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Melanoma: HELP
Articles by Alessandro A. E. Testori
Based on 95 articles published since 2010
(Why 95 articles?)
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Between 2010 and 2020, A. Testori wrote the following 95 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Editorial The role of BRAF V600 mutation in melanoma. 2012

Ascierto, Paolo A / Kirkwood, John M / Grob, Jean-Jacques / Simeone, Ester / Grimaldi, Antonio M / Maio, Michele / Palmieri, Giuseppe / Testori, Alessandro / Marincola, Francesco M / Mozzillo, Nicola. ·Department of Melanoma, Istituto Nazionale Tumori Fondazione G, Pascale, Naples, Italy. paolo.ascierto@gmail.com ·J Transl Med · Pubmed #22554099.

ABSTRACT: BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50 % of melanomas harbors activating BRAF mutations (over 90 % V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors. The first selective inhibitor of mutant BRAF, vemurafenib, after highly encouraging results of the phase I and II trial, was compared to dacarbazine in a phase III trial in treatment-naïve patients (BRIM-3). The study results showed a relative reduction of 63 % in risk of death and 74 % in risk of tumor progression. Considering all trials so far completed, median overall survival reached approximately 16 months for vemurafenib compared to less than 10 months for dacarbazine treatment. Vemurafenib has been extensively tested on melanoma patients expressing the BRAFV600E mutated form; it has been demonstrated to be also effective in inhibiting melanomas carrying the V600K mutation. In 2011, both FDA and EMA therefore approved vemurafenib for metastatic melanoma carrying BRAFV600 mutations. Some findings suggest that continuation of vemurafenib treatment is potentially beneficial after local therapy in a subset of patients with disease progression (PD). Among who continued vemurafenib >30 days after local therapy of PD lesion(s), a median overall survival was not reached, with a median follow-up of 15.5 months from initiation of BRAF inhibitor therapy. For patients who did not continue treatment, median overall survival from the time of disease progression was 1.4 months. A clinical phase I/II trial is evaluating the safety, tolerability and efficacy of vemurafenib in combination with the CTLA-4 inhibitor mAb ipilimumab. In the BRIM-7 trial vemurafenib is tested in association with GDC-0973, a potent and highly selective inhibitor of MEK1/2. Preliminary data seem to indicate that an additional inhibitor of mutated BRAF, GSK2118436, might be also active on a wider range of BRAF mutations (V600E-K-D-R); actually, treatment with such a compound is under evaluation in a phase III study among stage III-IV melanoma patients positive for BRAF mutations. Overall, BRAF inhibitors were well tolerated; common adverse events are arthralgia, rash, fatigue, alopecia, keratoacanthoma or cutaneous squamous-cell carcinoma, photosensitivity, nausea, and diarrhea, with some variants between different inhibitors.

2 Review Primary Melanoma: from History to Actual Debates. 2019

Testori, Alessandro A E / Blankenstein, Stephanie A / van Akkooi, Alexander C J. ·Dermatology, Fondazione IRCCS policlinico San Matteo, Fondazione IRCCS San Matteo, Pavia, Italy. info@alessandrotestori.it. · Department of Surgical Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, Netherlands. ·Curr Oncol Rep · Pubmed #31858280.

ABSTRACT: PURPOSE OF REVIEW: This review describes the long scientific background followed to design guidelines and everyday clinical practice applied to melanoma patients. Surgery is the first option to cure melanoma patients (PTS) at initial diagnosis, since primary cutaneous lesions are usually easily resectable. An excisional biopsy of the lesion, with minimal clear margins, can be obtained in the vast majority of cases. Punch biopsies may be proposed only in case of large lesions located on specific cosmetic or functional areas like the face, extremities, or genitals where a mutilating complete resection would not be performed without prior histological diagnosis. RECENT FINDINGS: After the histologic confirmation of melanoma, definite surgical excision of the scar and surrounding tissue is planned, to obtain microsatellite free margins. The width of these margins has been identified following the results of several clinical trials and it is either 1 or 2 cm, depending on the Breslow thickness of the primary tumor. Following the latest staging system proposed by the American Joint Cancer commission (AJCC), a sentinel node biopsy (SNB) is usually performed in case of a primary lesion > 0.8 mm thickness or for high-risk thinner lesions, if no evidence of nodal involvement has been identified clinically or radiographically. Surgical management of primary melanoma is well established. There is debate on the optimal surgical margins for 1-2 mm melanomas. There are specific considerations for special primaries (bulky, extremity, mucosal). Sentinel node (SN) evaluation does not improve survival, but is routinely used as staging.

3 Review Surgery for Metastatic Melanoma: an Evolving Concept. 2019

Testori, Alessandro A E / Blankenstein, Stephanie A / van Akkooi, Alexander C J. ·Dermatology, Fondazione IRCCS Policlinico San Matteo, v.le Golgi 19, 27100, Pavia, Italy. info@alessandrotestori.it. · Department of Surgical Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, Netherlands. ·Curr Oncol Rep · Pubmed #31696407.

ABSTRACT: PURPOSE OF REVIEW: This review describes the evolving role of surgery in stage III and IV melanoma. RECENT FINDINGS: Surgery has been the first option to cure melanoma patients at initial diagnosis of metastatic spread: a complete surgical excision of the disease either in stage III or IV has been the gold standard for decades. A positive sentinel node biopsy (SNB) has been followed by a complete lymph node dissection (CLND) since the early stages of modern surgical oncology. However, since two randomized trials have indicated that a CLND does not improve survival in patients with a positive SNB, a CLND is no longer considered mandatory. A therapeutic lymph node dissection (TLND) is still offered to patients with macroscopic nodal disease and in highly selected cases, patients with distant melanoma metastases can be treated surgically as well. Also the availability of adjuvant, and in the future possibly neoadjuvant, systemic therapy have shifted the landscape to less extensive surgery in metastatic melanoma. With the development of new systemic options, surgery in metastatic melanoma has become more and more part of a multidisciplinary treatment: surgical indications are moving from previous standards to a new role.

4 Review Adjuvant Treatment of Melanoma: Recent Developments and Future Perspectives. 2019

Testori, Alessandro A E / Ribero, Simone / Indini, Alice / Mandalà, Mario. ·Dermatology, Fondazione IRCCS San Matteo, Pavia, Italy. info@alessandrotestori.it. · Medical Sciences Department, Dermatologic Clinic, University of Turin, Turin, Italy. · Melanoma Unit, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. ·Am J Clin Dermatol · Pubmed #31177507.

ABSTRACT: Surgical excision is the treatment of choice for early stage melanoma, and this strategy is initially curative for the vast majority of patients. However, only approximately 40-60% of high-risk patients who undergo surgery alone will be disease-free at 5 years. These patients will ultimately experience loco-regional relapse or relapse at distant sites. The main aim of adjuvant therapies is to reduce the recurrence rate of radically operated patients at high risk and to potentially improve survival. Recent practice changing results with immune checkpoint inhibitors and targeted therapies have been published in stage III/IV melanoma patients, after surgical complete resection, and have dramatically improved the landscape of adjuvant therapy. Interferon-α, ipilimumab, and more recently anti-programmed cell death protein-1 antibodies and BRAF inhibitors plus MEK inhibitors have been approved in the adjuvant setting by the US Food and Drug Administration; similarly, the same drugs are approved by the European Medicines Agency with the exception of ipilimumab. A completely new scenario is emerging in the neoadjuvant setting as well: in locally advanced or metastatic disease, patients may partially respond to neoadjuvant therapy and become virtually resectable with systemic control of disease. This review summarizes the current state of the field and describes new strategies tracing the history of adjuvant therapy in melanoma, with a view on future projects.

5 Review Diagnosis and treatment of in-transit melanoma metastases. 2017

Testori, A / Ribero, S / Bataille, V. ·Divisione di Chirurgia Dermatoncologica, Istituto Europeo di Oncologia, Milano, Italy. Electronic address: alessandro.testori@ieo.it. · Dermatologia, Dipartimentto di Scienze mediche, Università di Torino, Italy. · West Herts NHS Trust, London, UK; Mount Vernon Cancer Centre, Northwood, UK. ·Eur J Surg Oncol · Pubmed #27923593.

ABSTRACT: In transit metastases (ITM) from extremity or trunk melanomas are subcutaneous or cutaneous lymphatic deposits of melanoma cells, distant from the primary site but not reaching the draining nodal basin. Superficial ITM metastases develop in 5-10% of melanoma patients and are thought to be caused by cells spreading along lymphatics; ITM appear biologically different from distant cutaneous metastases, these probably due to a haematogenous dissemination. The diagnosis is usually clinical and by patients, but patients need to be adequately educated in the recognition of this clinical situation. Ultrasound or more sophisticated instrumental devices may be required if the disease develops more deeply in the soft tissues. According to AJCC 2009 staging classification, ITM are included in stages IIIb and IIIc, which are considered local advanced disease with quite poor 5-year survival rates and outcomes of 24-54% at 5 years.

6 Review The risk of developing a second primary cancer in melanoma patients: a comprehensive review of the literature and meta-analysis. 2014

Caini, Saverio / Boniol, Mathieu / Botteri, Edoardo / Tosti, Giulio / Bazolli, Barbara / Russell-Edu, William / Giusti, Francesco / Testori, Alessandro / Gandini, Sara. ·Unit of Molecular and Nutritional Epidemiology, Institute for Cancer Research and Prevention, Via delle Oblate 2, 50139 Florence, Italy. Electronic address: s.caini@ispo.toscana.it. · International Prevention Research Institute, Lyon, France. · Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy. · Division of Melanoma and Muscolocutaneous sarcoma, European Institute of Oncology, Milan, Italy. · Library, European Institute of Oncology, Milan, Italy. · European Organisation for Research and Treatment of Cancer (EORTC), Brussels, Belgium. ·J Dermatol Sci · Pubmed #24680127.

ABSTRACT: The number of cutaneous melanoma survivors has been increasing for years due to improvements in early diagnosis and subsequent prolonged survival. These patients are at increased risk of developing a second melanoma and a second primary malignancy (SPM) at other sites as well. We performed a review of scientific literature and meta-analysis to evaluate the risk of developing a SPM (other than melanoma) among melanoma patients. Twenty-three independent papers and over 350,000 melanoma patients were included. Risk of cancer among melanoma survivors was increased overall (1.57, 95% CI 1.29-1.90) and at several sites: bone (2.09, 95% CI 1.08-4.05), non-melanoma skin cancer (4.01, 95% CI 1.81-8.87), soft tissue (6.80, 95% CI 1.29-35.98), colon-rectum (1.12, 95% CI 1.00-1.25), female breast (1.14, 95% CI 1.07-1.22), kidney (1.34, 95% CI 1.23-1.45), prostate (1.25, 95% CI 1.13-1.37) and non-Hodgkin lymphoma (1.37, 95% CI 1.22-1.54). The overall risk of SPM showed a tendency to decrease as the time from melanoma diagnosis lengthened. Most of our findings may be explained by the tendency of some exposures, which are risk factors for different tumors, to occur simultaneously in the same individuals. These results suggest primary and secondary cancer prevention counselling for melanoma survivors.

7 Review Treatment of metastatic melanoma with electrochemotherapy. 2014

Campana, Luca G / Testori, Alessandro / Mozzillo, Nicola / Rossi, Carlo Riccardo. · ·J Surg Oncol · Pubmed #24678530.

ABSTRACT: Superficially metastatic melanoma still represents a challenging situation for oncologists and a distressing condition for patients. In this circumstance, local treatment by electrochemotherapy, that is, the combination of brief permeabilizing electric pulses with a low‐toxicity anticancer drug, can be a valuable treatment option in selected patients who are ineligible/refractory to systemic treatments or require rapid palliation of symptomatic cutaneous disease.

8 Review Heat-shock proteins-based immunotherapy for advanced melanoma in the era of target therapies and immunomodulating agents. 2014

Tosti, Giulio / Cocorocchio, Emilia / Pennacchioli, Elisabetta / Ferrucci, Pier Francesco / Testori, Alessandro / Martinoli, Chiara. ·Istituto Europeo di Oncologia, Melanoma and Sarcoma Division , Via Ripamonti 435, 2014i Milano , Italy +39 02 57489459 ; +39 02 94379230 ; giulio.tosti@ieo.it. ·Expert Opin Biol Ther · Pubmed #24670226.

ABSTRACT: INTRODUCTION: Heat-shock proteins (HSPs) are highly conserved, stress-induced proteins that function as chaperones, stabilizing proteins and delivering peptides. Tumor-derived HSP peptide complexes (HSPPCs) induced immunity against several malignancies in preclinical models, exhibiting activity across tumor types. AREAS COVERED: HSPPC-based vaccination showed clinical activity in subsets of patients with different malignancies (e.g., gastric, colorectal, pancreatic, ovarian cancer, and glioblastoma). In Phase III clinical trials for advanced melanoma and renal cell carcinoma patients, HSPPC-based vaccine demonstrated an excellent safety profile, thus emerging as a flexible tumor- and patient-specific therapeutic approach. EXPERT OPINION: Melanoma, renal clear cell carcinoma, and glioblastoma are among suitable targets for HSP-based treatment as demonstrated by immune responses and clinical activity observed in subsets of patients, mainly those with early stage of disease and limited tumor burden. In order to further improve clinical activity, combinations of HSPPC-based vaccines with mutation-driven therapies, antiangiogenic agents, or immunomodulating monoclonal antibodies should be tested in controlled clinical trials.

9 Review Utility of electrochemotherapy in melanoma treatment. 2012

Testori, Alessandro / Rossi, Carlo R / Tosti, Giulio. ·European Institute of Oncology (IEO-IRCCS), Milan, Lombardy, Italy. alessandro.testori@ieo.it ·Curr Opin Oncol · Pubmed #22249204.

ABSTRACT: PURPOSE OF REVIEW: In the present study, the role of electrochemotherapy (ECT) in the advanced melanoma setting, either as alternative treatment modality to conventional therapies or as palliative care, is reviewed and the perspective to combine ECT with biological response modifiers and immunotherapeutic compounds is discussed. RECENT FINDINGS: ECT refers to the combination of electroporation and administration of anticancer drugs for local treatment of solid neoplasms. Electroporation uses short and intense electric pulses to induce a transient permeabilization of the cell membrane by creation of pores, thus allowing molecules, such as chemotherapeutic agents, to freely diffuse into the cytosol. ECT has shown to be effective and clinically well tolerated in the local control of primary and metastatic solid tumors of diverse histotypes in preclinical and clinical studies, thus, emerging as useful local treatment modality for disseminated superficial melanoma. So far, only a few data on the role of immunological response in ECT-treated patients have been reported. SUMMARY: Treatment regimens combining ECT to biological response modifiers (interleukin-2, interferon) and immunotherapeutic compounds should be further explored in animal and human cancer models; immunotherapy combined to ECT could broaden the therapeutic indications of ECT, by rendering it effective also on distant unreachable or untreated lesions.

10 Review Ipilimumab targeting CD28-CTLA-4 axis: new hope in the treatment of melanoma. 2012

Lens, Marko / Testori, Alessandro / Ferucci, Pier Francesco. ·King's College, Genetic Epidemiology Unit, St.Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, United Kingdom. markolens@aol.com ·Curr Top Med Chem · Pubmed #22196270.

ABSTRACT: Ipilimumab, a fully human monoclonal antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), is the new hope in the treatment of patients with advanced melanoma. Anti-CTLA-4 antibodies enhance T cell responses in vitro and in vivo and activate proliferation of tumour-specific T cells. The blockade of CTLA-4 by ipilimumab leads to immune-mediated tumor regression. Ipilimumab has been studied in metastatic melanoma in a number of clinical trials. Recently, a phase III, multi-center, randomized, double-blind trial showed a significant improvement in overall survival in patients with advanced melanomas treated with ipilimumab. Thus, ipilimumab was the first drug to demonstrate effect on overall survival in patients with metastatic melanoma. However, patients treated with ipilimumab develop various immune-related adverse events (irAEs), which are associated with objective and durable clinical responses. Use of new immune-related response criteria is recommended in patients on ipilimumab therapy to avoid premature treatment discontinuation. Further research is necessary to elucidate role of ipilimumab in adjuvant setting as well as in synergy with other novel modalities for the treatment of metastatic melanoma.

11 Review Newly identified tumor antigens as promising cancer vaccine targets for malignant melanoma treatment. 2012

Ferrucci, P F / Tosti, G / di Pietro, A / Passoni, C / Pari, C / Tedeschi, I / Cataldo, F / Martinoli, C / Testori, A. ·Melanoma and Muscle Cutaneous Sarcomas Division, IEO-European Institute of Oncology, Milan, Italy. pier.ferrucci@ieo.it ·Curr Top Med Chem · Pubmed #22196269.

ABSTRACT: Immunogenicity of tumour cells, immunomodulation and direct targeting of signalling pathways are promising avenues and matter of dated and innovative research in melanoma. Unfortunately, tumour cells are considered to be antigenic, but not immunogenic, either due to presentation of weakly recognized antigens or to the inability of the immune system to recognize them. However, spontaneous complete remission can be rarely observed in patients affected by melanoma, which are mainly attributed to the immune response against the tumour. Also, an elevated frequency of spontaneous humoral immune responses against tumour antigens was occasionally found in patients. These data confirm the existence of an interaction of the immune system with the tumour which can be used as a promising pathway for intervention and incorporates all portions of the immune system. The cancer immunotherapy approach is based on artificial activation of the immune system against the tumour and groups several types of treatments including immunization/vaccination but also modulation of immunity by cytokines or antibodies. Immunization approaches could either be based on undefined tumour antigens (e.g. whole tumour cells, tumour cell lysates, or tumour-antigen enriched fractions) or aimed at eliciting T-cell responses against specific tumour antigens. Novel and contemporary antigen-targeted therapy strategies, mainly directed to Cancer Testis and Heat Shock Proteins, leading to a possible active immunization against melanoma through T-cell specific activation, are discussed in this review.

12 Review Treatment of melanoma metastases in a limb by isolated limb perfusion and isolated limb infusion. 2011

Testori, Alessandro / Verhoef, Cornelis / Kroon, Hidde M / Pennacchioli, E / Faries, Mark B / Eggermont, Alexander M M / Thompson, John F. ·Melanoma and Sarcoma Division, European Institute of Oncology, Milan, Italy. alessandro.testori@ieo.it. ·J Surg Oncol · Pubmed #21858835.

ABSTRACT: In-transit melanoma metastases are often confined to a limb. In this circumstance, treatment by isolated limb perfusion or isolated limb infusion can be a remarkably effective regional treatment option.

13 Review Local and intralesional therapy of in-transit melanoma metastases. 2011

Testori, Alessandro / Faries, Mark B / Thompson, John F / Pennacchioli, E / Deroose, Jan P / van Geel, Albertus N / Verhoef, Cornelis / Verrecchia, Francesco / Soteldo, Javier. ·Melanoma and Sarcoma Division, European Institute of Oncology, Milan, Italy. alessandro.testori@ieo.it ·J Surg Oncol · Pubmed #21858834.

ABSTRACT: Regional relapse of melanoma may occur as satellite or in-transit metastases proximal to the primary tumor in the direction of the lymph flow. The management of in-transit metastases is challenging because the efficacy of treatment is largely dictated by the biological behavior of the patient's melanoma. This review examines local treatment modalities.

14 Review The immunological era in melanoma treatment: new challenges for heat shock protein-based vaccine in the advanced disease. 2011

di Pietro, Alessandra / Tosti, Giulio / Ferrucci, Pier Francesco / Testori, Alessandro. ·IEO, European Institute of Oncology, Melanoma Division, Via G. Ripamonti 435, 20141 Milan, Italy. ·Expert Opin Biol Ther · Pubmed #21801084.

ABSTRACT: INTRODUCTION: Tumor-derived heat shock protein (HSP)-peptide complexes (HSPPCs) induced immunity against malignancies in preclinical trials, working across tumor types and bypassing the need to identify single immunogenic peptides. These results paved the way for the use of human gp96 obtained from autologous tumor samples as an anti-cancer vaccine. AREAS COVERED: Autologous tumor-derived HSP gp96 peptide complex (HSPPC-96) vaccine is emerging as a tumor- and patient-specific cancer vaccine, with confirmed activity in several malignancies. It has been tested in Phase III clinical trials in advanced melanoma and kidney cancer with evidence for efficacy in patients with earlier stage disease. HSPPC-96-based vaccine demonstrated an excellent safety profile, thus emerging as a novel therapeutic approach with a suggestive role in cancer therapy. This review summarizes work on the use of HSPPC-96 as an autologous anti-tumor vaccine in advanced melanoma. Data were retrieved by PubMed and Medline research and using the authors' personal experience. EXPERT OPINION: Further investigations are needed to understand the biological basis of immune functions in order to improve the clinical outcome of HSP-based cancer therapy. In the near future, the combination of HSP-based vaccines with other biological compounds might represent a successful strategy in the therapy of advanced melanoma.

15 Review Anti-CTLA-4 antibody adjuvant therapy in melanoma. 2010

Eggermont, Alexander M M / Testori, Alessandro / Maio, Michele / Robert, Caroline. ·Institut d'Oncologie Gustave Roussy, Villejuif, France. alexander.eggermont@igr.fr ·Semin Oncol · Pubmed #21074060.

ABSTRACT: Thus far the development of adjuvant therapies in melanoma has suffered greatly from the lack of effective drugs in stage IV melanoma. Chemotherapy, cytokines, vaccines, and combinations of drugs have been used with minimal success. This has led to adjuvant therapies that are not used uniformly or widely because of the rather marginal benefits, as no consistent and clinically significant impact on survival has been demonstrated. A new development for interferon-based adjuvant therapy seems to be the observation that better effects are observed in patients with lower tumor load and in patients with an ulcerated primary melanoma. A benefit for patients with more advanced lymphnodal involvement is quite unsure, clearly requiring new drugs to be explored. A new era in the treatment of melanoma treatment has arrived with the anti-cytoxic T-lymphocyte antigen-4 (anti-CTLA-4) monoclonal antibodies. The randomized trial in advanced metastatic melanoma demonstrated a clear benefit with prolongation of survival. The anti-CTLA-4 monoclonal antibody ipilimumab has finally changed the landscape. It is therefore only logical that a worldwide adjuvant trial with ipilimumab versus placebo, the European Organization for Research and Treatment of Cancer (EORTC) 18071, is ongoing in patients with lymph node metastases, and that another adjuvant trial with ipilimumab compared to high-dose interferon (HDI) is planned in the United States. The EORTC 18071 trial will reach full accrual in 2011 and thus results are expected in 2013 or 2014.

16 Clinical Trial MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial. 2018

Dreno, Brigitte / Thompson, John F / Smithers, Bernard Mark / Santinami, Mario / Jouary, Thomas / Gutzmer, Ralf / Levchenko, Evgeny / Rutkowski, Piotr / Grob, Jean-Jacques / Korovin, Sergii / Drucis, Kamil / Grange, Florent / Machet, Laurent / Hersey, Peter / Krajsova, Ivana / Testori, Alessandro / Conry, Robert / Guillot, Bernard / Kruit, Wim H J / Demidov, Lev / Thompson, John A / Bondarenko, Igor / Jaroszek, Jaroslaw / Puig, Susana / Cinat, Gabriela / Hauschild, Axel / Goeman, Jelle J / van Houwelingen, Hans C / Ulloa-Montoya, Fernando / Callegaro, Andrea / Dizier, Benjamin / Spiessens, Bart / Debois, Muriel / Brichard, Vincent G / Louahed, Jamila / Therasse, Patrick / Debruyne, Channa / Kirkwood, John M. ·Department of Dermatooncology, Hotel Dieu Nantes University Hospital, Nantes, France. · Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. · Queensland Melanoma Project, Discipline of Surgery, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD, Australia. · Melanoma Sarcoma Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. · Service d'Oncologie Médicale, Hôpital François Mitterrand, Pau, France. · Skin Cancer Center Hannover, Department of Dermatology, Hannover Medical School, Hannover, Germany. · Petrov Research Institute of Oncology, St Petersburg, Russia. · Department of Soft Tissue, Bone Sarcoma, and Melanoma, Maria Sklodowska-Curie Institute, Oncology Center, Warsaw, Poland. · Department of Dermatology and Skin Cancers, La Timone APHM Hospital, Aix-Marseille University, Marseille, France. · Department of Skin and Soft Tissue Tumours, National Cancer Institute, Kiev, Ukraine. · Swissmed Centrum Zdrowia, Gdansk, Poland; Department of Surgical Oncology, Gdansk Medical University, Gdansk, Poland. · Dermatology Department, Hôpital Robert Debré, Université de Reims Champagne-Ardenne, Reims, France. · Department of Dermatology, Centre Hospitalier Universitaire, Tours, France; UFR de Médecine, Université François-Rabelais, Tours, France. · Melanoma Immunology and Oncology Group, Centenary Institute, University of Sydney, Sydney, NSW, Australia; Melanoma Institute Australia, Sydney, NSW, Australia. · Dermato-oncology Department, General University Hospital, Prague, Czech Republic. · Columbus Clinic Center, Milan, Italy. · Division of Hematology & Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. · Département de Dermatologie, Centre Hospitalier Universitaire, Hôpital Saint-Éloi, Montpellier, France. · Department of Medical Oncology, Erasmus MC Cancer institute, Rotterdam, Netherlands. · Cancer Research Center, Moscow, Russia. · Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Seattle Cancer Care Alliance, University of Washington, Seattle, WA, USA. · Department of Oncology and Medical Radiology, Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine. · Centrum Medyczne Bieńkowski, Klinika Chirurgii Plastycznej, Bydgoszcz, Poland; Department of Oncological Surgery, Oncology Center, Bydgoszcz, Poland. · Melanoma Unit, Dermatology Department, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain. · Instituto de Oncología Ángel H Roffo, Universidad de Buenos Aires, Buenos Aires, Argentina. · Department of Dermatology, Venereology, and Allergology, University Hospital Schleswig-Holstein, Kiel, Germany. · Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands. · GlaxoSmithKline, Rixensart, Belgium. Electronic address: fernando.x.ulloa-montoya@GSK.com. · GlaxoSmithKline, Rixensart, Belgium. · GlaxoSmithKline, Rixensart, Belgium; Immunology Translational Medicine, UCB, Brussels, Belgium. · GlaxoSmithKline, Rixensart, Belgium; Biostatistics Department, Janssen Research & Development, Beerse, Belgium. · GlaxoSmithKline, Rixensart, Belgium; ViaNova Biosciences, Brussels, Belgium. · GlaxoSmithKline, Rixensart, Belgium; Laboratoires Servier, Paris, France. · GlaxoSmithKline, Rixensart, Belgium; University Hospitals Leuven, Leuven, Belgium. · UPMC Hillman Cancer Center, Pittsburgh, PA, USA. ·Lancet Oncol · Pubmed #29908991.

ABSTRACT: BACKGROUND: Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting. METHODS: DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 μg MAGE-A3 antigen plus 420 μg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445. FINDINGS: Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3-35·5] in the MAGE-A3 group and 28·1 months [23·7-36·9] in the placebo group. Median disease-free survival was 11·0 months (95% CI 10·0-11·9) in the MAGE-A3 group and 11·2 months (8·6-14·1) in the placebo group (hazard ratio [HR] 1·01, 0·88-1·17, p=0·86). In the GS-positive population, median disease-free survival was 9·9 months (95% CI 5·7-17·6) in the MAGE-A3 group and 11·6 months (5·6-22·3) in the placebo group (HR 1·11, 0·83-1·49, p=0·48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [<1%] for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment. INTERPRETATION: An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped. FUNDING: GlaxoSmithKline Biologicals SA.

17 Clinical Trial Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. 2017

Faries, Mark B / Thompson, John F / Cochran, Alistair J / Andtbacka, Robert H / Mozzillo, Nicola / Zager, Jonathan S / Jahkola, Tiina / Bowles, Tawnya L / Testori, Alessandro / Beitsch, Peter D / Hoekstra, Harald J / Moncrieff, Marc / Ingvar, Christian / Wouters, Michel W J M / Sabel, Michael S / Levine, Edward A / Agnese, Doreen / Henderson, Michael / Dummer, Reinhard / Rossi, Carlo R / Neves, Rogerio I / Trocha, Steven D / Wright, Frances / Byrd, David R / Matter, Maurice / Hsueh, Eddy / MacKenzie-Ross, Alastair / Johnson, Douglas B / Terheyden, Patrick / Berger, Adam C / Huston, Tara L / Wayne, Jeffrey D / Smithers, B Mark / Neuman, Heather B / Schneebaum, Schlomo / Gershenwald, Jeffrey E / Ariyan, Charlotte E / Desai, Darius C / Jacobs, Lisa / McMasters, Kelly M / Gesierich, Anja / Hersey, Peter / Bines, Steven D / Kane, John M / Barth, Richard J / McKinnon, Gregory / Farma, Jeffrey M / Schultz, Erwin / Vidal-Sicart, Sergi / Hoefer, Richard A / Lewis, James M / Scheri, Randall / Kelley, Mark C / Nieweg, Omgo E / Noyes, R Dirk / Hoon, Dave S B / Wang, He-Jing / Elashoff, David A / Elashoff, Robert M. ·From the John Wayne Cancer Institute at Saint John's Health Center, Santa Monica (M.B.F., D.S.B.H.), and the Departments of Pathology (A.J.C.), Biomathematics (H.-J.W., D.A.E., R.M.E.), and Medicine (D.A.E.), University of California, Los Angeles - both in California · Melanoma Institute Australia and the University of Sydney, Sydney (J.F.T., O.E.N.), Peter MacCallum Cancer Centre, Melbourne, VIC (M.H.), Princess Alexandra Hospital, Brisbane, QLD (B.M.S.), and Newcastle Melanoma Unit, Waratah, NSW (P.H.) - all in Australia · Huntsman Cancer Institute, Salt Lake City (R.H.A., R.D.N.), and Intermountain Healthcare Cancer Services-Intermountain Medical Center, Murray (T.L.B.) - both in Utah · Istituto Nazionale dei Tumori Napoli, Naples (N.M.), Istituto Europeo di Oncologia, Milan (A.T.), and Istituto Oncologico Veneto-University of Padua, Padua (C.R.R.) - all in Italy · H. Lee Moffitt Cancer Center, Tampa, FL (J.S.Z.) · Helsinki University Hospital, Helsinki (T.J.) · Dallas Surgical Group, Dallas (P.D.B.) · Universitair Medisch Centrum Groningen, Groningen (H.J.H.), and Netherlands Cancer Institute, Amsterdam (M.W.J.M.W.) - both in the Netherlands · Norfolk and Norwich University Hospital, Norwich (M. Moncrieff), and Guy's and St. Thomas' NHS Foundation Trust, London (A.M.-R.) - both in the United Kingdom · Swedish Melanoma Study Group-University Hospital Lund, Lund, Sweden (C.I.) · University of Michigan, Ann Arbor (M.S.S.) · Wake Forest University, Winston-Salem (E.A.L.), and Duke University, Durham (R.S.) - both in North Carolina · Ohio State University, Columbus (D.A.) · University of Zurich, Zurich (R.D.), and Centre Hospitalier Universitaire Vaudois, Lausanne (M. Matter) - both in Switzerland · Penn State Hershey Cancer Institute, Hershey (R.I.N.), Thomas Jefferson University (A.C.B.) and Fox Chase Cancer Center (J.M.F.), Philadelphia, and St. Luke's University Health Network, Bethlehem (D.C.D.) - all in Pennsylvania · Greenville Health System Cancer Center, Greenville, SC (S.D.T.) · Sunnybrook Research Institute, Toronto (F.W.), and Tom Baker Cancer Centre, Calgary, AB (G.M.) - both in Canada · University of Washington, Seattle (D.R.B.) · Saint Louis University, St. Louis (E.H.) · Vanderbilt University (D.B.J., M.C.K.), Nashville, and University of Tennessee, Knoxville (J.M.L.) - both in Tennessee · University Hospital Schleswig-Holstein-Campus Lübeck, Lübeck (P.T.), University Hospital of Würzburg, Würzburg (A.G.), and City Hospital of Nürnberg, Nuremberg (E.S.) - all in Germany · SUNY at Stony Brook Hospital Medical Center, Stony Brook (T.L.H.), Memorial Sloan Kettering Cancer Center, New York (C.E.A.), and Roswell Park Cancer Institute, Buffalo (J.M.K.) - all in New York · Northwestern University Feinberg School of Medicine (J.D.W.) and Rush University Medical Center (S.D.B.), Chicago · University of Wisconsin, Madison (H.B.N.) · Tel Aviv Sourasky Medical Center, Tel Aviv, Israel (S.S.) · M.D. Anderson Medical Center, Houston (J.E.G.) · Johns Hopkins University School of Medicine, Baltimore (L.J.) · University of Louisville, Louisville, KY (K.M.M.) · Dartmouth-Hitchcock Medical Center, Lebanon, NH (R.J.B.) · Hospital Clinic Barcelona, Barcelona (S.V.-S.) · and Sentara CarePlex Hospital, Hampton, VA (R.A.H.). ·N Engl J Med · Pubmed #28591523.

ABSTRACT: BACKGROUND: Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. METHODS: In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. RESULTS: Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. CONCLUSIONS: Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .).

18 Clinical Trial Efficacy and safety of nilotinib in patients with KIT-mutated metastatic or inoperable melanoma: final results from the global, single-arm, phase II TEAM trial. 2017

Guo, J / Carvajal, R D / Dummer, R / Hauschild, A / Daud, A / Bastian, B C / Markovic, S N / Queirolo, P / Arance, A / Berking, C / Camargo, V / Herchenhorn, D / Petrella, T M / Schadendorf, D / Sharfman, W / Testori, A / Novick, S / Hertle, S / Nourry, C / Chen, Q / Hodi, F S. ·Department of Renal Cancer & Melanona, Peking University Cancer Hospital & Institute, Beijing, China. · Division of Hematology/Oncology, Columbia University Medical Center, New York, USA. · Skin Cancer Center, University Hospital of Zurich, Zurich, Switzerland. · Department of Dermatology, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany. · Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco. · Department of Hematology/Oncology, Mayo Clinic Cancer Center, Rochester, USA. · Department of Medical Oncology, National Research Institute for Cancer, Genova, Italy. · Department of Medical Oncology, Hospital Clinic, Barcelona, Spain. · Department of Dermatology & Allergology, University Hospital Munich (LMU), Munich, Germany. · Department of Medical Oncology, Cancer Institute of São Paulo, São Paulo. · Department of Clinical Oncology, National Institute of Cancer, Rio de Janeiro, Brazil. · Department of Medical Oncology, Sunnybrook Health Sciences Center, Toronto, Canada. · Department of Dermatology, Essen University Hospital, Essen, Germany. · Department of Oncology & Dermatology, Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Medicine, Lutherville, USA. · Melanoma and Muscle Cutaneous Sarcoma Division, European Institute of Oncology, Milano, Italy. · Oncology Business Unit, Novartis Pharmaceuticals Corporation, East Hanover, USA. · Oncology Business Unit, Novartis Pharma AG, Basel, Switzerland. · Melanoma Center, Dana-Farber Cancer Institute, Boston, USA. ·Ann Oncol · Pubmed #28327988.

ABSTRACT: Background: The single-arm, phase II Tasigna Efficacy in Advanced Melanoma (TEAM) trial evaluated the KIT-selective tyrosine kinase inhibitor nilotinib in patients with KIT-mutated advanced melanoma without prior KIT inhibitor treatment. Patients and methods: Forty-two patients with KIT-mutated advanced melanoma were enrolled and treated with nilotinib 400 mg twice daily. TEAM originally included a comparator arm of dacarbazine (DTIC)-treated patients; the design was amended to a single-arm trial due to an observed low number of KIT-mutated melanomas. Thirteen patients were randomized to DTIC before the protocol amendment removing this study arm. The primary endpoint was objective response rate (ORR), determined according to Response Evaluation Criteria In Solid Tumors. Results: ORR was 26.2% (n = 11/42; 95% CI, 13.9%-42.0%), sufficient to reject the null hypothesis (ORR ≤10%). All observed responses were partial responses (PRs; median response duration, 7.1 months). Twenty patients (47.6%) had stable disease and 10 (23.8%) had progressive disease; 1 (2.4%) response was unknown. Ten of the 11 responding patients had exon 11 mutations, four with an L576P mutation. The median progression-free survival and overall survival were 4.2 and 18.0 months, respectively. Three of the 13 patients on DTIC achieved a PR, and another patient had a PR following switch to nilotinib. Conclusion: Nilotinib activity in patients with advanced KIT-mutated melanoma was similar to historical data from imatinib-treated patients. DTIC treatment showed potential activity, although the low patient number limits interpretation. Similar to previously reported results with imatinib, nilotinib showed greater activity among patients with an exon 11 mutation, including L576P, suggesting that nilotinib may be an effective treatment option for patients with specific KIT mutations. Clinical Trial Registration: ClinicalTrials.gov, NCT01028222.

19 Clinical Trial Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. 2017

Coens, Corneel / Suciu, Stefan / Chiarion-Sileni, Vanna / Grob, Jean-Jacques / Dummer, Reinhard / Wolchok, Jedd D / Schmidt, Henrik / Hamid, Omid / Robert, Caroline / Ascierto, Paolo A / Richards, Jon M / Lebbé, Celeste / Ferraresi, Virginia / Smylie, Michael / Weber, Jeffrey S / Maio, Michele / Bottomley, Andrew / Kotapati, Srividya / de Pril, Veerle / Testori, Alessandro / Eggermont, Alexander M M. ·EORTC Headquarters, Brussels, Belgium. Electronic address: corneel.coens@eortc.be. · EORTC Headquarters, Brussels, Belgium. · IOV-IRCCS, Melanoma Oncology Unit, Padova, Italy. · Hôpital de la Timone, Marseille, France. · University of Zürich Hospital, Zürich, Switzerland. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Aarhus University Hospital, Aarhus, Denmark. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. · Istituto Nazionale Tumori Fondazione "G. Pascale", Naples, Italy. · Oncology Specialists S C, Park Ridge, IL, USA. · Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Paris. · Istituti Fisioterapici Ospitalieri, Rome, Italy. · Cross Cancer Institute, Edmonton, AB, Canada. · H Lee Moffitt Cancer Center, Tampa, FL, USA. · University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. · Bristol-Myers Squibb, Wallingford, CT, USA. · Bristol-Myers Squibb, Braine-l'Alleud, Belgium. · European Institute of Oncology, Milan, Italy. ·Lancet Oncol · Pubmed #28162999.

ABSTRACT: BACKGROUND: The EORTC 18071 phase 3 trial compared adjuvant ipilimumab with placebo in patients with stage III melanoma. The primary endpoint, recurrence-free survival, was significantly longer in the ipilimumab group than in the placebo group. Investigator-reported toxic effects of ipilimumab consisted mainly of skin, gastrointestinal, endocrine, and hepatic immune-related adverse events. Adjuvant treatment with ipilimumab in this setting was approved in October, 2014, by the US Food and Drug Administration based on the results of the primary outcome of this trial. Here, we report the results of the secondary endpoint, health-related quality of life (HRQoL), of this trial. METHODS: EORTC 18071 was a multinational, double-blind, randomised, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) in 19 countries worldwide. Participants were randomly assigned (1:1) centrally by an interactive voice response system, to receive either ipilimumab 10 mg/kg or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. HRQoL was assessed with the EORTC QLQ-C30 quality-of-life instrument at baseline, weeks 4, 7, 10, and 24, and every 12 weeks thereafter up to 2 years, irrespective of disease progression. Results were summarised by timepoint and in a longitudinal manner in the intention-to-treat population. Two summary scores were calculated for each HRQoL scale: the average score reported during induction (ipilimumab or placebo at a dose of 10 mg/kg, administered as one single dose at the start of days 1, 22, 43, and 64-ie, four doses in 3 weeks), and the average score reported after induction. A predefined threshold of a 10 point difference between arms was considered clinically relevant. The primary HRQoL endpoint was the global health scale, with the predefined hypothesis of no clinically relevant differences after induction between groups. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. FINDINGS: Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to treatment: 475 in the ipilimumab group and 476 in the placebo group. Compliance with completing the HRQoL questionnaire was 893 (94%) of 951 patients at baseline, 693 (75%) of 924 at week 24, and 354 (51%) of 697 at week 108. Patient mean global health scores during (77·32 [SD 17·36] vs 72·96 [17·82]; p=0·00011) and after induction (76·48 [17·52] vs 72·32 [18·60]; p=0·00067) were statistically significantly different between groups but were not clinically relevant. Mean global health scores differed most between the groups at week 7 (77 [SD 19] in the placebo group vs 72 [22] in the ipilimumab group) and week 10 (77 [20] vs 70 [23]). Mean HRQoL scores differed by more than 10 points at week 10 between treatment groups for diarrhoea (7·67 [SD 17·05] for placebo vs 18·17 [28·35] for ipilimumab) and insomnia (15·17 [22·53] vs 25·60 [29·19]). INTERPRETATION: Despite increased toxicity, which led to treatment discontinuation for most patients during the induction phase of ipilimumab administration, overall HRQoL, as measured by the EORTC QLQ-C30, was similar between groups, as no clinically relevant differences (10 points or more) in global health status scores were observed during or after induction. Clinically relevant deterioration for some symptoms was observed at week 10, but after induction, no clinically relevant differences remained. Together with the primary analysis, results from this trial show that treatment with ipilimumab results in longer recurrence-free survival compared with that for treatment with placebo, with little impairment in HRQoL despite grade 3-4 investigator-reported adverse events. FUNDING: Bristol-Myers Squibb.

20 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 .).

21 Clinical Trial Prospective assessment of a gene signature potentially predictive of clinical benefit in metastatic melanoma patients following MAGE-A3 immunotherapeutic (PREDICT). 2016

Saiag, P / Gutzmer, R / Ascierto, P A / Maio, M / Grob, J-J / Murawa, P / Dreno, B / Ross, M / Weber, J / Hauschild, A / Rutkowski, P / Testori, A / Levchenko, E / Enk, A / Misery, L / Vanden Abeele, C / Vojtek, I / Peeters, O / Brichard, V G / Therasse, P. ·General Dermatology and Oncology Service, Ambroise-Paré Hospital, AP-HP, University of Versailles-Saint-Quentin-en-Yvelines, Boulogne, France philippe.saiag@uvsq.fr. · Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany. · National Institute for Tumors Foundation 'G. Pascale', Napoli. · Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. · Department of Dermatology and Skin Cancers, La Timone APHM Hospital, Aix-Marseille University, Marseille, France. · Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, Poznań, Poland. · Dermatology Clinic, Hôtel-Dieu Hospital, CHU Nantes, Nantes, France. · Department of Surgical Oncology, UTMD Anderson Cancer Center, Houston. · Moffitt Cancer Center, Tampa, USA. · Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany. · Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Center and Institute of Oncology, Warsaw, Poland. · Melanoma and Soft Tissue Sarcoma Division, European Institute of Oncology, Milan, Italy. · Petrov Research Institute of Oncology, St Petersburg, Russian Federation. · Department of Dermatology, University of Heidelberg, Heidelberg, Germany. · Department of Dermatology, University Hospital of Brest, Brest, France. · GSK Vaccines, Rixensart, Belgium. ·Ann Oncol · Pubmed #27502712.

ABSTRACT: BACKGROUND: Genomic profiling of tumor tissue may aid in identifying predictive or prognostic gene signatures (GS) in some cancers. Retrospective gene expression profiling of melanoma and non-small-cell lung cancer led to the characterization of a GS associated with clinical benefit, including improved overall survival (OS), following immunization with the MAGE-A3 immunotherapeutic. The goal of the present study was to prospectively evaluate the predictive value of the previously characterized GS. PATIENTS AND METHODS: An open-label prospective phase II trial ('PREDICT') in patients with MAGE-A3-positive unresectable stage IIIB-C/IV-M1a melanoma. RESULTS: Of 123 subjects who received the MAGE-A3 immunotherapeutic, 71 (58.7%) displayed the predictive GS (GS+). The 1-year OS rate was 83.1%/83.3% in the GS+/GS- populations. The rate of progression-free survival at 12 months was 5.8%/4.1% in GS+/GS- patients. The median time-to-treatment failure was 2.7/2.4 months (GS+/GS-). There was one complete response (GS-) and two partial responses (GS+). The MAGE-A3 immunotherapeutic was similarly immunogenic in both populations and had a clinically acceptable safety profile. CONCLUSION: Treatment of patients with MAGE-A3-positive unresectable stage IIIB-C/IV-M1a melanoma with the MAGE-A3 immunotherapeutic demonstrated an overall 1-year OS rate of 83.5%. GS- and GS+ patients had similar 1-year OS rates, indicating that in this study, GS was not predictive of outcome. Unexpectedly, the objective response rate was lower in this study than in other studies carried out in the same setting with the MAGE-A3 immunotherapeutic. Investigation of a GS to predict clinical benefit to adjuvant MAGE-A3 immunotherapeutic treatment is ongoing in another melanoma study.This study is registered at www.clinicatrials.gov NCT00942162.

22 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.

23 Clinical Trial Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. 2015

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 / Konto, Cyril / Hoos, Axel / de Pril, Veerle / Gurunath, Ravichandra Karra / de Schaetzen, Gaetan / Suciu, Stefan / Testori, Alessandro. ·Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. Electronic address: alexander.eggermont@gustaveroussy.fr. · IOV-IRCCS, Melanoma Oncology Unit, Padova, Italy. · Aix-Marseille University, Hôpital de La Timone APHM, Marseille, France. · University of Zürich Hospital, Zürich, Switzerland. · Memorial Sloan-Kettering Cancer Center, New York, NY, USA. · Aarhus University Hospital, Aarhus, Denmark. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. · Istituto Nazionale Tumori Fondazione G Pascale, Naples, Italy. · Oncology Specialists SC, Park Ridge, IL, USA. · Assistance Publique Hôpitaux de Paris, Dermatology and CIC Departments, Hôpital Saint Louis, University Paris 7, INSERM U976, France. · Istituti Fisioterapici Ospitalieri, Rome, Italy. · Cross Cancer Institute, Edmonton, Alberta, Canada. · H Lee Moffitt Cancer Center, Tampa, FL, USA. · University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. · Bristol-Myers Squibb, Wallingford, CT, USA. · Bristol-Myers Squibb, Braine-l'Alleud, Belgium. · EORTC Headquarters, Brussels, Belgium. · European Institute of Oncology, Milan, Italy. ·Lancet Oncol · Pubmed #25840693.

ABSTRACT: BACKGROUND: Ipilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence. METHODS: We did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. FINDINGS: Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2·74 years (IQR 2·28-3·22), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26·1 months (95% CI 19·3-39·3) in the ipilimumab group versus 17·1 months (95% CI 13·4-21·6) in the placebo group (hazard ratio 0·75; 95% CI 0·64-0·90; p=0·0013); 3-year recurrence-free survival was 46·5% (95% CI 41·5-51·3) in the ipilimumab group versus 34·8% (30·1-39·5) in the placebo group. The most common grade 3-4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50 [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barré syndrome. INTERPRETATION: Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value. FUNDING: Bristol-Myers Squibb.

24 Clinical Trial Dacarbazine in combination with bevacizumab for the treatment of unresectable/metastatic melanoma: a phase II study. 2015

Ferrucci, Pier F / Minchella, Ida / Mosconi, Massimo / Gandini, Sara / Verrecchia, Francesco / Cocorocchio, Emilia / Passoni, Claudia / Pari, Chiara / Testori, Alessandro / Coco, Paola / Munzone, Elisabetta. ·aOncology of Melanoma Unit bEarly Drug Development for Innovative Therapies Division cDermatoncological Division dDepartment of Epidemiology and Biostatistics, European Institute of Oncology, Milan eRoche S.p.A., Monza, Italy. ·Melanoma Res · Pubmed #25746039.

ABSTRACT: The combined treatment of dacarbazine with an antiangiogenic drug such as bevacizumab may potentiate the therapeutic effects of dacarbazine in metastatic melanoma (MM). Preliminary antitumour activity of dacarbazine plus bevacizumab is evaluated, together with the toxicity and safety profile, in MM patients. This prospective, open-label, phase II study included patients with previously untreated MM or unresectable melanoma. Patients received dacarbazine and bevacizumab until progressive disease or unacceptable toxicity. The primary efficacy variable was the overall response rate. The secondary efficacy parameters included duration of response, duration of stable disease, time to progression/progression-free survival, time to treatment failure and overall survival. The safety analysis included recordings of adverse events and exposure to study treatment. The intention-to-treat population included 37 patients (24 men and 13 women, mean age 54.2±13.1 years). Overall response rate was 18.9% (seven patients achieved a response) and clinical benefit was 48.6%. In patients who achieved a response, the median duration of response was 16.9 months and the median duration of stable disease was 12.5 months. The median time to progression/progression-free survival and time to treatment failure were 5.5 and 3.1 months, respectively. The median overall survival was 11.4 months. Almost all patients (94.6%) experienced at least one adverse event; however, no new area of toxicity of bevacizumab emerged. The dacarbazine/bevacizumab combination provides benefits compared with dacarbazine monotherapy in historical controls, with an acceptable safety profile. This combination appears to be a valid option in specific subgroups of patients, namely, those triple negative (BRAF, C-KIT and NRAS wild type) or with a BRAF mutation who have already received, or are not eligible for, immunomodulating or targeted agents.

25 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.

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