuif, France. · Equipe d'accueil 4129, Université Claude Bernard Lyon 1, Lyon, France. · Service de Génétique, CHU Angers, Angers CEDEX, France. · Université Claude Bernard Lyon 1-Santé, Lyon, France. · Centre de Recherche en Cancérologie de Lyon, INSERM U1052/CNRS UMR5286, Lyon France. ·JAMA Dermatol · Pubmed #28903138.

ABSTRACT: Importance: Genetic testing for melanoma-prone mutation in France, a country with low to moderate incidence of melanoma, is proposed in cases with 2 invasive cutaneous melanomas and/or related cancers in the same patient, or in first- or second-degree relatives (rule of 2). In preclinical studies, these rules led to disclosure of mutation(s) in more than 10% of these families, the threshold widely accepted to justify genetic testing for cancers. Objective: To reconsider these criteria in a general population testing of patients. Design, Setting, and Participants: This was a retrospective study, performed from 2004 to 2015 at Angers and Lyons University Hospitals, of a cohort of 1032 patients who underwent genetic testing. Main Outcomes and Measures: Frequency of mutation in high (CDKN2A, CDK4, and BAP1) and intermediate (MITF) susceptibility genes; statistical effect of histologic subtype, age, dysplastic nevi syndrome, and associated cancers on mutation rate; and evaluation of cases with anamnestic uncertainty. Results: The mutation rate was 67 of 1032 patients (6.5%). Their mean (SD) age was 54.5 (14.2) years [range, 18-89 years], and 543 (52.6%) were men. It increased to 38 of 408 patients (9.3%) when applying a rule of 3 (those with ≥3 primary melanomas or genetically related cancers) (P = .68) and to 27 of 150 patients (18.0%) with a rule of 4 (4 primary melanomas or related cancer) (P < .001). The impact of age at first melanoma was observed only in those younger than 40 years, with a rate of 32 of 263 (12.1%) (P = .12) for the rule of 2 and 22 of 121 (18.2%) (P = .001) for the rule of 3. Use of the rule of 2 in patients younger than 40 years reduced the number of missed CDKN2A-mutated-families when applying the rule of 3 from 14 of 43 to 7 of 43. Anamnestic uncertainty, found in 88 families (8.5%), if excluded, would have led us to withdraw of only 21 cases (23.8%), and only 1 mutation would have been missed. Conclusions and Relevance: We propose using the rule of 3 to recommend genetic testing in France and countries with low to moderate incidence of melanoma, except in families and patients with a first melanoma occurrence before age 40 years in whom the rule of 2 could be maintained.

25 Article Acute interstitial nephritis after sequential ipilumumab - nivolumab therapy of metastatic melanoma. 2017

Bottlaender, Lea / Breton, Anne-Laure / de Laforcade, Louis / Dijoud, Frederique / Thomas, Luc / Dalle, Stephane. ·Service de Dermatologie, ImmuCare, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Bénite cedex, France. · Université Claude Bernard Lyon 1, Lyon, France. · Service de Dermatologie, ImmuCare, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Bénite cedex, France. annelbreton@gmail.com. · Université Claude Bernard Lyon 1, Lyon, France. annelbreton@gmail.com. · Centre de Recherche en Cancérologie de Lyon, Lyon, France. annelbreton@gmail.com. · Service de Néphrologie, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Bénite cedex, France. · Service d'Anatomie et de Cytologie pathologique, Hospices Civils de Lyon, Groupement Hospitalier Est, Bron cedex, France. · Centre de Recherche en Cancérologie de Lyon, Lyon, France. ·J Immunother Cancer · Pubmed #28716106.

ABSTRACT: BACKGROUND: The anti-Programmed Death receptor 1 (anti-PD-1) antibodies nivolumab and pembrolizumab are new treatments in metastatic melanoma. Immunotherapies are best known to be responsible for thrombotic microangiopathy. However, immune interstitial nephritis has been described in a patient treated by nivolumab and ipilimumab concomitantly, and three cases of granulomatous interstitial nephritis have been reported with ipilimumab monotherapy. We report herein a case of acute interstitial immune nephritis in a patient treated with nivolumab after ipilimumab for pulmonary metastatic melanoma. CASE PRESENTATION: Interstitial nephritis was diagnosed after acute kidney injury following three cycles and was confirmed by kidney biopsy. Kidney injury responded rapidly to prednisolone, which was then gradually reduced. As a follow-up computed tomography scan indicated mixed response, with minimal size progression of a pulmonary nodule, but a significant reduction in the size of the other nodules, nivolumab was reintroduced after renal function improvement. Low-dose corticosteroids were first maintained during nivolumab treatment and subsequently discontinued. Only one month after prednisolone discontinuation, creatinine levels increased. A second kidney biopsy confirmed relapse of acute interstitial nephritis. CONCLUSIONS: To our knowledge, this is the first case of nivolumab-induced acute interstitial immune nephritis. This case highlights that anti-PD-1 immunotherapy may be continued when renal function is adequate, and this requires close interaction between dermatologists and nephrologists. This adverse effect should be made known to prescribers as nivolumab is associated with significant improvement of survival in metastatic melanoma and may be used in many different types of cancer.

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