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Melanoma: HELP
Articles by Richard F. Kefford
Based on 139 articles published since 2008
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Between 2008 and 2019, R. Kefford wrote the following 139 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6
1 Editorial Drug treatment for melanoma: progress, but who pays? 2012

Kefford, Richard F. · ·Med J Aust · Pubmed #22900855.

ABSTRACT: -- No abstract --

2 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.

3 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.

4 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.

5 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.

6 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.

7 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.

8 Review Selection criteria for genetic assessment of patients with familial melanoma. 2009

Leachman, Sancy A / Carucci, John / Kohlmann, Wendy / Banks, Kimberly C / Asgari, Maryam M / Bergman, Wilma / Bianchi-Scarrà, Giovanna / Brentnall, Teresa / Bressac-de Paillerets, Brigitte / Bruno, William / Curiel-Lewandrowski, Clara / de Snoo, Femke A / Debniak, Tadeusz / Demierre, Marie-France / Elder, David / Goldstein, Alisa M / Grant-Kels, Jane / Halpern, Allan C / Ingvar, Christian / Kefford, Richard F / Lang, Julie / MacKie, Rona M / Mann, Graham J / Mueller, Kurt / Newton-Bishop, Julia / Olsson, Håkan / Petersen, Gloria M / Puig, Susana / Rigel, Darrell / Swetter, Susan M / Tucker, Margaret A / Yakobson, Emanuel / Zitelli, John A / Tsao, Hensin. ·Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112-5550, USA. sancy.leachman@hci.utah.edu ·J Am Acad Dermatol · Pubmed #19751883.

ABSTRACT: Approximately 5% to 10% of melanoma may be hereditary in nature, and about 2% of melanoma can be specifically attributed to pathogenic germline mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A). To appropriately identify the small proportion of patients who benefit most from referral to a genetics specialist for consideration of genetic testing for CDKN2A, we have reviewed available published studies of CDKN2A mutation analysis in cohorts with invasive, cutaneous melanoma and found variability in the rate of CDKN2A mutations based on geography, ethnicity, and the type of study and eligibility criteria used. Except in regions of high melanoma incidence, such as Australia, we found higher rates of CDKN2A positivity in individuals with 3 or more primary invasive melanomas and/or families with at least one invasive melanoma and two or more other diagnoses of invasive melanoma and/or pancreatic cancer among first- or second-degree relatives on the same side of the family. The work summarized in this review should help identify individuals who are appropriate candidates for referral for genetic consultation and possible testing.

9 Review Cutaneous melanoma in the era of molecular profiling. 2009

Thompson, John F / Scolyer, Richard A / Kefford, Richard F. ·Melanoma Institute Australia, North Sydney, NSW 2060, Australia. john.thompson@smu.org.au ·Lancet · Pubmed #19647595.

ABSTRACT: -- No abstract --

10 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

11 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 .).

12 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.

13 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:

14 Clinical Trial Phase III Randomized Study of 4 Weeks of High-Dose Interferon-α-2b in Stage T2bNO, T3a-bNO, T4a-bNO, and T1-4N1a-2a (microscopic) Melanoma: A Trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E1697). 2017

Agarwala, Sanjiv S / Lee, Sandra J / Yip, Waiki / Rao, Uma N / Tarhini, Ahmad A / Cohen, Gary I / Reintgen, Douglas S / Evans, Terry L / Brell, Joanna M / Albertini, Mark R / Atkins, Michael B / Dakhil, Shaker R / Conry, Robert M / Sosman, Jeffrey A / Flaherty, Lawrence E / Sondak, Vernon K / Carson, William E / Smylie, Michael G / Pappo, Alberto S / Kefford, Richard F / Kirkwood, John M. ·Sanjiv S. Agarwala, Saint Luke's University Hospital, Easton · Uma N. Rao, Ahmad A. Tarhini, Terry L. Evans, and John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, PA · Sandra J. Lee, and Waiki Yip, Dana Farber Cancer Institute-ECOG-ACRIN Biostatistics Center, Boston, MA · Gary I. Cohen, Greater Baltimore Medical Center, Baltimore, MD · Douglas S. Reintgen, Lakeland Regional Cancer Center, Lakeland · Vernon K. Sondak, H. Lee Moffitt Cancer Center, Tampa, FL · Joanna M. Brell, MetroHealth Medical Center, Cleveland · William E. Carson, The Ohio State University Comprehensive Cancer Center, Columbus, OH · Mark R. Albertini, University of Wisconsin Hospital, Madison, WI · Michael B. Atkins, Georgetown Medical Center, Washington, DC · Shaker R. Dakhil, Cancer Center of Kansas, Wichita, KS · Robert M. Conry, University of Alabama at Birmingham, Birmingham, AL · Jeffrey A. Sosman, Vanderbilt University, Nashville · Alberto S. Pappo, Saint Jude Children's Research Hospital Oncology, Memphis, TN · Lawrence E. Flaherty, Wayne State University/Karmanos Cancer Institute, Detroit, MI · Michael G. Smylie, Cross Cancer Institute, Edmonton, Canada · and Richard F. Kefford, Sydney West Area Health Service, Westmead, Australia. ·J Clin Oncol · Pubmed #28135150.

ABSTRACT: Purpose To test the efficacy of 4 weeks of intravenous (IV) induction with high-dose interferon (IFN) as part of the Eastern Cooperative Oncology Group regimen compared with observation (OBS) in patients with surgically resected intermediate-risk melanoma. Patients and Methods In this intergroup international trial, eligible patients had surgically resected cutaneous melanoma in the following categories: (1) T2bN0, (2) T3a-bN0, (3) T4a-bN0, and (4) T1-4N1a-2a (microscopic). Patients were randomly assigned to receive IFN α-2b at 20 MU/m

15 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.

16 Clinical Trial Programmed Death-Ligand 1 Expression and Response to the Anti-Programmed Death 1 Antibody Pembrolizumab in Melanoma. 2016

Daud, Adil I / Wolchok, Jedd D / Robert, Caroline / Hwu, Wen-Jen / Weber, Jeffrey S / Ribas, Antoni / Hodi, F Stephen / Joshua, Anthony M / Kefford, Richard / Hersey, Peter / Joseph, Richard / Gangadhar, Tara C / Dronca, Roxana / Patnaik, Amita / Zarour, Hassane / Roach, Charlotte / Toland, Grant / Lunceford, Jared K / Li, Xiaoyun Nicole / Emancipator, Kenneth / Dolled-Filhart, Marisa / Kang, S Peter / Ebbinghaus, Scot / Hamid, Omid. ·Adil I. Daud, University of California, San Francisco, San Francisco · Antoni Ribas, University of California, Los Angeles · Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles · Charlotte Roach and Grant Toland, Dako North America, Carpinteria, CA · Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY · Wen-Jen Hwu, The University of Texas MD Anderson Cancer Center, Houston · Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX · Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa · Richard Joseph, Mayo Clinic, Jacksonville, FL · F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA · Tara C. Gangadhar, Abramson Cancer Center at the University of Pennsylvania, Philadelphia · Hassane Zarour, University of Pittsburgh, Pittsburgh, PA · Roxana Dronca, Mayo Clinic, Rochester, MN · Jared K. Lunceford, Xiaoyun Nicole Li, Kenneth Emancipator, Marisa Dolled-Filhart, S. Peter Kang, and Scot Ebbinghaus, Merck & Co, Kenilworth, NJ · Caroline Robert, Gustave Roussy and Paris-Sud University, Villejuif, France · Anthony M. Joshua, Princess Margaret Cancer Centre, Toronto, ON, Canada · Richard Kefford, Crown Princess Mary Cancer Centre, Westmead Hospital and Melanoma Institute Australia · Richard Kefford, Macquarie University · and Richard Kefford and Peter Hersey, University of Sydney, Sydney, NSW, Australia. ·J Clin Oncol · Pubmed #27863197.

ABSTRACT: Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 (PD-1). This study explored the relationship between anti-PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks. Tumor response was assessed every 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent central review. Primary outcome was objective response rate. Secondary outcomes included progression-free survival (PFS) and overall survival (OS). Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique melanoma (MEL) scale of 0 to 5 by one of three pathologists who were blinded to clinical outcome; a score ≥ 2 (membranous staining in ≥ 1% of cells) was considered positive. Results Of 451 patients with evaluable PD-L1 expression, 344 (76%) had PD-L1-positive tumors. Demographic and staging variables were equally distributed among PD-L1-positive and -negative patients. An association between higher MEL score and higher response rate and longer PFS (hazard ratio, 0.76; 95% CI, 0.71 to 0.82) and OS (hazard ratio, 0.76; 95% CI, 0.69 to 0.83) was observed ( P < .001 for each). Objective response rate was 8%, 12%, 22%, 43%, 57%, and 53% for MEL 0, 1, 2, 3, 4, and 5, respectively. Conclusion PD-L1 expression in pretreatment tumor biopsy samples was correlated with response rate, PFS, and OS; however, patients with PD-L1-negative tumors may also achieve durable responses.

17 Clinical Trial Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. 2016

Ribas, Antoni / Hamid, Omid / Daud, Adil / Hodi, F Stephen / Wolchok, Jedd D / Kefford, Richard / Joshua, Anthony M / Patnaik, Amita / Hwu, Wen-Jen / Weber, Jeffrey S / Gangadhar, Tara C / Hersey, Peter / Dronca, Roxana / Joseph, Richard W / Zarour, Hassane / Chmielowski, Bartosz / Lawrence, Donald P / Algazi, Alain / Rizvi, Naiyer A / Hoffner, Brianna / Mateus, Christine / Gergich, Kevin / Lindia, Jill A / Giannotti, Maxine / Li, Xiaoyun Nicole / Ebbinghaus, Scot / Kang, S Peter / Robert, Caroline. ·Division of Hematology and Oncology, University of California-Los Angeles, Los Angeles. · Department of Hematology/Oncology, The Angeles Clinic and Research Institute, Los Angeles, California. · Department of Hematology/Oncology, University of California-San Francisco, San Francisco. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital and Melanoma Institute Australia, Sydney, Australia7Department of Clinical Medicine, Macquarie University, Sydney, Australia. · Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · Department of Clinical Research, South Texas Accelerated Research Therapeutics, San Antonio. · Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston. · Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida. · Division of Hematology and Oncology, Abramson Cancer Center at the University of Pennsylvania, Philadelphia. · Department of Medicine, University of Sydney, Sydney, Australia. · Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota. · Department of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida. · Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. · Department of Hematology/Oncology, Massachusetts General Hospital, Boston. · Department of Medical Oncology, Gustave-Roussy Cancer Campus and Paris Sud University, Villejuif Paris-Sud, France. · Department of Clinical Oncology, Merck & Co, Inc, Kenilworth, New Jersey. · BARDS, Merck & Co, Inc, Kenilworth, New Jersey. ·JAMA · Pubmed #27092830.

ABSTRACT: IMPORTANCE: The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab. OBJECTIVE: To characterize the association of pembrolizumab with tumor response and overall survival among patients with advanced melanoma. DESIGN, SETTINGS, AND PARTICIPANTS: Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013). Median duration of follow-up was 21 months. The study was performed in academic medical centers in Australia, Canada, France, and the United States. Eligible patients were aged 18 years and older and had advanced or metastatic melanoma. Data were pooled from 655 enrolled patients (135 from a nonrandomized cohort [n = 87 ipilimumab naive; n = 48 ipilimumab treated] and 520 from randomized cohorts [n = 226 ipilimumab naive; n = 294 ipilimumab treated]). Cutoff dates were April 18, 2014, for safety analyses and October 18, 2014, for efficacy analyses. EXPOSURES: Pembrolizumab 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks continued until disease progression, intolerable toxicity, or investigator decision. MAIN OUTCOMES AND MEASURES: The primary end point was confirmed objective response rate (best overall response of complete response or partial response) in patients with measurable disease at baseline per independent central review. Secondary end points included toxicity, duration of response, progression-free survival, and overall survival. RESULTS: Among the 655 patients (median [range] age, 61 [18-94] years; 405 [62%] men), 581 had measurable disease at baseline. An objective response was reported in 194 of 581 patients (33% [95% CI, 30%-37%]) and in 60 of 133 treatment-naive patients (45% [95% CI, 36% to 54%]). Overall, 74% (152/205) of responses were ongoing at the time of data cutoff; 44% (90/205) of patients had response duration for at least 1 year and 79% (162/205) had response duration for at least 6 months. Twelve-month progression-free survival rates were 35% (95% CI, 31%-39%) in the total population and 52% (95% CI, 43%-60%) among treatment-naive patients. Median overall survival in the total population was 23 months (95% CI, 20-29) with a 12-month survival rate of 66% (95% CI, 62%-69%) and a 24-month survival rate of 49% (95% CI, 44%-53%). In treatment-naive patients, median overall survival was 31 months (95% CI, 24 to not reached) with a 12-month survival rate of 73% (95% CI, 65%-79%) and a 24-month survival rate of 60% (95% CI, 51%-68%). Ninety-two of 655 patients (14%) experienced at least 1 treatment-related grade 3 or 4 adverse event (AE) and 27 of 655 (4%) patients discontinued treatment because of a treatment-related AE. Treatment-related serious AEs were reported in 59 patients (9%). There were no drug-related deaths. CONCLUSIONS AND RELEVANCE: Among patients with advanced melanoma, pembrolizumab administration was associated with an overall objective response rate of 33%, 12-month progression-free survival rate of 35%, and median overall survival of 23 months; grade 3 or 4 treatment-related AEs occurred in 14%. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01295827.

18 Clinical Trial Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With Pembrolizumab. 2016

Hodi, F Stephen / Hwu, Wen-Jen / Kefford, Richard / Weber, Jeffrey S / Daud, Adil / Hamid, Omid / Patnaik, Amita / Ribas, Antoni / Robert, Caroline / Gangadhar, Tara C / Joshua, Anthony M / Hersey, Peter / Dronca, Roxana / Joseph, Richard / Hille, Darcy / Xue, Dahai / Li, Xiaoyun Nicole / Kang, S Peter / Ebbinghaus, Scot / Perrone, Andrea / Wolchok, Jedd D. ·F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA · Wen-Jen Hwu, The University of Texas MD Anderson Cancer Center, Houston · Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX · Richard Kefford, Westmead Hospital, Melanoma Institute Australia, and Macquarie University · Peter Hersey, University of Sydney, Sydney, Australia · Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa · Richard Joseph, Mayo Clinic, Jacksonville, FL · Adil Daud, University of California San Francisco, San Francisco · Omid Hamid, The Angeles Clinic and Research Institute · Antoni Ribas, University of California Los Angeles, Los Angeles, CA · Caroline Robert, Gustave-Roussy and Paris-Sud University, Villejuif-Paris-Sud, France · Tara C. Gangadhar, Abramson Cancer Center, Philadelphia, PA · Anthony M. Joshua, Princess Margaret Hospital, Toronto, Ontario, Canada · Roxana Dronca, Mayo Clinic, Rochester, MN · Darcy Hille, Dahai Xue, Xiaoyun Nicole Li, S. Peter Kang, Scot Ebbinghaus, and Andrea Perrone, Merck, Kenilworth, NJ · and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY. ·J Clin Oncol · Pubmed #26951310.

ABSTRACT: PURPOSE: We evaluated atypical response patterns and the relationship between overall survival and best overall response measured per immune-related response criteria (irRC) and Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) in patients with advanced melanoma treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). PATIENTS AND METHODS: Patients received pembrolizumab 2 or 10 mg/kg every 2 weeks or every 3 weeks. Atypical responses were identified by using centrally assessed irRC data in patients with ≥ 28 weeks of imaging. Pseudoprogression was defined as ≥ 25% increase in tumor burden at week 12 (early) or any assessment after week 12 (delayed) that was not confirmed as progressive disease at next assessment. Response was assessed centrally per irRC and RECIST v1.1. RESULTS: Of the 655 patients with melanoma enrolled, 327 had ≥ 28 weeks of imaging follow-up. Twenty-four (7%) of these 327 patients had atypical responses (15 [5%] with early pseudoprogression and nine [3%] with delayed pseudoprogression). Of the 592 patients who survived ≥ 12 weeks, 84 (14%) experienced progressive disease per RECIST v1.1 but nonprogressive disease per irRC. Two-year overall survival rates were 77.6% in patients with nonprogressive disease per both criteria (n = 331), 37.5% in patients with progressive disease per RECIST v1.1 but nonprogressive disease per irRC (n = 84), and 17.3% in patients with progressive disease per both criteria (n = 177). CONCLUSION: Atypical responses were observed in patients with melanoma treated with pembrolizumab. Based on survival analysis, conventional RECIST might underestimate the benefit of pembrolizumab in approximately 15% of patients; modified criteria that permit treatment beyond initial progression per RECIST v1.1 might prevent premature cessation of treatment.

19 Clinical Trial Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib. 2016

Long, Georgina V / Weber, Jeffrey S / Infante, Jeffrey R / Kim, Kevin B / Daud, Adil / Gonzalez, Rene / Sosman, Jeffrey A / Hamid, Omid / Schuchter, Lynn / Cebon, Jonathan / Kefford, Richard F / Lawrence, Donald / Kudchadkar, Ragini / Burris, Howard A / Falchook, Gerald S / Algazi, Alain / Lewis, Karl / Puzanov, Igor / Ibrahim, Nageatte / Sun, Peng / Cunningham, Elizabeth / Kline, Amy S / Del Buono, Heather / McDowell, Diane Opatt / Patel, Kiran / Flaherty, Keith T. ·Georgina V. Long, Melanoma Institute Australia · The University of Sydney · Richard F. Kefford, Melanoma Institute Australia · The University of Sydney · Macquarie University, Sydney · Westmead Hospital, Westmead · Jonathan Cebon, Austin Health, Melbourne, Victoria, Australia · Jeffrey S. Weber and Ragini Kudchadkar, Moffitt Cancer Center, Tampa, FL · Jeffrey R. Infante and Howard A. Burris III, Sarah Cannon Research Institute/Tennessee Oncology · Kevin B. Kim, California Pacific Medical Center · Adil Daud, Alain Algazi, University of California, San Francisco, San Francisco · Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles, CA · Rene Gonzalez, Karl Lewis, University of Colorado · Gerald S. Falchook, Sarah Cannon Research Institute at HealthONE, Denver, CO · Jeffrey A. Sosman, Igor Puzanov, Vanderbilt University Medical Center, Nashville, TN · Lynn Schuchter, University of Pennsylvania Abramson Cancer Center · Nageatte Ibrahim, Elizabeth Cunningham, Merck · Peng Sun, Amy S. Kline, Heather Del Buono, Diane Opatt McDowell, GlaxoSmithKline, Philadelphia, PA · Donald Lawrence and Kiran Patel, Incyte Corporation, Wilmington, DE · and Keith T. Flaherty, Massachusetts General Hospital Cancer Center, Boston, MA. ·J Clin Oncol · Pubmed #26811525.

ABSTRACT: PURPOSE: To report the overall survival (OS) and clinical characteristics of BRAF inhibitor-naive long-term responders and survivors treated with dabrafenib plus trametinib in a phase I and II study of patients with BRAF V600 mutation-positive metastatic melanoma. METHODS: BRAF inhibitor-naive patients treated with dabrafenib 150 mg twice daily plus trametinib 2 mg daily (the 150/2 group) from the non-randomly assigned (part B) and randomly assigned (part C) cohorts of the study were analyzed for progression-free and OS separately. Baseline characteristics and factors on treatment were analyzed for associations with durable responses and OS. RESULTS: For BRAF inhibitor-naive patients in the 150/2 groups (n = 78), the progression-free survival at 1, 2, and 3 years was 44%, 22%, and 18%, respectively, for part B (n = 24) and 41%, 25%, and 21%, respectively, for part C (n = 54). Median OS was 27.4 months in part B and 25 months in part C. OS at 1, 2, and 3 years was 72%, 60%, and 47%, respectively, for part B and 80%, 51%, and 38%, respectively, for part C. Prolonged survival was associated with metastases in fewer than three organ sites and lower baseline lactate dehydrogenase. OS at 3 years was 62% in patients with normal baseline lactate dehydrogenase and 63% in patients with a complete response. CONCLUSION: Dabrafenib plus trametinib results in a median OS of more than 2 years in BRAF inhibitor-naive patients with BRAF V600 mutation-positive metastatic melanoma, and approximately 20% were progression free at 3 years. Durable responses occurred in patients with good prognostic features at baseline, which may be predictive.

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

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

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

21 Clinical Trial Characteristics of pyrexia in BRAFV600E/K metastatic melanoma patients treated with combined dabrafenib and trametinib in a phase I/II clinical trial. 2015

Menzies, A M / Ashworth, M T / Swann, S / Kefford, R F / Flaherty, K / Weber, J / Infante, J R / Kim, K B / Gonzalez, R / Hamid, O / Schuchter, L / Cebon, J / Sosman, J A / Little, S / Sun, P / Aktan, G / Ouellet, D / Jin, F / Long, G V / Daud, A. ·Melanoma Institute Australia and The University of Sydney, Sydney, Australia alexander.menzies@sydney.edu.au. · University of California San Francisco, San Francisco. · Clinical Statistics, GlaxoSmithKline, Collegeville, USA. · Melanoma Institute Australia and The University of Sydney, Sydney, Australia Westmead Hospital, University of Sydney, Sydney Westmead Millennium Institute, University of Sydney, Sydney, Australia. · Massachusetts General Hospital Center, Boston. · Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa. · Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville. · California Pacific Medical Center, San Francisco. · Department of Medical Oncology, The University of Colorado Cancer Center, Aurora. · Department of Oncology, The Angeles Clinic and Research Institute, Santa Monica. · Penn Medicine, The University of Pennsylvania, Philadelphia, USA. · Oncology Unit, Ludwig Institute for Cancer Research, Heidelberg, Australia. · Department of Oncology, Vanderbilt University Medical Centre, Nashville, USA. · Melanoma Institute Australia and The University of Sydney, Sydney, Australia Westmead Millennium Institute, University of Sydney, Sydney, Australia. ·Ann Oncol · Pubmed #25411413.

ABSTRACT: BACKGROUND: Pyrexia is a frequent adverse event with combined dabrafenib and trametinib therapy (CombiDT), but little is known of its clinical associations, etiology, or appropriate management. PATIENTS AND METHODS: All patients on the BRF133220 phase I/II trial of CombiDT treated at the standard dose (150/2) were included for assessment of pyrexia (n = 201). BRAF and MEK inhibitor-naïve patients (n = 117) were included for efficacy analyses. Pyrexia was defined as temperature ≥38°C (≥100.4(°)F) or related symptoms. RESULTS: Fifty-nine percent of patients developed pyrexia during treatment, 24% of which had pyrexia symptoms without a recorded elevation in body temperature. Pyrexia was grade 2+ in 60% of pyrexia patients. Median time to onset of first pyrexia was 19 days, with a median duration of 9 days. Pyrexia patients had a median of two pyrexia events, but 21% had three or more events. Various pyrexia management approaches were conducted in this study. A trend was observed between dabrafenib and hydroxy-dabrafenib exposure and pyrexia. No baseline clinical characteristics predicted pyrexia, and pyrexia was not statistically significantly associated with treatment outcome. CONCLUSIONS: Pyrexia is a frequent and recurrent toxicity with CombiDT treatment. No baseline features predict pyrexia, and it is not associated with clinical outcome. Dabrafenib and metabolite exposure may contribute to the etiology of pyrexia. The optimal secondary prophylaxis for pyrexia is best studied in a prospective trial.

22 Clinical Trial Cutaneous adverse events in patients treated with BRAF inhibitor-based therapies for metastatic melanoma for longer than 52 weeks. 2015

Anforth, R / Carlos, G / Clements, A / Kefford, R / Fernandez-Peñas, P. ·Department of Dermatology, Westmead Hospital, Darcy Rd, Westmead, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. ·Br J Dermatol · Pubmed #25040674.

ABSTRACT: BACKGROUND: BRAF inhibitor-based therapies have been shown to induce cutaneous toxicities, with onset generally in the first 8-26 weeks of therapy. OBJECTIVES: To determine whether cutaneous toxicities persist in patients who have remained on BRAF inhibitor-based therapies for longer than 52 weeks, and therefore whether ongoing dermatology assessment is required. METHODS: All patients treated with the BRAF inhibitors vemurafenib or dabrafenib or combination BRAF inhibitor and mitogen-activated protein kinase kinase (MEK) inhibitor therapy at Westmead Hospital, Sydney, Australia underwent regular dermatological assessments for the duration of therapy. All patients enrolled in a clinical trial, and 18% of patients in the compassionate access scheme underwent a baseline assessment prior to commencement of therapy and every 4-8 weeks thereafter. Patients' adverse events were recorded in a specific database. RESULTS: Patients continued to develop cutaneous adverse events after 52 weeks of continuous therapy. Patients on single-agent BRAF inhibitor therapy suffered from Grover disease (45%), plantar hyperkeratosis (45%), verrucal keratosis (18%) and even cutaneous squamous cell carcinoma (16%). The most frequent adverse event seen in patients in the combination BRAF and MEK inhibitor group was an acneiform eruption (40%). CONCLUSIONS: Patients on BRAF inhibitor-based therapies need to continue to have regular dermatological follow-up independent of the duration of their therapy.

23 Clinical Trial Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. 2014

Johnson, Douglas B / Flaherty, Keith T / Weber, Jeffrey S / Infante, Jeffrey R / Kim, Kevin B / Kefford, Richard F / Hamid, Omid / Schuchter, Lynn / Cebon, Jonathan / Sharfman, William H / McWilliams, Robert R / Sznol, Mario / Lawrence, Donald P / Gibney, Geoffrey T / Burris, Howard A / Falchook, Gerald S / Algazi, Alain / Lewis, Karl / Long, Georgina V / Patel, Kiran / Ibrahim, Nageatte / Sun, Peng / Little, Shonda / Cunningham, Elizabeth / Sosman, Jeffrey A / Daud, Adil / Gonzalez, Rene. ·Douglas B. Johnson and Jeffrey A. Sosman, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center · Jeffrey R. Infante and Howard A. Burris III, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN · Keith T. Flaherty and Donald P. Lawrence, Massachusetts General Hospital Cancer Center, Boston MA · Jeffrey S. Weber and Geoffrey T. Gibney, Moffitt Cancer Center, Tampa, FL · Kevin B. Kim and Gerald S. Falchook, University of Texas MD Anderson Cancer Center, Houston, TX · Richard F. Kefford and Georgina V. Long, Melanoma Institute Australia, University of Sydney and Westmead Hospital, Sydney, New South Wales · Jonathan Cebon, Joint Ludwig-Austin Oncology Unit, Austin Health, Melbourne, Victoria, Australia · Omid Hamid, Angeles Clinic and Research Institute, Los Angeles · Alain Algazi and Adil Daud, University of California, San Francisco, San Francisco, CA · Lynn Schuchter, University of Pennsylvania Abramson Cancer Center · Nageatte Ibrahim, Peng Sun, Shonda Little, and Elizabeth Cunningham, GlaxoSmithKline, Philadelphia, PA · William H. Sharfman, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD · Robert R. McWilliams, Mayo Clinic, Rochester, MN · Mario Sznol, Yale University School of Medicine and Smilow Cancer Center, Yale-New Haven Hospital, New Haven, CT · Karl Lewis and Rene Gonzalez, University of Colorado, Denver, CO · and Kiran Patel, Incyte, Wilmington, DE. ·J Clin Oncol · Pubmed #25287827.

ABSTRACT: PURPOSE: Preclinical and early clinical studies have demonstrated that initial therapy with combined BRAF and MEK inhibition is more effective in BRAF(V600)-mutant melanoma than single-agent BRAF inhibitors. This study assessed the safety and efficacy of dabrafenib and trametinib in patients who had received prior BRAF inhibitor treatment. PATIENTS AND METHODS: In this open-label phase I/II study, we evaluated the pharmacology, safety, and efficacy of dabrafenib and trametinib. Here, we report patients treated with combination therapy after disease progression with BRAF inhibitor treatment administered before study enrollment (part B; n = 26) or after cross-over at progression with dabrafenib monotherapy (part C; n = 45). RESULTS: In parts B and C, confirmed objective response rates (ORR) were 15% (95% CI, 4% to 35%) and 13% (95% CI, 5% to 27%), respectively; an additional 50% and 44% experienced stable disease ≥ 8 weeks, respectively. In part C, median progression-free survival (PFS) was 3.6 months (95% CI, 2 to 4), and median overall survival was 11.8 months (95% CI, 8 to 25) from cross-over. Patients who previously received dabrafenib ≥ 6 months had superior outcomes with the combination compared with those treated < 6 months; median PFS was 3.9 (95% CI, 3 to 7) versus 1.8 months (95% CI, 2 to 4; hazard ratio, 0.49; P = .02), and ORR was 26% (95% CI, 10% to 48%) versus 0% (95% CI, 0% to 15%). CONCLUSION: Dabrafenib plus trametinib has modest clinical efficacy in patients with BRAF inhibitor-resistant melanoma. This regimen may be a therapeutic strategy for patients who previously benefited from BRAF inhibitor monotherapy ≥ 6 months but demonstrates minimal efficacy after rapid progression with BRAF inhibitor therapy.

24 Clinical Trial Features and management of pyrexia with combined dabrafenib and trametinib in metastatic melanoma. 2014

Lee, Clara I / Menzies, Alexander M / Haydu, Lauren E / Azer, Mary / Clements, Arthur / Kefford, Richard F / Long, Georgina V. ·aWestmead Hospital bWestmead Institute for Cancer Research, Westmead cMelanoma Institute Australia dSydney Medical School, The University of Sydney, Sydney, New South Wales, Australia. ·Melanoma Res · Pubmed #25054915.

ABSTRACT: The combination of dabrafenib and trametinib (CombiDT) is an effective treatment for BRAF-mutant metastatic melanoma; however, over 70% of patients develop drug-related pyrexia, and little is known about this toxicity. We sought to examine the features and management of CombiDT pyrexia. The association between pyrexia and patient demographics, disease characteristics and outcome variables was assessed in patients treated with CombiDT at a single institution. The clinicopathological features of pyrexic events were analysed. Fourteen of 32 (44%) patients developed pyrexia (temperature≥38.5°C). Pyrexia was recurrent in 11/14 (79%). The median time to pyrexia was 38 days. Pyrexia was not associated with age, sex nor disease burden, and did not correlate with RECIST response, progression-free nor overall survival. Paracetamol, NSAIDs and/or dose reduction (DR) were ineffective secondary prophylaxis for pyrexia, whereas corticosteroids were effective in all patients (n=8), including two with multiple previous pyrexic events despite several DRs. In patients with previous DRs who commenced steroids (n=3), CombiDT doses were re-escalated without pyrexia. Pyrexia is a frequent and recurrent toxicity with CombiDT, with no predictive clinical characteristics. Pyrexia does not correlate with clinical outcome. Neither DR nor antipyretics are effective secondary prophylaxis, whereas corticosteroids are effective, prevent DR and enable re-escalation of CombiDT dosing.

25 Clinical Trial Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. 2014

Robert, Caroline / Ribas, Antoni / Wolchok, Jedd D / Hodi, F Stephen / Hamid, Omid / Kefford, Richard / Weber, Jeffrey S / Joshua, Anthony M / Hwu, Wen-Jen / Gangadhar, Tara C / Patnaik, Amita / Dronca, Roxana / Zarour, Hassane / Joseph, Richard W / Boasberg, Peter / Chmielowski, Bartosz / Mateus, Christine / Postow, Michael A / Gergich, Kevin / Elassaiss-Schaap, Jeroen / Li, Xiaoyun Nicole / Iannone, Robert / Ebbinghaus, Scot W / Kang, S Peter / Daud, Adil. ·Gustave Roussy and INSERM U981, Paris-Sud, France. Electronic address: caroline.robert@gustaveroussy.fr. · University of California Los Angeles, Los Angeles, CA, USA. · Memorial Sloan-Kettering Cancer Center, New York, NY, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Crown Princess Mary Cancer Centre, Westmead Hospital and Melanoma Institute Australia, Westmead, NSW, Australia; University of Sydney, Sydney, NSW, Australia. · H Lee Moffitt Cancer Center, Tampa, FL, USA. · Princess Margaret Cancer Centre, Toronto, ON, Canada. · University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA. · South Texas Accelerated Research Therapeutics, San Antonio, TX, USA. · Mayo Clinic, Rochester, MN, USA. · University of Pittsburgh, Pittsburgh, PA, USA. · Mayo Clinic, Jacksonville, FL, USA. · Gustave Roussy and INSERM U981, Paris-Sud, France. · Merck, Whitehouse Station, NJ, USA. · University of California San Francisco, San Francisco, CA, USA. ·Lancet · Pubmed #25034862.

ABSTRACT: BACKGROUND: The anti-programmed-death-receptor-1 (PD-1) antibody pembrolizumab has shown potent antitumour activity at different doses and schedules in patients with melanoma. We compared the efficacy and safety of pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced melanoma. METHODS: In an open-label, international, multicentre expansion cohort of a phase 1 trial, patients (aged ≥18 years) with advanced melanoma whose disease had progressed after at least two ipilimumab doses were randomly assigned with a computer-generated allocation schedule (1:1 final ratio) to intravenous pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks until disease progression, intolerable toxicity, or consent withdrawal. Primary endpoint was overall response rate (ORR) assessed with the Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) by independent central review. Analysis was done on the full-analysis set (all treated patients with measurable disease at baseline). This study is registered with ClinicalTrials.gov, number NCT01295827. FINDINGS: 173 patients received pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84). Median follow-up duration was 8 months. ORR was 26% at both doses--21 of 81 patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group (difference 0%, 95% CI -14 to 13; p=0·96). Treatment was well tolerated, with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths. The most common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg groups were fatigue (29 [33%] vs 31 [37%]), pruritus (23 [26%] vs 16 [19%]), and rash (16 [18%] vs 15 [18%]). Grade 3 fatigue, reported in five (3%) patients in the 2 mg/kg pembrolizumab group, was the only drug-related grade 3 to 4 adverse event reported in more than one patient. INTERPRETATION: The results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options. FUNDING: Merck Sharp and Dohme.

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