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Melanoma: HELP
Articles from Westmead Hospital
Based on 161 articles published since 2008
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These are the 161 published articles about Melanoma that originated from Westmead Hospital during 2008-2019.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7
1 Editorial Is chemotherapy still an option in the treatment of melanoma? 2015

Carlino, M S / Long, G V. ·Melanoma Institute Australia, Sydney The Sydney Medical School, The University of Sydney, Sydney Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney. · Melanoma Institute Australia, Sydney The Sydney Medical School, The University of Sydney, Sydney The Mater Hospital, North Sydney, Australia georgina.long@sydney.edu.au. ·Ann Oncol · Pubmed #26374287.

ABSTRACT: -- No abstract --

2 Editorial Molecular biomarkers of prognosis in melanoma: how far are we from the clinic? 2013

Schramm, Sarah-Jane / Menzies, Alexander M / Mann, Graham J. ·aThe University of Sydney at Westmead Millennium Institute for Medical Research bMelanoma Institute Australia, Sydney, New South Wales, Australia. ·Melanoma Res · Pubmed #24165033.

ABSTRACT: -- No abstract --

3 Review Oncogenic signaling in uveal melanoma. 2018

Park, John J / Diefenbach, Russell J / Joshua, Anthony M / Kefford, Richard F / Carlino, Matteo S / Rizos, Helen. ·Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia. · Melanoma Institute Australia, Sydney, New South Wales, Australia. · Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, New South Wales, Australia. · Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, New South Wales, Australia. ·Pigment Cell Melanoma Res · Pubmed #29738114.

ABSTRACT: Uveal melanoma is the most common primary cancer of the eye, and despite rapidly emerging insights into the molecular profile of this disease, prognosis of patients with metastatic uveal melanoma remains poor with mortality rates unchanged in over 35 years. Early genetic events activate G protein-coupled receptor signaling in nearly all uveal tumors via mutually exclusive mutations in the GNAQ, GNA11, CYSLTR2, or PLCB4 genes. A multitude of signaling cascades downstream of G protein activation, including protein kinase C and mitogen-activated protein kinase activity, are actionable, and many ongoing clinical trials are targeting these pathways. Additional cytogenetic and genetic changes, however, including chromosome 3 monosomy, mutations in the BAP1 tumor suppressor gene, alterations in the splicing factors SRSF2/SF3B1, and mutations in the translation initiation factor EIF1AX, modulate signaling output in uveal tumors and modify the risk of metastases. Here, we review the complex interactions between genetic, molecular signaling, and prognostic profiles in uveal melanoma; the clinical implications of these interactions; and the latest potential targets for rational therapy.

4 Review Metastases to the parotid gland - A review of the clinicopathological evolution, molecular mechanisms and management. 2018

Badlani, James / Gupta, Ruta / Smith, Joel / Ashford, Bruce / Ch'ng, Sydney / Veness, Michael / Clark, Jonathan. ·Sydney Head and Neck Cancer Institute, Department of Head and Neck Surgery, Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia; Department of Oral and Maxillofacial Surgery, Gold Coast University Hospital, Southport, Queensland, Australia. Electronic address: jsbadlani@yahoo.com. · Department of Pathology, Royal Prince Alfred Hospital, New South Wales, Australia; Central Clinical School, University of Sydney, New south Wales, Australia. · Sydney Head and Neck Cancer Institute, Department of Head and Neck Surgery, Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia. · Sydney Head and Neck Cancer Institute, Department of Head and Neck Surgery, Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia; Department of Surgery, Wollongong Hospital, Wollongong, New South Wales, Australia. · Central Clinical School, University of Sydney, New south Wales, Australia; Department of Radiation Oncology, Westmead Hospital, Westmead, New South Wales, Australia. · Sydney Head and Neck Cancer Institute, Department of Head and Neck Surgery, Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia; Central Clinical School, University of Sydney, New south Wales, Australia. ·Surg Oncol · Pubmed #29549903.

ABSTRACT: Metastases to the parotid gland are the commonest cause of parotid malignancies in many regions of the world including Australia. The most common etiology of these metastases is head and neck cutaneous squamous cell carcinoma (HNcSCC) followed by melanoma of the head and neck. This article focuses on the management of the aforementioned pathologies including Merkel cell carcinoma (MCC).

5 Review Liquid biomarkers in melanoma: detection and discovery. 2018

Lim, Su Yin / Lee, Jenny H / Diefenbach, Russell J / Kefford, Richard F / Rizos, Helen. ·Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia. · Melanoma Institute Australia, Sydney, NSW, Australia. · Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, NSW, Australia. · Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia. Helen.rizos@mq.edu.au. · Melanoma Institute Australia, Sydney, NSW, Australia. Helen.rizos@mq.edu.au. · Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, 2 Technology Place, Sydney, NSW, 2109, Australia. Helen.rizos@mq.edu.au. ·Mol Cancer · Pubmed #29343260.

ABSTRACT: A vast array of tumor-derived genetic, proteomic and cellular components are constantly released into the circulation of cancer patients. These molecules including circulating tumor DNA and RNA, proteins, tumor and immune cells are emerging as convenient and accurate liquid biomarkers of cancer. Circulating cancer biomarkers provide invaluable information on cancer detection and diagnosis, prognosticate patient outcomes, and predict treatment response. In this era of effective molecular targeted treatments and immunotherapies, there is now an urgent need to implement use of these circulating biomarkers in the clinic to facilitate personalized therapy. In this review, we present recent findings in circulating melanoma biomarkers, examine the challenges and promise of evolving technologies used for liquid biomarker discovery, and discuss future directions and perspectives in melanoma biomarker research.

6 Review Cutaneous Adverse Events of New Anti-melanoma Therapies: Classification and Management. 2017

Hwang, S J E / Anforth, R / Carlos, G / Fernandez-Peñas, P. ·Department of Dermatology, Westmead Hospital, Westmead, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. ·Actas Dermosifiliogr · Pubmed #27642030.

ABSTRACT: Over the past decade, targeted therapies such as BRAF inhibitors, MEK inhibitors and immunotherapies such as anti-CTLA4 and anti-PD1 antibodies have emerged as novel treatments of advanced melanoma. Along with increased use of these therapies, a range of cutaneous adverse events have also emerged, varying from more serious and frequent cutaneous squamous cell carcinoma to mere cosmetic changes such as curly hair or rare severe toxic epidermal necrolysis. Early detection and management of these cutaneous adverse events will aid patients to receive accurate treatment, avoid unnecessary discontinuation of anti-tumour treatment and improve the patient's overall quality of life. This review will describe various cutaneous adverse events of anti-melanoma therapies and its management.

7 Review Ipilimumab Combined with Nivolumab: A Standard of Care for the Treatment of Advanced Melanoma? 2016

Carlino, Matteo S / Long, Georgina V. ·Melanoma Institute Australia, The University of Sydney, and Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, Australia. · Melanoma Institute Australia, The University of Sydney, and Royal North Shore and Mater Hospitals, Sydney, Australia. georgina.long@sydney.edu.au. ·Clin Cancer Res · Pubmed #27340279.

ABSTRACT: Ipilimumab, an inhibitor of CTLA-4 on T cells, was the first drug to improve overall survival in patients with advanced melanoma. Subsequently, inhibitors of PD-1, including nivolumab and pembrolizumab, were shown to be superior to ipilimumab with a more favorable safety profile. The combination of ipilimumab and nivolumab is associated with a further improvement in response rate and progression-free survival; however, the combination is associated with an increased rate of immune-related toxicities. In 2015, the FDA approved the combination for the treatment of BRAF wild-type advanced melanoma. This review examines the preclinical rationale for the combination of ipilimumab and nivolumab as well as the efficacy and toxicity data from clinical trials in patients with advanced melanoma. Finally, alternative treatment options are discussed with a focus on patient selection. Clin Cancer Res; 22(16); 3992-8. ©2016 AACR.

8 Review PD-1 and PD-L1 inhibitors in melanoma treatment: past success, present application and future challenges. 2016

Lee, Jenny / Kefford, Richard / Carlino, Matteo. ·Crown Princess Mary Cancer Centre, Westmead hospital, Westmead, NSW 2145, Australia. · Departments of Clinical Medicine and Biomedical Sciences, Macquarie University, NSW 2109, Australia. · Melanoma Institute Australia, North Sydney, NSW, Australia. · University of Sydney, Sydney, NSW, Australia. ·Immunotherapy · Pubmed #27197541.

ABSTRACT: Anti-programmed death (PD)-1 antibodies have now become the standard of care for advanced melanoma, with two drugs gaining US FDA approval in recent years: nivolumab and pembrolizumab. Both have demonstrated significant activity and durable response with a manageable toxicity profile. Despite initial success, ongoing challenges include patient selection and predictors of response, innate resistance and optimizing combination strategies. In this overview, we take a closer look at the history and development of therapeutic targets to the PD-1/PD-ligand (L)1 pathway, clinical evidence, availability of biomarkers and their limitations in clinical practice and future strategies to improve treatment outcomes.

9 Review Identification, Review, and Systematic Cross-Validation of microRNA Prognostic Signatures in Metastatic Melanoma. 2016

Jayawardana, Kaushala / Schramm, Sarah-Jane / Tembe, Varsha / Mueller, Samuel / Thompson, John F / Scolyer, Richard A / Mann, Graham J / Yang, Jean. ·School of Mathematics and Statistics, The University of Sydney, Sydney, NSW, Australia. · The Westmead Millennium Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia; Melanoma Institute Australia, Sydney, NSW, Australia. Electronic address: sarah-jane.schramm@sydney.edu.au. · The Westmead Millennium Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia; Melanoma Institute Australia, Sydney, NSW, Australia. · Melanoma Institute Australia, Sydney, NSW, Australia; Discipline of Surgery, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. · Melanoma Institute Australia, Sydney, NSW, Australia; Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. ·J Invest Dermatol · Pubmed #26763444.

ABSTRACT: In metastatic melanoma, it is vital to identify and validate biomarkers of prognosis. Previous studies have systematically evaluated protein biomarkers or mRNA-based expression signatures. No such analyses have been applied to microRNA (miRNA)-based prognostic signatures. As a first step, we identified two prognostic miRNA signatures from publicly available data sets (Gene Expression Omnibus/The Cancer Genome Atlas) of global miRNA expression profiling information. A 12-miRNA signature predicted longer survival after surgery for resection of American Joint Committee on Cancer stage III disease (>4 years, no sign of relapse) and outperformed American Joint Committee on Cancer standard-of-care prognostic markers in leave-one-out cross-validation analysis (error rates 34% and 38%, respectively). A similar 15-miRNA biomarker derived from The Cancer Genome Atlas miRNA-seq data performed slightly worse (39%) than these current biomarkers. Both signatures were then assessed for replication in two independent data sets and subjected to systematic cross-validation together with the three other miRNA-based prognostic signatures proposed in the literature to date. Five miRNAs (miR-142-5p, miR-150-5p, miR-342-3p, miR-155-5p, and miR-146b-5p) were reproducibly associated with patient outcome and have the greatest potential for application in the clinic. Our extensive validation approach highlighted among multiple independent cohorts the translational potential and limitations of miRNA signatures, and pointed to future directions in the analysis of this emerging class of markers.

10 Review Targeting oncogenic BRAF and aberrant MAPK activation in the treatment of cutaneous melanoma. 2015

Carlino, Matteo S / Long, Georgina V / Kefford, Richard F / Rizos, Helen. ·Departments of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia; Centre for Cancer Research, Westmead Millennium Institute, Westmead, New South Wales, Australia; Melanoma Institute Australia, Sydney, New South Wales, Australia; The Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia. Electronic address: matteo.carlino@sydney.edu.au. · Melanoma Institute Australia, Sydney, New South Wales, Australia; The Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia; The Mater Hospital, North Sydney, New South Wales, Australia. · Departments of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia; Centre for Cancer Research, Westmead Millennium Institute, Westmead, New South Wales, Australia; Melanoma Institute Australia, Sydney, New South Wales, Australia; Faculty of Medicine and Health Science, Macquarie University, New South Wales, Australia. · Centre for Cancer Research, Westmead Millennium Institute, Westmead, New South Wales, Australia; Melanoma Institute Australia, Sydney, New South Wales, Australia; Faculty of Medicine and Health Science, Macquarie University, New South Wales, Australia. ·Crit Rev Oncol Hematol · Pubmed #26358420.

ABSTRACT: BRAF and MEK inhibitors, alone or in combination, are highly active in the 40% of patients with BRAF mutant metastatic melanoma. Despite this activity resistance often develops in patients treated with these agents. This review summarises the biology of the mitogen activated protein kinase (MAPK) pathway, with particular reference to the effects of BRAF and MEK inhibitors in BRAF mutant melanoma. The clinical and molecular predictors of response and mechanisms of resistance are discussed in detail along with the biological rationale and evidence for future treatment strategies in both MAPK inhibitor naïve and resistant BRAF mutant melanoma.

11 Review Treatment algorithms in stage IV melanoma. 2015

Espinosa, Enrique / Grob, Jean-Jacques / Dummer, Reinhard / Rutkowski, Piotr / Robert, Caroline / Gogas, Helen / Kefford, Richard / Eggermont, Alexander M M / Martin Algarra, Salvador / Hauschild, Axel / Schadendorf, Dirk. ·1Service of Oncology, Hospital La Paz, Madrid, Spain · 2Department of Dermatology, Hopital Ste Marguerite, Marseille, France · 3Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland · 4Department of Sarcoma and Melanoma, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland · 5Department of Dermatology (CR), and General Director (AE), Institute Gustave Roussy, Villejuif Cedex, France · 6First Department of Medicine, University of Athens Medical School, Athens, Greece · 7Department of Oncology, Westmead Hospital and Melanoma Institute Australia, University of Sydney, Sydney, Australia · 8Service of Oncology, Clinica Universitaria de Navarra, Pamplona, Spain · 9Department of Dermatology, University of Kiel, Kiel, Germany · and 10Department of Dermatology, University Hospital Essen, Essen, Germany. ·Am J Ther · Pubmed #24413374.

ABSTRACT: The molecular classification of melanoma and the advent of new drugs are changing the paradigm of therapy for advanced melanoma. A review of the recent key studies was performed, followed by a discussion in an expert forum. The aim of this review was to generate a therapeutic algorithm for stage IV melanoma. Tumor genotyping for BRAF and/or KIT should be performed before selection of therapy. For most BRAF-mutated melanoma patients and particularly those with a high tumor load, vemurafenib or other BRAF inhibitors such as dabrafenib are the treatment of choice. KIT inhibitors can be effective in KIT-mutant tumors, especially in those patients with mutations at exons 11 and 13. Ipilimumab is a good option for patients with nontargetable or nondetected mutations and those who progress under therapy with vemurafenib or a KIT inhibitor. There is still a role for conventional chemotherapy either as first-line treatment in BRAF wild-type patients or as salvage therapy in second or third line, or after other treatment modalities. Participation in clinical trials is strongly encouraged, either in first or in subsequent lines. New therapeutic options for advanced melanoma are guided by tumor genotyping. The current therapeutic algorithm includes kinase inhibitors, anti-CTLA4 therapy, immunotherapy, and chemotherapy, depending on the tumor genotype and response to previous treatments. Participation in clinical trials should always be encouraged because the treatment goal is long-term survival and potential cure in a subset of patients.

12 Review Hepatic resection for metastatic melanoma: a systematic review. 2014

Hameed, Ahmer M / Ng, E-Ern I / Johnston, Emma / Hollands, Michael J / Richardson, Arthur J / Pleass, Henry C / Lam, Vincent W T. ·aDepartment of Surgery, Westmead Hospital bDiscipline of Surgery, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. ·Melanoma Res · Pubmed #24300091.

ABSTRACT: Melanoma metastatic to the liver has a very poor prognosis, and has traditionally been treated using systemic chemotherapy with limited efficacy. Surgery is increasingly being explored as a therapeutic option for melanoma liver metastases, with varying levels of success. A systematic review was undertaken to explore the short-term and long-term outcomes associated with hepatectomy for melanoma metastases, in addition to identifying prognostic factors favouring increased survival. All eligible studies were identified through an electronic search of Medline and Embase (January 1990-March 2013). Each study was independently analysed by two reviewers, with relevant data extracted and tabulated according to predetermined criteria. Thirteen studies were selected that fulfilled the selection criteria, with a total of 551 patients undergoing hepatic resection for melanoma metastases. Metastases to the liver occurred at a median interval of 54 months. The median perioperative morbidity and mortality were 10% (range 0-28.6%) and 0% (range 0-7.1%), respectively. The median overall survival for operative patients was 24 months, with median survival being greater in the R0 resection group (25 months; range 9.5-65.6 months) compared with the R1/2 resection group (16 months; range 11.7-29 months). Overall median 1-, 3- and 5-year survival rates were 70% (range 39-100%), 36% (range 10.2-53%) and 24% (range 3-53%), respectively. Positive prognostic factors may include single hepatic metastases, a longer time to development of hepatic metastases and R0 resection. Hepatic resection for metastatic melanoma might confer a distinct survival benefit in a select group of patients, although disease recurrence is the norm.

13 Review Cutaneous toxicities of RAF inhibitors. 2013

Anforth, Rachael / Fernandez-Peñas, Pablo / Long, Georgina V. ·Department of Dermatology, Westmead Hospital, Sydney, NSW, Australia. ·Lancet Oncol · Pubmed #23276366.

ABSTRACT: The RAF inhibitors vemurafenib and dabrafenib are emerging as the standard of care for Val600 BRAF-mutant metastatic melanoma. These drugs have shown clinical benefit over the standard care (dacarbazine); however, they are associated with frequent cutaneous adverse events, which can be concerning to the patient and their physician. Herein, we review the range of cutaneous disorders that seem to be induced by RAF inhibitors, including cutaneous squamous-cell carcinoma, hyperkeratotic lesions, Grover's disease, keratosis pilaris-like reactions, and photosensitivity. These disorders often affect patients' quality of life; therefore, dermatological assessment and timely management is essential to ensure that patients continue to use RAF inhibitors.

14 Review Treatment of melanoma brain metastases: a new paradigm. 2012

Carlino, Matteo S / Fogarty, Gerald B / Long, Georgina V. ·Westmead Institute for Cancer Research, Westmead Millennium Institute, Sydney, Australia. ·Cancer J · Pubmed #22453023.

ABSTRACT: Brain metastases occur commonly in patients with metastatic melanoma, are associated with a poor prognosis, and cause significant morbidity. Both surgery and stereotactic radiosurgery are used to control brain metastases and, in selected patients, improve survival. In those with extensive brain involvement, whole-brain radiotherapy can alleviate symptoms. Historically, systemic therapy has had little role to play in the management of melanoma brain metastases; however, early clinical trials of BRAF inhibitors have shown promising activity. This review examines the evidence for local and systemic treatments in the management of patients with melanoma brain metastases. We present a new treatment algorithm for melanoma patients with brain metastases, which integrates the evolving evidence for the use of BRAF inhibitors.

15 Review Review and cross-validation of gene expression signatures and melanoma prognosis. 2012

Schramm, Sarah-Jane / Campain, Anna E / Scolyer, Richard A / Yang, Yee Hwa / Mann, Graham J. ·Sydney Medical School, The University of Sydney at Westmead Millennium Institute, Sydney, New South Wales, Australia. graham.mann@sydney.edu.au ·J Invest Dermatol · Pubmed #21956122.

ABSTRACT: In melanoma, there is an urgent need to identify novel biomarkers with prognostic performance superior to traditional clinical and histological parameters. Gene expression-based prognostic signatures offer promise, but studies have been challenged by sample scarcity, cohort heterogeneity, and doubts about the efficacy of such signatures relative to current clinical practices. Motivated by new studies that have begun to address these challenges, we reviewed prognostic signatures derived from gene expression microarray analysis of human melanoma tissue. We used REMARK-based criteria to select the most relevant studies and directly compared their signature gene lists. Through functional ontology enrichment analysis, we observed that these independent data sets converge in part upon immune response processes and the G-protein signaling NRAS-regulation pathway, both important in melanoma development and progression. The signatures correctly predicted patient outcome in independent gene expression data sets with some notably low misclassification rates, particularly among studies involving more advanced-stage tumors. This successful cross-validation indicates that gene expression analysis-based signatures are becoming translationally relevant to care of melanoma patients, as well as improving understanding of the aspects of melanoma biology that determine patient outcome.

16 Review Melanoma prognosis: a REMARK-based systematic review and bioinformatic analysis of immunohistochemical and gene microarray studies. 2011

Schramm, Sarah-Jane / Mann, Graham J. ·Melanoma Genomics and Genetic Epidemiology Research Group, The University of Sydney at Westmead Millennium Institute, Westmead, NSW, Australia. ·Mol Cancer Ther · Pubmed #21659462.

ABSTRACT: Despite intensive research efforts, within-stage survival rates for melanoma vary widely. Pursuit of molecular biomarkers with improved prognostic significance over clinicohistological measures has produced extensive literature. Reviews have synthesized these data, but none have systematically partitioned high-quality studies from the remainder across different molecular methods nor examined system properties of that output. Databases were searched for studies analyzing protein expression by immunohistochemistry (n = 617, extending the only systematic review to date by 102 studies) or for gene expression microarray studies (n = 45) in melanoma in relation to outcome. REMARK-derived criteria were applied to identify high-quality studies. Biomarkers and pathways were functionally assessed by using gene ontology software. Most manuscripts did not meet REMARK-based criteria, an ongoing trend that can impede translational research. Across REMARK-compliant literature, 41 proteins were significantly associated with outcome. Multimarker tests consistently emerged among the most promising potential biomarkers, indicating a need to continue assessing candidates in that composite setting. Twenty-one canonical pathways were populated by outcome-related proteins but not by those that failed to show such an association; we propose that this set of pathways warrants closer investigation to understand drivers of poor outcome in melanoma. Two-gene expression microarray studies met REMARK-based criteria reflecting a genuine paucity of literature in the area. The 254 outcome-related genes were examined for correspondences with the systematically identified protein signature. This analysis highlighted proliferating cell nuclear antigen and survivin as priorities for further examination as biomarkers in melanoma prognosis, and illustrated ongoing need to integrate alternative approaches to biomarker discovery in melanoma translational research.

17 Review The important role of radiotherapy in patients with non-melanoma skin cancer and other cutaneous entities. 2008

Veness, M J. ·Department of Radiation Oncology, Westmead Cancer Care Centre, Westmead Hospital, Sydney, New South Wales, Australia. michael.veness@swahs.health.nsw.gov.au ·J Med Imaging Radiat Oncol · Pubmed #18477123.

ABSTRACT: Non-melanoma skin cancer is the commonest malignancy worldwide and a significant public health issue. Although most non-melanoma skin cancers are small and easily excised or ablated, a recommendation of definitive radiotherapy is often made in patients where the outcome (cosmetic and/or functional) will probably be better with radiotherapy compared to surgery. The aim of adjuvant radiotherapy is to reduce the risk of loco-regional recurrence and the role of palliative radiotherapy is important in improving the quality of life in patients with advanced and/or incurable disease. The aim of this review article is to broadly discuss the various clinical settings in which a recommendation of radiotherapy may be made and also includes a discussion on less frequently encountered cutaneous entities (e.g. in situ squamous cell carcinoma, keratocanthoma, lentigo maligna, cutaneous lymphomas and malignant fibrous tumours).

18 Clinical Trial Outcomes by line of therapy and programmed death ligand 1 expression in patients with advanced melanoma treated with pembrolizumab or ipilimumab in KEYNOTE-006: A randomised clinical trial. 2018

Carlino, Matteo S / Long, Georgina V / Schadendorf, Dirk / Robert, Caroline / Ribas, Antoni / Richtig, Erika / Nyakas, Marta / Caglevic, Christian / Tarhini, Ahmed / Blank, Christian / Hoeller, Christoph / Bar-Sela, Gil / Barrow, Catherine / Wolter, Pascal / Zhou, Honghong / Emancipator, Kenneth / Jensen, Erin H / Ebbinghaus, Scot / Ibrahim, Nageatte / Daud, Adil. ·Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, NSW, Australia; Blacktown Hospital, Blacktown, NSW, Australia; Melanoma Institute Australia, Sydney, NSW, Australia; School of Medicine, University of Sydney, Sydney, NSW, Australia. Electronic address: Matteo.carlino@sydney.edu.au. · Melanoma Institute Australia, Sydney, NSW, Australia; Department of Medical Oncology and Translational Research, University of Sydney, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia; Mater Hospital, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au. · Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. Electronic address: Dirk.Schadendorf@uk-essen.de. · Department of Oncology, Gustave Roussy, Villejuif, France; Paris-Sud University, Orsay, France. Electronic address: Caroline.Robert@igr.fr. · Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: aribas@mednet.ucla.edu. · Department of Dermatology, Medical University of Graz, Graz, Austria. Electronic address: erika.richtig@medunigraz.at. · Department of Clinical Cancer Research, Oslo University Hospital, Oslo, Norway. Electronic address: marnya@ous-hf.no. · Unit of Investigational Cancer Drugs, Instituto Oncologico Fundación Arturo López Pérez, Santiago, Chile. Electronic address: oncodemia@yahoo.com. · Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: tarhiniaa@upmc.edu. · Division of Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands. Electronic address: c.blank@nki.nl. · Department of Dermatology, Medical University of Vienna, Vienna, Austria. Electronic address: christoph.hoeller@meduniwien.ac.at. · Division of Oncology, Rambam Health Care Campus, Haifa, Israel. Electronic address: g_barsela@rambam.health.gov.il. · Wellington Blood and Cancer Centre, Wellington Hospital, Wellington, New Zealand. Electronic address: Catherine.Barrow@ccdhb.org.nz. · Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium. Electronic address: pascalwolter@hotmail.com. · Department of BARDS, Merck & Co., Inc., Kenilworth, NJ, USA. Electronic address: honghongz@gmail.com. · Companion Diagnostics, Merck & Co., Inc., Kenilworth, NJ, USA. Electronic address: kenneth.emancipator@merck.com. · LDS - Medical Communications, Merck & Co., Inc., North Wales, PA, USA. Electronic address: erin_jensen2@merck.com. · Department of Clinical Oncology, Merck & Co., Inc., North Wales, PA, USA. Electronic address: scot_ebbinghaus@merck.com. · Department of Clinical Oncology, Merck & Co., Inc., North Wales, PA, USA. Electronic address: nageatte.ibrahim@merck.com. · University of California, San Francisco, San Francisco, CA, USA. Electronic address: adaud@medicine.ucsf.edu. ·Eur J Cancer · Pubmed #30096704.

ABSTRACT: BACKGROUND: Predictive biomarkers of patients likely to benefit from anti-programmed death 1 inhibitor therapy have clinical relevance. We examined whether line of therapy or tumour programmed death ligand 1 (PD-L1) expression affects the efficacy and safety of pembrolizumab, compared with ipilimumab, in advanced melanoma. METHODS: Of 834 patients enrolled in the randomised, open-label phase III KEYNOTE-006 study, 833 were included in this analysis. Patients were randomly assigned 1:1:1 to receive pembrolizumab 10 mg/kg every 2 or 3 weeks (for 24 months) or ipilimumab 3 mg/kg every 3 weeks (for four doses) until disease progression/intolerable toxicity. This analysis evaluated progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). Data cut-off: 03 November 2016. RESULTS: Of the patients, 60.3% were male, 65.9% were treatment naive and 80.6% had PD-L1-positive tumours (median follow-up was 33.9 months). Twenty-four-month survival rates were higher with pembrolizumab than with ipilimumab in treatment-naive (PFS 31.0% versus 14.6%; OS 58.0% versus 44.7%) and previously treated patients (PFS 25.7% versus 11.3%; OS 49.2% versus 37.9%). Twenty-four-month survival rates were higher with pembrolizumab than with ipilimumab in patients with PD-L1-positive tumours (PFS 33.2% versus 13.1%; OS 58.4% versus 45.0%) and similar in PD-L1-negative tumours (PFS 14.9% versus NR [no data at 24 months for a PFS estimate]; OS 43.6% versus 31.8%). Safety of pembrolizumab by subgroup was consistent with previous reports. CONCLUSIONS: Findings support pembrolizumab monotherapy as standard of care in patients with advanced melanoma, regardless of first- or second-line therapy or PD-L1 status. CLINICALTRIALS. GOV IDENTIFIER: NCT01866319.

19 Clinical Trial Survival and prognostic factors for patients with melanoma brain metastases in the era of modern systemic therapy. 2018

Tio, Martin / Wang, Xuan / Carlino, Matteo S / Shivalingam, Brindha / Fogarty, Gerald B / Guminski, Alexander D / Lo, Serigne / Hong, Angela M / Menzies, Alexander M / Long, Georgina V. ·Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW, Australia. · Peking University Cancer Hospital and Institute, Beijing, China. · Melanoma Institute Australia, North Sydney, NSW, Australia. · Crown Princess Mary Cancer Centre Westmead, Sydney, NSW, Australia. · Sydney Medical School, The University of Sydney, Camperdown, NSW, Australia. · Royal Prince Alfred Hospital, Camperdown, NSW, Australia. · Mater Hospital, North Sydney, NSW, Australia. · Genesis Cancer Care, Mater Radiation Oncology, North Sydney, NSW, Australia. ·Pigment Cell Melanoma Res · Pubmed #29277979.

ABSTRACT: Historically, the prognosis of patients with melanoma brain metastases is poor, with median overall survival (OS) of 4-6 months. Little is known of OS in the era of modern systemic therapies and local therapy with stereotactic radiosurgery (SRS) or surgery. Patients diagnosed with melanoma brain metastases at Melanoma Institute Australia from January 2011 to December 2014 were included. OS and prognostic factors were analysed using Cox regression and Kaplan-Meier survival analyses.355 patients were included. The median OS was 7.1 months (95% confidence interval [CI] 6.0-8.1). Median OS differed by treatment modality: systemic therapy and SRS and/or surgery 14.9 months (95% CI 10.7-19.0), SRS and/or surgery with or without whole brain radiotherapy (WBRT) 6.4 months (95% CI 5.4-7.5), systemic therapy 5.4 months (95% CI 3.1-7.7), systemic therapy and WBRT 5.2 months (95% CI 4.1-6.4), WBRT 4.4 months (95% CI 2.4-6.3), and best supportive care 1.8 months (95% CI 1.2-2.3). OS for patients with melanoma brain metastases appears improved in the modern era, particularly for patients who are candidates for systemic therapy with SRS and/or surgery.

20 Clinical Trial Metastasis-specific patterns of response and progression with anti-PD-1 treatment in metastatic melanoma. 2018

Lee, Jenny H J / Lyle, Megan / Menzies, Alexander M / Chan, Matthew M K / Lo, Serigne / Clements, Arthur / Carlino, Matteo S / Kefford, Richard F / Long, Georgina V. ·Departments of Biomedical Sciences and Clinical Medicine, Macquarie University, Sydney, NSW, Australia. · Melanoma Institute Australia, Sydney, NSW, Australia. · Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, NSW, Australia. · University of Sydney, Sydney, NSW, Australia. · Liz Plummer Cancer Care Centre, Cairns Hospital, Cairns, QLD, Australia. · Royal North Shore Hospital, Sydney, NSW, Australia. · Gosford Hospital, Gosford, NSW, Australia. · Norwest hospital, Sydney, NSW, Australia. · Sydney Adventist Hospital, Sydney, NSW, Australia. ·Pigment Cell Melanoma Res · Pubmed #29171176.

ABSTRACT: This study evaluated patterns of response as discerned by comprehensive metastasis-specific analysis in metastatic melanoma patients receiving anti-PD-1 antibodies. Bi-dimensional measurements of every metastasis in patients enrolled in the KEYNOTE-001 trial at a single institution were obtained at baseline and throughout treatment. Twenty-seven evaluable patients had 399 baseline metastases measurable on CT imaging. Complete response (CR) which occurred in 52.6% of metastases was smaller (mean 223 mm

21 Clinical Trial Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. 2017

Long, Georgina V / Hauschild, Axel / Santinami, Mario / Atkinson, Victoria / Mandalà, Mario / Chiarion-Sileni, Vanna / Larkin, James / Nyakas, Marta / Dutriaux, Caroline / Haydon, Andrew / Robert, Caroline / Mortier, Laurent / Schachter, Jacob / Schadendorf, Dirk / Lesimple, Thierry / Plummer, Ruth / Ji, Ran / Zhang, Pingkuan / Mookerjee, Bijoyesh / Legos, Jeff / Kefford, Richard / Dummer, Reinhard / Kirkwood, John M. ·From the Melanoma Institute Australia, University of Sydney, Royal North Shore and Mater Hospitals (G.V.L.), and Macquarie University, Melanoma Institute Australia, University of Sydney, and Westmead Hospital (R.K.), Sydney, Princess Alexandra Hospital, Gallipoli Medical Research Foundation, University of Queensland, Brisbane (V.A.), and Alfred Hospital, Melbourne, VIC (A. Haydon) - all in Australia · University Hospital Schleswig-Holstein, Kiel (A. Hauschild), and University Hospital Essen, Essen, and the German Cancer Consortium, Heidelberg (D.S.) - all in Germany · Fondazione Istituto Nazionale Tumori, Milan (M.S.), Papa Giovanni XXIII Cancer Center Hospital, Bergamo (M.M.), and the Melanoma Oncology Unit, Veneto Oncology Institute, Padua (V.C.-S.) - all in Italy · Rikshospitalet-Radiumhospitalet, Oslo (M.N.) · Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux (C.D.), Institute Gustave Roussy, Paris (C.R.), Université de Lille, INSERM Unité 1189, Centre Hospitalier Régional Universitaire de Lille, Lille (L.M.), and the Medical Oncology Department, Centre Eugène Marquis, Rennes (T.L.) - all in France · Ella Institute for Melanoma, Sheba Medical Center, Tel Hashomer, Israel (J.S.) · Royal Marsden NHS Foundation Trust, London (J. Larkin), and Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne (R.P.) - both in the United Kingdom · Novartis Pharmaceuticals, East Hanover, NJ (R.J., P.Z., B.M., J. Legos) · University Hospital Zürich Skin Cancer Center, Zurich, Switzerland (R.D.) · and the Melanoma Program, Hillman UPMC Cancer Center, University of Pittsburgh, Pittsburgh (J.M.K.). ·N Engl J Med · Pubmed #28891408.

ABSTRACT: BACKGROUND: Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety. RESULTS: At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval [CI], 0.39 to 0.58; P<0.001). The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P=0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma. CONCLUSIONS: Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov, NCT01682083 ; EudraCT number, 2012-001266-15 .).

22 Clinical Trial Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. 2017

Wolchok, Jedd D / Chiarion-Sileni, Vanna / Gonzalez, Rene / Rutkowski, Piotr / Grob, Jean-Jacques / Cowey, C Lance / Lao, Christopher D / Wagstaff, John / Schadendorf, Dirk / Ferrucci, Pier F / Smylie, Michael / Dummer, Reinhard / Hill, Andrew / Hogg, David / Haanen, John / Carlino, Matteo S / Bechter, Oliver / Maio, Michele / Marquez-Rodas, Ivan / Guidoboni, Massimo / McArthur, Grant / Lebbé, Celeste / Ascierto, Paolo A / Long, Georgina V / Cebon, Jonathan / Sosman, Jeffrey / Postow, Michael A / Callahan, Margaret K / Walker, Dana / Rollin, Linda / Bhore, Rafia / Hodi, F Stephen / Larkin, James. ·From the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (J.D.W., M.A.P., M.K.C.) · Oncology Institute of Veneto Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua (V.C.-S.), European Institute of Oncology, Milan (P.F.F.), Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena (M.M.), the Immunotherapy and Somatic Cell Therapy Unit, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (M.G.), and Istituto Nazionale Tumori Fondazione Pascale, Naples (P.A.A.) - all in Italy · University of Colorado, Denver (R.G.) · Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.) · Aix-Marseille University, Hôpital de la Timone, Marseille (J.-J.G.), and Assistance Publique-Hôpitaux de Paris, Dermatology and Centres d'Investigation Clinique, INSERM Unité 976, Hôpital Saint-Louis, Université Paris Diderot, Paris (C.L.) - both in France · Texas Oncology-Baylor Cancer Center, Dallas (C.L.C.) · University of Michigan, Ann Arbor (C.D.L.) · the College of Medicine, Swansea University, Swansea (J.W.), and Royal Marsden NHS Foundation Trust, London (J.L.) - both in the United Kingdom · the Department of Dermatology, University of Essen, Essen, and the German Cancer Consortium, Heidelberg - both in Germany (D.S.) · Cross Cancer Institute, Edmonton, AB (M.S.), and Princess Margaret Cancer Centre, Toronto (D.H.) - both in Canada · Universitäts Spital, Zurich, Switzerland (R.D.) · Tasman Oncology Research, Southport Gold Coast, QLD (A.H.), Crown Princess Mary Cancer Centre, Melanoma Institute Australia, University of Sydney (M.S.C.), and Melanoma Institute Australia, University of Sydney, and Royal North Shore and Mater Hospitals (G.V.L.), Sydney, and Peter MacCallum Cancer Centre (G.M.) and the Olivia Newton-John Cancer Research Institute, University of Melbourne (J.C.), Melbourne, VIC - all in Australia · Netherlands Cancer Institute, Amsterdam (J.H.) · University Hospitals Leuven, KU Leuven, Leuven, Belgium (O.B.) · General University Hospital Gregorio Marañón, Madrid (I.M.-R.) · Northwestern University, Chicago (J.S.) · Bristol-Myers Squibb, Princeton, NJ (D.W., L.R., R.B.) · and the Dana-Farber Cancer Institute, Boston (F.S.H.). ·N Engl J Med · Pubmed #28889792.

ABSTRACT: BACKGROUND: Nivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial. METHODS: We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group versus the ipilimumab group. RESULTS: At a minimum follow-up of 36 months, the median overall survival had not been reached in the nivolumab-plus-ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group. CONCLUSIONS: Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505 .).

23 Clinical Trial Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. 2017

Long, Georgina V / Atkinson, Victoria / Cebon, Jonathan S / Jameson, Michael B / Fitzharris, Bernie M / McNeil, Catriona M / Hill, Andrew G / Ribas, Antoni / Atkins, Michael B / Thompson, John A / Hwu, Wen-Jen / Hodi, F Stephen / Menzies, Alexander M / Guminski, Alexander D / Kefford, Richard / Kong, Benjamin Y / Tamjid, Babak / Srivastava, Archana / Lomax, Anna J / Islam, Mohammed / Shu, Xinxin / Ebbinghaus, Scot / Ibrahim, Nageatte / Carlino, Matteo S. ·Melanoma Institute Australia, University of Sydney, Mater Hospital, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au. · Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, QLD, Australia; University of Queensland, Brisbane, QLD, Australia. · Olivia Newton-John Cancer Research Institute, Austin Health, School of Cancer Medicine, LaTrobe University, Heidelberg, VIC, Australia. · Regional Cancer Centre, Waikato Hospital, Hamilton, New Zealand. · Canterbury District Health Board, Christchurch Hospital, Christchurch, New Zealand. · Royal Prince Alfred Hospital, Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Chris O'Brien Lifehouse, Camperdown, NSW, Australia. · Tasman Oncology Research, Southport Gold Coast, QLD, Australia. · Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. · Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA. · Department of Medicine, University of Washington, Seattle, WA, USA. · University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Melanoma Institute Australia, University of Sydney, Mater Hospital, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia. · Westmead Hospital, Melanoma Institute Australia, Macquarie University, Sydney, NSW, Australia. · Westmead Hospital, Westmead, NSW, Australia; Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Blacktown Hospital, Blacktown, NSW, Australia. · Merck & Co, Kenilworth, NJ, USA. ·Lancet Oncol · Pubmed #28729151.

ABSTRACT: BACKGROUND: Reduced-dose nivolumab in combination with standard-dose ipilimumab improves objective response and progression-free survival compared with standard-dose ipilimumab alone, but increases toxicity. We assessed the safety and anti-tumour activity of standard-dose pembrolizumab in combination with reduced-dose ipilimumab. METHODS: In this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA. Eligible patients were aged at least 18 years, had advanced melanoma, had an Eastern Coooperative Oncology Group performance status of 0 or 1, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, had adequate organ function, had resolution of toxic effects of the most recent previous chemotherapy to grade 1 or less, had no active autoimmune disease requiring systemic steroids or immunosuppressive agents, had no active non-infectious pneumonitis, had no uncontrolled thyroid dysfunction or diabetes, had no active brain metastases, and had not received previous immune checkpoint inhibitor therapy. Patients received intravenous pembrolizumab 2 mg/kg plus intravenous ipilimumab 1 mg/kg every 3 weeks for four doses, followed by intravenous pembrolizumab 2 mg/kg every 3 weeks for up to 2 years or disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was safety and tolerability. The proportion of patients achieving an objective response assessed per RECIST version 1.1 by independent central review and overall survival were secondary endpoints. We also assessed progression-free survival. The primary endpoint was assessed in all patients who received at least one dose of combination therapy. Activity was assessed in all enrolled patients. This trial is registered with ClinicalTrials.gov, number NCT02089685. Enrolment into this cohort is closed, but patients are still being monitored for safety and anti-tumour activity. FINDINGS: Between Jan 13, 2015, and Sept 17, 2015, we enrolled and treated 153 patients. As of the Oct 17, 2016, cutoff date, median follow-up was 17·0 months (IQR 14·8-18·8). 110 (72%) of 153 patients received all four pembrolizumab plus ipilimumab doses; 64 (42%) remained on pembrolizumab monotherapy. 110 grade 3-4 treatment-related adverse events occurred in 69 (45%) patients. No treatment-related deaths occurred. Treatment-related adverse events led to discontinuation of pembrolizumab and ipilimumab in 22 (14%) patients, including 17 (11%) who discontinued both treatments for the same event and five (3%) who discontinued ipilimumab for one event and later discontinued pembrolizumab for another. 12 (8%) patients discontinued ipilimumab only and 14 (9%) discontinued pembrolizumab only because of treatment-related adverse events. 158 immune-mediated adverse events of any grade occurred in 92 (60%) patients, and 50 immune-mediated adverse events of grade 3-4 occurred in 42 (27%) patients; the most common immune-mediated adverse events were hypothyroidism (25 [16%]) and hyperthyroidism (17 [11%]). 93 (61% [95% CI 53-69]) patients achieved an objective response. Estimated 1 year progression-free survival was 69% (95% CI 60-75), and estimated 1 year overall survival was 89% (95% CI 83-93). INTERPRETATION: Standard-dose pembrolizumab given in combination with four doses of reduced-dose ipilimumab followed by standard-dose pembrolizumab has a manageable toxicity profile and provides robust anti-tumour activity in patients with advanced melanoma. These data suggest that standard-dose pembrolizumab plus reduced-dose ipilimumab might be a tolerable, efficacious treatment option for patients with advanced melanoma. A randomised phase 2 trial of alternative dosing strategies of this combination is underway. FUNDING: Merck & Co, Inc.

24 Clinical Trial Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic 2017

Delord, Jean-Pierre / Robert, Caroline / Nyakas, Marta / McArthur, Grant A / Kudchakar, Ragini / Mahipal, Amit / Yamada, Yasuhide / Sullivan, Ryan / Arance, Ana / Kefford, Richard F / Carlino, Matteo S / Hidalgo, Manuel / Gomez-Roca, Carlos / Michel, Daniela / Seroutou, Abdelkader / Aslanis, Vassilios / Caponigro, Giordano / Stuart, Darrin D / Moutouh-de Parseval, Laure / Demuth, Tim / Dummer, Reinhard. ·Institut Universitaire du Cancer, Toulouse, France. delord.jean-pierre@iuct-oncopole.fr. · Gustave Roussy and Paris-Sud University, Villejuif, France. · Oslo University Hospital, Norway. · Peter MacCallum Cancer Centre and the University of Melbourne, Australia. · Winship Cancer Institute of Emory University, Atlanta, Georgia. · Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. · National Cancer Center Hospital, Tokyo, Japan. · Massachusetts General Hospital, Boston, Massachusetts. · Department of Medical Oncology and Translational Genomics and Targeted Therapeutics in Solid Tumors, Hospital Clínic, Barcelona, Spain. · Crown Princess Mary Cancer Centre Westmead Hospital, Melanoma Institute Australia, University of Sydney, Sydney, New South Wales, Australia. · Macquarie University, Sydney, New South Wales, Australia. · Spanish National Cancer Research Centre (CNIO) and Centro Integral Oncologico Clara Campal, Madrid, Spain. · Institut Universitaire du Cancer, Toulouse, France. · Novartis Pharma AG, Basel, Switzerland. · Novartis Institutes for Biomedical Research, Cambridge, Massachusetts. · University Hospital Zurich, Zurich, Switzerland. ·Clin Cancer Res · Pubmed #28611198.

ABSTRACT:

25 Clinical Trial Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study. 2017

McArthur, G A / Maio, M / Arance, A / Nathan, P / Blank, C / Avril, M-F / Garbe, C / Hauschild, A / Schadendorf, D / Hamid, O / Fluck, M / Thebeau, M / Schachter, J / Kefford, R / Chamberlain, M / Makrutzki, M / Robson, S / Gonzalez, R / Margolin, K. ·Department of Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne and University of Melbourne, Parkville, Australia. · AOU Senese Policlinico Santa Maria Alle Scotte, Siena, Italy. · Department of Medical Oncology, Hospital Clínic Barcelona, Spain. · Mount Vernon Hospital, Centre for Cancer Treatment, Northwood, UK. · The Netherlands Cancer Institute, Amsterdam, The Netherlands. · University Paris Descartes, Hospital Cochin, APHP, Paris, France. · Department of Dermatology, University Hospital Tuebingen, Tuebingen. · Department of Dermatology, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel. · Department of Dermatology, Comprehensive Cancer Center, University Hospital Essen, Essen, Germany. · Angeles Clinic and Research Institute, Los Angeles, USA. · Fachklinik Hornheide, Munster, Germany. · Moffitt Cancer Center, Tampa, USA. · Chaim Sheba Medical Centre, Oncology Institute, Ramat-Gan, Israel. · Crown Princess Cancer Centre Westmead Hospital and Department of Clinical Medicine, Macquarie University, Sydney NSW, Australia. · Seattle Cancer Care Alliance, Seattle, USA. · F. Hoffmann-La Roche Ltd, Basel, Switzerland. · University of Colorado Cancer Center, Aurora. · City of Hope, Duarte, USA. ·Ann Oncol · Pubmed #27993793.

ABSTRACT: Background: Vemurafenib has shown activity in patients with BRAFV600 mutated melanoma with brain metastases (BM). This phase 2 study evaluated vemurafenib in patients with/without prior treatment for BM. Methods: Patients with BRAFV600 mutated melanoma with BM were enrolled into cohort 1 (previously untreated BM) and cohort 2 (previously treated BM) and received vemurafenib (960 mg BID) until disease progression (PD) or intolerance. Primary endpoint was best overall response rate (BORR) in the brain in cohort 1 that was evaluated using modified RECIST 1.1 criteria using lesions ≥0.5 cm to assess response. Results: 146 patients were treated (cohort 1 n = 90; cohort 2 n = 56), 62% of whom were male. Median (range) time since diagnosis of BM: 1.0 (0-9) month in cohort 1 and 4.2 (1-68) months in cohort 2. Median duration of treatment was 4.1 months (range 0.3-34.5) in cohort 1 and 4.1 months (range 0.2-27.6) in cohort 2. Intracranial BORR in cohort 1 by an independent review committee (IRC) was 18% (2 CRs, 14 PRs). Extracranial BORR by IRC was 33% in cohort 1 and 23% in cohort 2. Median PFS (brain only, investigator-assessed) was 3.7 months (range 0.03-33.4; IQR 1.9-5.6) in cohort 1 and 4.0 months (range 0.3-27.4; IQR 2.2-7.4) in cohort 2. Median OS was 8.9 months (range 0.6-34.5; IQR 4.9-17.0) in cohort 1 and 9.6 months (range 0.7-34.3; IQR 4.5-18.4) in cohort 2. Adverse events (AEs) were similar in type, grade and frequency to other studies of single-agent vemurafenib. Grade 3/4 AEs occurred in 59 (66%) patients in cohort 1 and 36 (64%) in cohort 2. Overall, 84% of patients died during the study (86% in cohort 1 and 80% in cohort 2), mainly due to disease progression. Conclusions: The study demonstrates clinically meaningful response rates of melanoma BM to vemurafenib, which was well tolerated and without significant CNS toxicity.

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