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Melanoma: HELP
Articles by Georgina V. Long
Based on 184 articles published since 2008
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Between 2008 and 2019, G. Long wrote the following 184 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7 · 8
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 From dismal prognosis to rising star: melanoma leading the way with new generation cancer therapies. 2015

Long, Georgina V. ·Melanoma Institute Australia, Sydney, NSW, Australia. Georgina.Long@sydney.edu.au. ·Med J Aust · Pubmed #25669459.

ABSTRACT: -- No abstract --

3 Review Impact of genomics on the surgical management of melanoma. 2018

Ferguson, P M / Long, G V / Scolyer, R A / Thompson, J F. ·Melanoma Institute Australia, Sydney, New South Wales, Australia. · Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. · Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. · Department of Medical Oncology, Royal North Shore Hospital, Sydney, New South Wales, Australia. · Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. ·Br J Surg · Pubmed #29341162.

ABSTRACT: BACKGROUND: Although surgery for early-stage melanoma offers the best chance of cure, recent advances in molecular medicine have revolutionized the management of late-stage melanoma, leading to significant improvements in clinical outcomes. Research into the genomic drivers of disease and cancer immunology has not only ushered in a new era of targeted and immune-based therapies for patients with metastatic melanoma, but has also provided new tools for monitoring disease recurrence and selecting therapeutic strategies. These advances present new opportunities and challenges to the surgeon treating patients with melanoma. METHODS: The literature was reviewed to evaluate diagnostic and therapeutic advances in the management of cutaneous melanoma, and to highlight the impact of these advances on surgical decision-making. RESULTS: Genomic testing is not required in the surgical management of primary melanoma, although it can provide useful information in some situations. Circulating nucleic acids from melanoma cells can be detected in peripheral blood to predict disease recurrence before it manifests clinically, but validation is required before routine clinical application. BRAF mutation testing is the standard of care for all patients with advanced disease to guide therapy, including the planning of surgery in adjuvant and neoadjuvant settings. CONCLUSION: Surgery remains central for managing primary melanoma, and is an important element of integrated multidisciplinary care in advanced disease, particularly for patients with resectable metastases. The field will undergo further change as clinical trials address the relationships between surgery, radiotherapy and systemic therapy for patients with high-risk, early-stage and advanced melanoma.

4 Review Radiological manifestations of immune-related adverse effects observed in patients with melanoma undergoing immunotherapy. 2017

Sidhu, Parveen / Menzies, Alexander M / Long, Georgina / Carlino, Matteo / Lorens, Shirleen / Kapoor, Rony. ·Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. · Melanoma Institute Australia, North Sydney, New South Wales, Australia. · Royal North Shore Hospital, Sydney, New South Wales, Australia. · University of Notre Dame Sydney, Darlinghurst, New South Wales, Australia. ·J Med Imaging Radiat Oncol · Pubmed #29024572.

ABSTRACT: Immunotherapy drugs work by stimulating the patient's own immune system to recognize and destroy cancer cells. This subclass of drugs is increasingly administered to patients with advanced melanoma. They are also commonly incorporated into other cancer therapies such as non-small cell lung cancer, renal cancer, head and neck cancers and Hodgkin lymphoma. The most commonly administered immunotherapeutic agents in the treatment of melanoma include programmed cell death protein 1 (PD-1) inhibitors, cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors and a subclass of cytokines. During treatment with these antibodies, a unique set of adverse effects may occur which are often called immune-related adverse events (irAEs). It is vital for radiologists to be aware of and document these side effects during routine staging or body imaging during therapy. Some of these include pneumonitis, colitis, hypophysitis, lymphadenopathy or sarcoid-like syndrome and myositis. IrAEs such as sarcoid-like lymphadenopathy can mimic progression of disease. Serious side effects are seen in less than 10% of patients, and typically emerge between 6 and 12 weeks after commencing treatment. The clinical manifestations of these side effects typically vary from mild to severe and so do the radiological findings. Patients with mild side effects are often treated successfully with systemic corticosteroids, while severe cases require cessation of immunotherapy. We provide a pictorial article on the common irAEs and the associated radiological manifestations.

5 Review Systemic therapy in advanced melanoma: integrating targeted therapy and immunotherapy into clinical practice. 2017

Silva, Inês P / Long, Georgina V. ·aMelanoma Institute Australia, Sydney, Australia bRoyal North Shore, Sydney, Australia cMater Hospital, Sydney, Australia dUniversity of Sydney, Sydney, Australia. ·Curr Opin Oncol · Pubmed #28914644.

ABSTRACT: PURPOSE OF REVIEW: Here we review the results from relevant phase III trials and discuss treatment strategies for challenging subgroups of melanoma patients. RECENT FINDINGS: Targeted therapies induce rapid responses in the majority of BRAF-mutant patients, however, 50% of these responders will develop resistance within approximately 13 months. In contrast, inhibitors of checkpoints on T cells, particularly inhibitors of PD-1, induce responses in 40-55% of patients (monotherapy or whenever combined with anti-CTLA-4), and these responses tend to be durable. Data from subgroup analyses of large clinical trials, as well as patient-centred factors, help guide clinicians in their choice of first-line therapy. SUMMARY: Immune checkpoint inhibitors and MAP kinase pathway-targeted therapies have revolutionized the management of advanced melanoma, and significantly prolong the overall survival of patients with this disease. The median overall survival is over 2 years for both anti-PD-1-based therapy and combined BRAF and MEK inhibition. Without head-to-head comparison data for either therapy, choice of first-line drug treatment is difficult.

6 Review Immune mediated neuropathy following checkpoint immunotherapy. 2017

Gu, Yufan / Menzies, Alexander M / Long, Georgina V / Fernando, S L / Herkes, G. ·Department of Neurology, Royal North Shore Hospital, Sydney, NSW, Australia. Electronic address: yufan.gu@health.nsw.gov.au. · Melanoma Institute of Australia, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW, Australia. Electronic address: alexander.menzies@sydney.edu.au. · Melanoma Institute of Australia, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au. · The University of Sydney, Sydney, NSW, Australia; Department of Clinical Immunology and Allergy, Royal North Shore Hospital, Sydney, NSW, Australia; ImmunoRhuematology Laboratory, Pathology North, Sydney, NSW, Australia. Electronic address: suran.fernando@health.nsw.gov.au. · Department of Neurology, Royal North Shore Hospital, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia. Electronic address: geoffrey.herkes@health.nsw.gov.au. ·J Clin Neurosci · Pubmed #28765062.

ABSTRACT: Checkpoint immunotherapy has revolutionised cancer therapy and is now standard treatment for many malignancies including metastatic melanoma. Acute inflammatory neuropathies, often labelled as Guillain-Barre syndrome, are an uncommon but potentially severe complication of checkpoint immunotherapy with individual cases described but never characterised as a group. We describe a case of acute sensorimotor and autonomic neuropathy following a single dose of combination ipilimumab and nivolumab for metastatic melanoma. A literature search was performed, identifying 14 other cases of acute neuropathy following checkpoint immunotherapy, with the clinical, electrophysiological and laboratory features summarised. Most cases described an acute sensorimotor neuropathy (92%) with hyporeflexia (92%) that could occur from induction up till many weeks after the final dose of therapy. In contrast to Guillain-Barre syndrome, the cerebrospinal fluid (CSF) analysis often shows a lymphocytic picture (50%) and the electrophysiology showed an axonal pattern (55%). Treatment was variable and often in combination. 11 cases received steroid therapy with only 1 death within this group, whereas of the 4 patients who did not receive steroid therapy there were 3 deaths. In conclusion checkpoint immunotherapy - induced acute neuropathies are distinct from and progress differently to Guillain-Barre syndrome. As with other immunotherapy related adverse events corticosteroid therapy should be initiated in addition to usual therapy.

7 Review Survival of patients with advanced metastatic melanoma: the impact of novel therapies-update 2017. 2017

Ugurel, Selma / Röhmel, Joachim / Ascierto, Paolo A / Flaherty, Keith T / Grob, Jean Jacques / Hauschild, Axel / Larkin, James / Long, Georgina V / Lorigan, Paul / McArthur, Grant A / Ribas, Antoni / Robert, Caroline / Schadendorf, Dirk / Garbe, Claus. ·Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. Electronic address: selma.ugurel@uk-essen.de. · Bremen, Germany. · Melanoma, Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", Naples, Italy. · Massachusetts General Hospital, Boston, MA, USA. · Department of Dermatology, Timone Hospital and Aix-Marseille University, Marseille, France. · Department of Dermatology, University Hospital of Schleswig-Holstein, Kiel, Germany. · Royal Marsden Hospital NHS Foundation Trust, London, UK. · Melanoma Institute Australia, The University of Sydney, and Royal North Shore Hospital, Sydney, NSW, Australia. · University of Manchester, The Christie NHS Foundation Trust, Manchester, UK. · Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia and University of Melbourne, Parkville, VIC, Australia. · University of California, Los Angeles, CA, USA. · Gustave Roussy Cancer Campus, Villejuif Grand-Paris, France. · Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. · Center for Dermatooncology, Department of Dermatology, University of Tuebingen, Tuebingen, Germany. ·Eur J Cancer · Pubmed #28756137.

ABSTRACT: The treatment of metastatic melanoma is still undergoing a process of major change. The two most important novel therapeutic strategies, selective kinase inhibitors and immune checkpoint blockers, both significantly prolong survival times of patients with advanced metastatic disease. Different agents, dose regimens and combinations have been tested against each other vigorously within these two groups. However, results from prospective head-to-head comparative studies of both strategies are still lacking. We performed an exploratory analysis of survival data from selected clinical trials representative for the new treatment strategies in advanced metastatic melanoma. Eighty-three Kaplan-Meier survival curves from 25 trials were digitised and grouped by therapeutic strategy and treatment line. For each of these groups, mean survival curves were generated for progression-free (PFS) and overall survival (OS) by weighted averaging. Survival curves grouped together by therapeutic strategy revealed a high concordance, particularly in the first-line setting. For kinase inhibitors, the most favourable PFS and OS in all therapy lines were observed for combined BRAF plus MEK inhibition. For immune checkpoint inhibitors, combined PD-1 plus CTLA-4 inhibition demonstrated the best survival outcome in all categories except for OS in first-line therapy. For the latter, combined PD-1 plus CTLA-4 inhibition showed similar outcomes as single-agent PD-1 inhibition. Comparison of kinase inhibitors and checkpoint blockers revealed a superiority of combined BRAF plus MEK inhibition within the first 6 months, later changing to a superiority of PD-1 blockers alone or in combination with CTLA-4 blockers. These results need confirmation by prospective clinical trials.

8 Review Targeted agents and immunotherapies: optimizing outcomes in melanoma. 2017

Luke, Jason J / Flaherty, Keith T / Ribas, Antoni / Long, Georgina V. ·Department of Medicine, Division of Hematology/Oncology, University of Chicago Comprehensive Cancer Center, 5841 South Maryland Avenue MC2115, Chicago, Illinois 60637, USA. · Department of Medicine, Harvard Medical School, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA. · Department of Medicine, Division of Hematology/Oncology, University of California Los Angeles Jonsson Comprehensive Cancer Center, 10833 Le Conte Avenue, Los Angeles, California 90024, USA. · Melanoma Institute Australia, The University of Sydney, and The Mater Hospital, Rocklands Road, North Sydney, New South Wales 2060, Australia. · Royal North Shore Hospital, Reserve Road, St Leonards, New South Wales 2065, Australia. ·Nat Rev Clin Oncol · Pubmed #28374786.

ABSTRACT: Treatment options for patients with metastatic melanoma, and especially BRAF-mutant melanoma, have changed dramatically in the past 5 years, with the FDA approval of eight new therapeutic agents. During this period, the treatment paradigm for BRAF-mutant disease has evolved rapidly: the standard-of-care BRAF-targeted approach has shifted from single-agent BRAF inhibition to combination therapy with a BRAF and a MEK inhibitor. Concurrently, immunotherapy has transitioned from cytokine-based treatment to antibody-mediated blockade of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and, now, the programmed cell-death protein 1 (PD-1) immune checkpoints. These changes in the treatment landscape have dramatically improved patient outcomes, with the median overall survival of patients with advanced-stage melanoma increasing from approximately 9 months before 2011 to at least 2 years - and probably longer for those with BRAF-V600-mutant disease. Herein, we review the clinical trial data that established the standard-of-care treatment approaches for advanced-stage melanoma. Mechanisms of resistance and biomarkers of response to BRAF-targeted treatments and immunotherapies are discussed, and the contrasting clinical benefits and limitations of these therapies are explored. We summarize the state of the field and outline a rational approach to frontline-treatment selection for each individual patient with BRAF-mutant melanoma.

9 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.

10 Review Resistance to combination BRAF and MEK inhibition in metastatic melanoma: Where to next? 2016

Welsh, Sarah J / Rizos, Helen / Scolyer, Richard A / Long, Georgina V. ·Faculty of Medicine and Health Sciences, Department of Biomedical Sciences, Macquarie University, 2 Technology Place, Sydney, NSW 2109, Australia; Melanoma Institute Australia, 40 Rocklands Road, Wollstonecraft, NSW 2065, Australia. · Melanoma Institute Australia, 40 Rocklands Road, Wollstonecraft, NSW 2065, Australia; The University of Sydney, Sydney, NSW 2006, Australia. · Melanoma Institute Australia, 40 Rocklands Road, Wollstonecraft, NSW 2065, Australia; The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: georgina.long@melanoma.org.au. ·Eur J Cancer · Pubmed #27232329.

ABSTRACT: Treatment of BRAF-mutant metastatic melanoma with mitogen-activated protein kinase (MAPK) pathway targeted therapies (BRAF/MEK inhibitors) and immune checkpoint inhibitors has revolutionised management and improved outcomes for patients with advanced stage disease. However, acquired resistance to MAPK inhibitor therapy develops in the majority of patients at approximately 12 months and multiple mechanisms lead to resistance. Understanding the mechanisms of resistance is therefore critical for the development of more effective therapeutic strategies in BRAF-mutant melanoma. Recently, several distinct mechanisms of resistance to BRAF-inhibition have been proposed based on data obtained in experimental melanoma cell models and small series of human tumour samples. These include reactivation of the MAPK pathway resulting in continued extracellular signal-regulated kinase activation and activation of parallel signalling pathways including the PI3K-mTOR (phosphoinositide 3-kinase-mammalian target of rapamycin) pathway. Alterations in how the cells of the immune system respond to melanoma cells treated with targeted therapy may also influence response and progression. In this review, we discuss these mechanisms and identify potential therapeutic strategies to overcome resistance which, in turn, will lead to improved outcomes for patients with metastatic melanoma.

11 Review Targeted therapies and immune checkpoint inhibitors in the treatment of metastatic melanoma patients: a guide and update for pathologists. 2016

Kakavand, Hojabr / Wilmott, James S / Long, Georgina V / Scolyer, Richard A. ·Melanoma Institute Australia, North Sydney, Australia; The University of Sydney, Sydney, Australia. · Melanoma Institute Australia, North Sydney, Australia; The University of Sydney, Sydney, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia. Electronic address: richard.scolyer@sswahs.nsw.gov.au. ·Pathology · Pubmed #27020392.

ABSTRACT: The previously dismal prospects for patients with advanced stage metastatic melanoma have greatly improved in recent years. Enhanced understanding of both the pathogenesis of melanoma and its molecular drivers, as well as the importance and regulation of anti-tumour immune responses, have provided new therapeutic opportunities for melanoma patients. There are two major distinct categories of systemic treatments with activity for patients with metastatic melanoma: (1) targeted therapies, which act to inhibit the oncogenes that drive the aberrant growth and dissemination of the tumour; and (2) immune checkpoint inhibitor therapies, which act to enhance anti-tumour immune responses by blocking negative regulators of immunity. Pathologists play a critical and expanding role in the selection of the most appropriate treatment for individual metastatic melanoma patients in the modern era of personalised/precision medicine. The molecular pathology testing of melanoma tumour tissue for the presence of targetable oncogenic mutations is already part of routine practice in many institutions. In addition, other potential oncogenic therapeutic targets continue to be identified and pathology testing techniques must readily adapt to this rapidly changing field. Recent research findings suggest that pathological assessment of tumour associated immune cells and immunosuppressive ligand expression of the tumour are likely to be important in identifying patients most likely to benefit from immune checkpoint inhibitors. Similarly, pathological and molecular observations of on-treatment tumour tissue biopsies taken from patients on targeted therapies have provided new insights into the mechanisms of action of targeted molecular therapies, have contributed to the identification of resistance mechanisms to these novel therapies and may be of higher value for selecting patients most likely to benefit from therapies. These data have already provided a rational biological basis for the exciting prospect of combining them to further improve survival rates and this is currently being investigated in clinical trials. Ultimately it may be the responsibility of the pathologist to identify which therapy or combination of therapies is most likely to benefit individual patients.

12 Review Survival of patients with advanced metastatic melanoma: The impact of novel therapies. 2016

Ugurel, Selma / Röhmel, Joachim / Ascierto, Paolo A / Flaherty, Keith T / Grob, Jean Jacques / Hauschild, Axel / Larkin, James / Long, Georgina V / Lorigan, Paul / McArthur, Grant A / Ribas, Antoni / Robert, Caroline / Schadendorf, Dirk / Garbe, Claus. ·Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. Electronic address: selma.ugurel@uk-essen.de. · 28355 Bremen, Germany. · Melanoma, Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples, Italy. · Massachusetts General Hospital, Boston, MA, USA. · Dermatology Department, Timone Hospital and Aix-Marseille University, Marseille, France. · University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany. · Royal Marsden Hospital NHS Foundation Trust, London, UK. · Melanoma Institute Australia and The University of Sydney, Sydney, NSW, Australia. · University of Manchester, The Christie NHS Foundation Trust, Manchester, UK. · Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; University of Melbourne, Parkville, VIC, Australia. · University of California, Los Angeles, CA, USA. · Gustave Roussy Cancer Campus, Villejuif Grand-Paris, France. · Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. · Center for Dermatooncology, Department of Dermatology, University Tuebingen, 72074 Tuebingen, Germany. ·Eur J Cancer · Pubmed #26707829.

ABSTRACT: The survival of advanced metastatic melanoma has been greatly improved within the past few years. New therapeutic strategies like kinase inhibitors for BRAF-mutant melanoma and immune checkpoint blockers proved to prolong survival times within clinical trials, and many of them have already entered routine clinical use. However, these different treatment modalities have not yet been tested against each other, which complicate therapy decisions. We performed an explorative analysis of survival data from recent clinical trials. Thirty-five Kaplan-Meier survival curves from 17 trials were digitised, re-grouped by matching inclusion criteria and treatment line, and averaged by therapy strategy. Notably, the survival curves grouped by therapy strategy revealed a very high concordance, even if different agents were used. The greatest survival improvement was observed with the combination of BRAF plus MEK inhibitors as well as with Programmed-death-1 (PD1) blockers with or without cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockers, respectively, with these two treatment strategies showing similar survival outcomes. For first-line therapy, averaged survival proportions of patients alive at 12 months were 74.5% with BRAF plus MEK inhibitor treatment versus 71.9% with PD-1 blockade. This explorative comparison shows the kinase inhibitors as similarly effective as immune checkpoint blockers with regard to survival. However, to confirm these first trends for implementation into an individualised treatment of melanoma patients, data from prospective clinical trials comparing the different treatment strategies head-to-head have to be awaited.

13 Review Disease kinetics for decision-making in advanced melanoma: a call for scenario-driven strategy trials. 2015

Grob, Jean Jacques / Long, Georgina V / Schadendorf, Dirk / Flaherty, Keith. ·Aix-Marseille University and APHM Hospital CHU Timone, Marseille, France. Electronic address: jean-jacques.grob@ap-hm.fr. · Melanoma Institute Australia, University of Sydney, and Mater Hospital, Sydney, NSW, Australia. · University Hospital Essen and German Cancer Consortium, Essen, Germany. · Massachusetts General Hospital Cancer Center, Boston, MA, USA. ·Lancet Oncol · Pubmed #26433825.

ABSTRACT: In the past 5 years, the treatment of metastatic melanoma has changed from almost no effective treatment to the use of targeted and immune therapies with proven improvements in survival. The time has now come to define the optimal drug combinations, sequence of treatment, and drug regimens (intermittent vs continuous dosing) in the treatment of patients with metastatic melanoma. In view of the prevalence of advanced melanoma, finite resources, and the heterogeneity of disease characteristics, not all possibilities can be tested in therapeutic trials starting from an unselected population of patients with metastatic melanoma. In practice, clinicians rely on a few clinically derived signals, especially dynamic signals, to categorise patients into scenarios, from fast disease kinetics to slow disease kinetics, which drive clinicians' therapeutic decision making. The realistic goals of therapy are different in each scenario. We recommend that these scenarios are incorporated into clinical trials as either patient inclusion criteria or stratification factors. This approach is not only feasible but is also the only way to generate evidence for more effective and individualised treatment strategies for patients with metastatic melanoma.

14 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.

15 Review Systemic therapies for melanoma brain metastases: which drug for whom and when? 2015

Ramanujam, Sangeetha / Schadendorf, Dirk / Long, Georgina V. ·Melanoma Institute Australia, Sydney, Australia. · University Hospital Essen, Essen, Germany. · Melanoma Institute Australia and The University of Sydney, 40 Rocklands Rd, North Sydney, NSW 2060, Australia. georgina.long@sydney.edu.au. ·Chin Clin Oncol · Pubmed #26112811.

ABSTRACT: Melanoma brain metastases are common, difficult to treat, and are associated with a poor prognosis. Historically, due to the poor activity of chemotherapeutic agents in melanoma, the management of brain metastases was centred on local treatments such as surgery, stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT) depending on the clinical presentation. New systemic therapies have now evolved; kinase inhibitors targeting BRAF mutated melanoma cells and activating checkpoint inhibitors that activate an immune anti-tumour response, resulting in significantly improved survival and quality of life for patients with metastatic melanoma and these drugs have demonstrated activity in melanoma brain metastases. As the landscape shifts to incorporate these new systemic agents with the available local therapies, further research into using appropriate combinations or sequences of various treatments, especially for active or progressing melanoma brain metastasis, is required. This review will examine the evidence for systemic therapies in patients with active melanoma brain metastasis (untreated or treated and progressed) and highlight active and evolving clinical trials in this challenging field.

16 Review Systemic treatment for BRAF-mutant melanoma: where do we go next? 2014

Menzies, Alexander M / Long, Georgina V. ·Melanoma Institute Australia, Sydney, NSW, Australia; University of Sydney, Sydney, NSW, Australia. ·Lancet Oncol · Pubmed #25079100.

ABSTRACT: After decades of treatment failure for metastatic melanoma, the development of BRAF inhibitors was highly anticipated to dramatically improve outcomes for patients with oncogene-addicted BRAF-mutant metastatic melanoma. Rapid and frequent responses occurred with BRAF inhibitors, but clinical benefit was usually transient because of the rapid emergence of drug resistance. Concurrently, and by contrast, ipilimumab, a novel immune checkpoint inhibitor, was shown to provide long-term clinical benefit, but only in a minority of patients. This situation generated an ongoing debate about how to best use these drugs in patients with BRAF-mutant melanoma. Recently, however, several new compounds and combinations of cell pathway signalling inhibitors and immunotherapies have been developed that look set to improve patient outcomes even further. In this Review, we discuss the existing evidence for the newest treatments for BRAF-mutant melanoma, including combined BRAF and MEK inhibition and PD-1-PD-L1 checkpoint inhibitors, and assess future treatment strategies that could change metastatic melanoma from a rapidly fatal terminal illness to a chronic disease for most patients.

17 Review The use of vemurafenib in Australian patients with unresectable or metastatic melanoma containing the V600 BRAF gene mutation. 2014

Brown, Michael P / Long, Georgina V. ·Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia. ·Asia Pac J Clin Oncol · Pubmed #24712861.

ABSTRACT: Metastatic melanoma remains one of the major causes of death related to skin cancers and has been resistant to traditional anticancer therapies. The clinical development of vemurafenib in the treatment of metastatic melanoma with the V600 mutation of the BRAF gene has provided meaningful improvements in the overall survival and progression-free survival of metastatic melanoma patients. However, significant side effects have been noted with this therapy, in particular cutaneous adverse events (AEs) such as rashes, squamous cell carcinoma and severe photosensitivity to UVA light among others. With an emphasis on the Australian perspective, this review provides an overview of the clinical development of vemurafenib, its attendant dose-limiting toxicities and other AEs, recommendations for safety monitoring, supportive treatments of AEs and dose modifications, with the aim of maximizing the chances of continuing beneficial treatment.

18 Review The role of systemic therapies in the management of melanoma brain metastases. 2014

Lyle, Megan / Long, Georgina V. ·aMelanoma Institute Australia bThe University of Sydney, Sydney, Australia. ·Curr Opin Oncol · Pubmed #24434634.

ABSTRACT: PURPOSE OF REVIEW: Brain metastases in metastatic melanoma are highly prevalent and are associated with significant morbidity and a poor prognosis. Local therapy (surgery or radiotherapy) has been the mainstay of treatment, due in part to the lack of efficacy of systemic therapy. This review will focus on new systemic therapies for metastatic melanoma and their evolving role in the management of brain metastases. RECENT FINDINGS: BRAF inhibitors have demonstrated efficacy in active (i.e. untreated or progressing) brain metastases in BRAF mutated metastatic melanoma. The cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody, ipilimumab, has also shown activity, particularly in asymptomatic metastases. Studies of programmed death 1/programmed death ligand 1 checkpoint inhibitors and combination BRAF and MEK inhibitor therapy in brain metastases are planned. Emerging evidence on the molecular biology of melanoma brain metastases, particularly the role of the phosphatidylinositol 3-kinase-AKT pathway, may identify additional therapeutic targets. SUMMARY: The development of systemic therapy effective in controlling both intra-cranial and extra-cranial melanoma metastases has resulted in a change in the paradigm of management. More research is required in patients with active brain metastases to improve patient outcomes, including studies early in the development of novel therapies, and studies to determine the safe and effective combination or sequencing of local and systemic therapies.

19 Review Recent advances in melanoma systemic therapy. BRAF inhibitors, CTLA4 antibodies and beyond. 2013

Menzies, Alexander M / Long, Georgina V. ·Melanoma Institute Australia, Sydney, Australia; The University of Sydney, Sydney, Australia. ·Eur J Cancer · Pubmed #23870385.

ABSTRACT: Metastatic melanoma has a poor prognosis and until recently systemic therapy was ineffective. Advances in the understanding of tumour biology and immune regulation have led to the development of targeted agents that have changed clinical practice, with further improvements expected with new compounds and combinations. The first major advance was the development of selective mitogen-activated protein (MAP) kinase inhibitors (BRAF and MEK inhibitors) and immune checkpoint blockade with a CTLA4 antibody (ipilimumab). These drugs proved vastly superior to conventional chemotherapy, however response, resistance and toxicity were limitations. The second major advance is the development of other immune checkpoint blocking agents, including PD-1 and PD-L1 antibodies, and the use of BRAF and MEK inhibitors in combination, with a higher proportion of durable responses coupled with less toxicity. In an effort to improve outcomes for patients with melanoma further, trials are underway examining the combination of MAPK inhibitors, immunotherapies and other pathway inhibitors and adjuvant studies of many of these agents have commenced.

20 Review Multidisciplinary approach to brain metastasis from melanoma: the emerging role of systemic therapies. 2013

Long, Georgina V / Margolin, Kim A. ·From the Melanoma Institute Australia, The University of Sydney, Sydney, Australia; University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA. ·Am Soc Clin Oncol Educ Book · Pubmed #23714558.

ABSTRACT: Melanoma brain metastases are common, difficult to treat, and carry a poor prognosis. Until recently, systemic therapy was ineffective. Local therapy (including surgery, stereotactic radiotherapy, and whole brain radiotherapy) was considered the only option for a chance of disease control in the brain, and was highly dependent on the patient's performance status and age, number and size of brain metastases, and the presence of extracranial metastases. Since 2010, three drugs have demonstrated activity in progressing or "active" brain metastases including the anti-CTLA4 antibody ipilimumab (phase II study of 72 patients), and the BRAF inhibitors dabrafenib (phase II study of 172 patients, both previously treated and untreated brain metastases) and vemurafenib (a pilot study of 24 patients with heavily pretreated brain metastases). The challenge and unanswered question for clinicians is how to sequence all the available therapies, both local and systemic, to optimize the patient's quality of life and survival. This is an area of intense clinical research. The treatment of patients with melanoma brain metastases should be discussed by a multidisciplinary team of melanoma experts including a neurosurgeon, medical oncologist, and radiation oncologist. Important clinical features that help determine appropriate first line therapy include single compared with solitary brain metastasis, resectablity, BRAF mutation status of melanoma, rate of progression/performance status, and the presence of extracranial disease.

21 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.

22 Review Dabrafenib and its potential for the treatment of metastatic melanoma. 2012

Menzies, Alexander M / Long, Georgina V / Murali, Rajmohan. ·Melanoma Institute Australia, Sydney, New South Wales, Australia. ·Drug Des Devel Ther · Pubmed #23251089.

ABSTRACT: The purpose of this study is to review the development of BRAF inhibitors, with emphasis on the trials conducted with dabrafenib (GSK2118436) and the evolving role of dabrafenib in treatment for melanoma patients. Fifty percent of cutaneous melanomas have mutations in BRAF, resulting in elevated activity of the mitogen-activated protein kinase signaling pathway. Dabrafenib inhibits the mutant BRAF (BRAF(mut)) protein in melanomas with BRAF(V600E) and BRAF(V600K) genotypes. BRAF(V600E) metastatic melanoma patients who receive dabrafenib treatment exhibit high clinical response rates and compared with dacarbazine chemotherapy, progression-free survival. Efficacy has also been demonstrated in BRAF(V600K) patients and in those with brain metastases. Dabrafenib has a generally mild and manageable toxicity profile. Cutaneous squamous cell carcinomas and pyrexia are the most significant adverse effects. Dabrafenib appears similar to vemurafenib with regard to efficacy but it is associated with less toxicity. It is expected that new combinations of targeted drugs, such as the combination of dabrafenib and trametinib (GSK1120212, a MEK inhibitor), will provide higher response rates and more durable clinical benefit than dabrafenib monotherapy.

23 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.

24 Review Evolving concepts in melanoma classification and their relevance to multidisciplinary melanoma patient care. 2011

Scolyer, Richard A / Long, Georgina V / Thompson, John F. ·Melanoma Institute Australia, Sydney, NSW, Australia. richard.scolyer@sswahs.nsw.gov.au ·Mol Oncol · Pubmed #21482206.

ABSTRACT: In the initial period after melanoma was recognised as a disease entity in the early 1800's, it was subclassified on the basis of its presumed origin (from a precursor naevus, from a melanocytic precursor lesion acquired during adult life or in previously blemish-fee skin). In 1967 the eminent American pathologist, Dr Wallace Clark, proposed a histogenetic classification for melanoma in which the disease was subdivided predominantly on the basis of histopathological features of the intra-epidermal component of the tumour adjacent to any dermal invasive component. The subtypes were superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM) and nodular melanoma (NM). Whilst additional entities, including acral lentiginous melanoma, mucosal melanoma, desmoplastic melanoma and naevoid melanoma have since been recognised, SSM, LMM and NM remain in the latest (2006) version of the WHO melanoma classification. Clark's histogenetic classification has been criticised because the criteria upon which it is based include clinical features (such as the site of the melanoma) and non-tumourous histopathological features (such as the character of the associated epidermis and the degree of solar elastosis) and also because of overlap in defining features, lack of an independent association with patient outcome and minimal relevance as a determinant of clinical management. However, such criticisms fail to acknowledge its importance in highlighting the myriad of clinical and histological guises of melanoma, which if not recognized by clinicians and pathologists will inevitably lead to a delay in diagnosis and a concomitant adverse clinical outcome. Recently, mutually exclusive oncogenic mutations in melanomas involving NRAS (15-20%), BRAF (50%), CKIT (2%), and GNAQ/GNA11 (50% of uveal melanomas) have been identified. This might herald the beginning of a new molecular classification of melanoma in which the biologically distinct subsets share a common oncogenic mechanism, behave clinically in a similar fashion and require similar clinical management. These discoveries are already being successfully exploited as therapeutic targets in clinical trials of metastatic melanoma patients with promising activity. Whilst there remains much to be discovered in this rapidly evolving field, there is already great optimism that more rational and effective therapies for melanoma patients will soon be widely available.

25 Review Targeting BRAF for patients with melanoma. 2011

Arkenau, H-T / Kefford, R / Long, G V. ·Sarah Cannon Research UK, 93 Harley Street, London W1G 6AD, UK. tobias.arkenau@sarahcannonresearch.co.uk ·Br J Cancer · Pubmed #21139585.

ABSTRACT: The prognosis of patients with metastatic melanoma is poor and not influenced by systemic therapy with cytotoxic drugs. New targeted agents directed against the RAS-RAF-MEK-ERK pathway show promising activity in early clinical development and particular interest is focused on selective inhibitors of mutant BRAF, which is present in one half of the cases of metastatic melanoma. The majority of patients on early trials of these drugs develop secondary resistance and subsequent disease progression and it is, therefore, critical to understand the underlying escape mechanisms leading to resistance.

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