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Melanoma: HELP
Articles by Peter Hersey
Based on 77 articles published since 2010
(Why 77 articles?)
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Between 2010 and 2020, P. Hersey wrote the following 77 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Editorial Synergistic effects of MAPK and immune checkpoint inhibitors in melanoma: what is the best combination strategy? 2015

Wilmott, James S / Hersey, Peter / Long, Georgina V / Scolyer, Richard A. ·Melanoma Institute Australia, Sydney, New South Wales, Australia. · The University of Sydney, Sydney, New South Wales, Australia. · Tissue Pathology & Diagnostic Oncology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, Sydney, New South Wales, 2050, Australia. ·Melanoma Manag · Pubmed #30190826.

ABSTRACT: -- No abstract --

2 Review Do innate killing mechanisms activated by inflammasomes have a role in treating melanoma? 2020

Emran, Abdullah Al / Tseng, Hsin-Yi / Coleman, Mikaela C / Tiffen, Jessamy / Cook, Stuart / McGuire, Helen M / Gallagher, Stuart / Feng, Carl / Hersey, Peter. ·Melanoma Immunology and Oncology Group, The Centenary Institute, Royal Prince Alfred Hospital, University of Sydney, Camperdown, New South Wales, Australia. · Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. · Immunology and Host Defence Group, Department of Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia. · Tuberculosis Research Program, Centenary Institute, Camperdown, New South Wales, Australia. · Ramaciotti Facility for Human Systems Biology, The University of Sydney, Sydney, New South Wales, Australia. · Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia. · Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia. ·Pigment Cell Melanoma Res · Pubmed #32027447.

ABSTRACT: Melanoma, as for many other cancers, undergoes a selection process during progression that limits many innate and adaptive tumor control mechanisms. Immunotherapy with immune checkpoint blockade overcomes one of the escape mechanisms but if the tumor is not eliminated other escape mechanisms evolve that require new approaches for tumor control. Some of the innate mechanisms that have evolved against infections with microorganisms and viruses are proving to be active against cancer cells but require better understanding of how they are activated and what inhibitory mechanisms may need to be targeted. This is particularly so for inflammasomes which have evolved against many different organisms and which recruit a number of cytotoxic mechanisms that remain poorly understood. Equally important is understanding of where these mechanisms will fit into existing treatment strategies and whether existing strategies already involve the innate killing mechanisms.

3 Review Targeting DNA Methylation and EZH2 Activity to Overcome Melanoma Resistance to Immunotherapy. 2019

Emran, Abdullah Al / Chatterjee, Aniruddha / Rodger, Euan J / Tiffen, Jessamy C / Gallagher, Stuart J / Eccles, Michael R / Hersey, Peter. ·Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia; These authors contributed equally. · Department of Pathology, Dunedin School of Medicine, University of Otago, 270 Great King Street, Dunedin 9054, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Level, 3A Symonds Street, Auckland, New Zealand; These authors contributed equally. · Department of Pathology, Dunedin School of Medicine, University of Otago, 270 Great King Street, Dunedin 9054, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Level, 3A Symonds Street, Auckland, New Zealand. · Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia. · Department of Pathology, Dunedin School of Medicine, University of Otago, 270 Great King Street, Dunedin 9054, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Level, 3A Symonds Street, Auckland, New Zealand; Senior author. · Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia; Senior author. Electronic address: p.hersey@centenary.org.au. ·Trends Immunol · Pubmed #30853334.

ABSTRACT: Methylation of DNA at CpG sites is the most common and stable of epigenetic changes in cancer. Hypermethylation acts to limit immune checkpoint blockade immunotherapy by inhibiting endogenous interferon responses needed for recognition of cancer cells. By contrast, global hypomethylation results in the expression of programmed death ligand 1 (PD-L1) and inhibitory cytokines, accompanied by epithelial-mesenchymal changes that can contribute to immunosuppression. The drivers of these contrasting methylation states are not well understood. DNA methylation also plays a key role in cytotoxic T cell 'exhaustion' associated with tumor progression. We present an updated exploratory analysis of how DNA methylation may define patient subgroups and can be targeted to develop tailored treatment combinations to help improve patient outcomes.

4 Review EZH2 as a mediator of treatment resistance in melanoma. 2016

Tiffen, Jessamy C / Gallagher, Stuart J / Tseng, Hsin-Yi / Filipp, Fabian V / Fazekas de St. Groth, Barbara / Hersey, Peter. ·Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Camperdown, NSW, Australia. · Systems Biology and Cancer Metabolism, Program for Quantitative Systems Biology, University of California Merced, Merced, CA, USA. · T Cell Biology Program, The Centenary Institute, University of Sydney, Camperdown, NSW, Australia. · Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Camperdown, NSW, Australia. peter.hersey@centenary.org.au. ·Pigment Cell Melanoma Res · Pubmed #27063195.

ABSTRACT: Direct treatments of cancer such as chemotherapy, radiotherapy and targeted therapy have been shown to depend on recruitment of the immune system for their effectiveness. Recent studies have shown that development of resistance to direct therapies such as BRAF inhibitors in melanoma is associated with suppression of immune responses. We point to emerging data that implicate activation of the polycomb repressive complex 2 (PRC2) and its catalytic component-enhancer of zeste homolog 2 (EZH2)-in progression of melanoma and suppression of immune responses. EZH2 appears to have an important role in differentiation of CD4 T cells and particularly in the function of T regulatory cells, which suppress immune responses to melanoma. We review mechanisms of EZH2 activation at the genomic level and from activation of the MAP kinase, E2F or NF-kB2 pathways. These studies are consistent with activation of EZH2 as a common mechanism for induction of immune suppression in patients failing direct therapies and suggest EZH2 inhibitors may have a role in combination with immunotherapy and targeted therapies to prevent development of immunosuppression.

5 Review Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. 2015

Hersey, Peter / Gowrishankar, Kavitha. ·Kolling Medical Research Institute, Royal North Shore Hospital, University of Sydney, St Leonards, NSW 2065, Australia. ·Future Oncol · Pubmed #25572788.

ABSTRACT: Pembrolizumab (MK-3475) is a monoclonal antibody that binds to the PD-1 receptor on T cells and prevents binding to its ligands PD-L1 and PD-L2. Blocking this receptor frees T cells from the inhibitory effects of PD-L1 and allows them to mediate antitumor effects against cancer cells. In a large Phase I study of 411 patients with melanoma, high durable response rates over a range of doses and schedules have been shown with very little toxicity. A Phase III study of pembrolizumab comparing two schedules of administration with the current standard treatment with the anti-CTLA-4 monoclonal antibody is in progress. Combinations with other checkpoint inhibitors as well as other anticancer agents are also being evaluated. Approval of pembrolizumab for the treatment of melanoma is expected.

6 Review EZH2: an emerging role in melanoma biology and strategies for targeted therapy. 2015

Tiffen, Jessamy / Gallagher, Stuart J / Hersey, Peter. ·Melanoma Research Group, Kolling Institute of Medical Research, University of Sydney, St Leonards, NSW, Australia. ·Pigment Cell Melanoma Res · Pubmed #24912396.

ABSTRACT: Histone modifications are increasingly being recognized as important epigenetic mechanisms that govern chromatin structure and gene expression. EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2), responsible for tri-methylation of lysine 27 on histone 3 (H3K27me3) that leads to gene silencing. This highly conserved histone methyltransferase is found to be overexpressed in many different types of cancers including melanoma, where it is postulated to abnormally repress tumor suppressor genes. Somatic mutations have been identified in approximately 3% of melanomas, and activating mutations described within the catalytic SET domain of EZH2 confer its oncogenic activity. In the following review, we discuss the evidence that EZH2 is an important driver of melanoma progression and we summarize the progress of EZH2 inhibitors against this promising therapeutic target.

7 Review Side effects and toxicities of targeted therapies in stage IV melanoma. 2015

Ascierto, Paolo A / Bastholt, Lars / Hersey, Peter / Cinat, Gabriela / Eggermont, Alexander M M / Hauschild, Axel / Espinosa, Enrique / Robert, Caroline. ·1 Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori—Fondazione G. Pascale, Naples, Italy; · 2 Odense University Hospital, Odense, Denmark; · 3 Newcastle University, Newcastle, Australia; · 4 Instituto de Onco-logia Angel Rolfo, Buenos Aires, Argentina; · 5 Institut Gustave Roussy, Villejuif, France; · 6 University of Kiel, Kiel, Germany; · 7 Hospital La Paz, Madrid, Spain; · 8 Institut Gustave Roussy, Villejuif, France. ·Am J Ther · Pubmed #24185314.

ABSTRACT: As the incidence of melanoma continues to increase worldwide, the search for new therapies for advanced (stage IV) melanoma brings with it new patterns of toxicity to contend with. This review covers the toxicity profiles of new treatments for advanced melanoma currently in development. Therefore, the latest literature on melanoma treatment was surveyed for data on reported toxicities. The new types of treatments can be roughly divided into targeted tyrosine kinase inhibitors and immunomodulating agents. Each has its own set of toxicities particular to type and to individual drug. Targeted tyrosine kinase inhibitors generally cause fatigue, whereas immunomodulatory agents induce a specific set of adverse events known as immune-related adverse events (irAEs). Despite the incidence of adverse events, these agents hold promise for the treatment of stage IV melanoma. With new treatment opportunities come increased chance of toxic reactions. The key to successful melanoma treatment in the future is likely to be novel combinations of new therapeutic agents.

8 Review How anti-PD1 treatments are changing the management of melanoma. 2014

Hersey, Peter / Kakavand, Hojabr / Wilmott, James / van der Westhuizen, Andre / Gallagher, Stuart / Gowrishankar, Kavitha / Scolyer, Richard. ·Kolling Institute, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. · Melanoma Institute of Australia, Rocklands Road, North Sydney, NSW, Australia. · Department of Anatomical Pathology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia. · Calvary Mater Hospital, Sydney, NSW, Australia. ·Melanoma Manag · Pubmed #30190821.

ABSTRACT: The introduction of immunotherapy based on the blockade of the PD1/PD-L1 checkpoints has been associated with high response rates and durable remissions of disease in patients with metastatic melanoma, to the extent that it is now considered the standard of care for a wide range of patients, irrespective of their

9 Review Intralesional immunotherapy for melanoma. 2014

Hersey, Peter / Gallagher, Stuart. ·Melanoma Institute Australia, North Sydney, NSW, Australia; Kolling Institute, The University of Sydney, St Leonards, NSW, Australia. ·J Surg Oncol · Pubmed #24301265.

ABSTRACT: Intralesional immunotherapy of melanoma has two complementary aims. One is to cause regression of the injected metastasis. The other is to incite or modulate systemic immune responses in such a way that non-injected metastases will also undergo regression. A number of phase 1 and phase II studies with cytokines, viral, or bacterial agents have been conducted but their use has remained sporadic and has not progressed to become established treatments. Two treatments have progressed to randomized phase III studies. The most promising of these is based on intralesional injection of a genetically modified herpes simplex virus (HSV) (T-Vec). Initial results have shown a significant effect on durable response rates (DRR) but effects on overall survival remain under study. The second involved injection of plasmids coding for the HLA B7 antigen (Allovectin). Despite encouraging early results the treatment did not reach its endpoints and its use has been discontinued. A phase II study involving intralesional injection of oncolytic A21 coxsackie virus (Cavatak) is also under way and is showing promise.

10 Review Histone deacetylases (HDACs) as mediators of resistance to apoptosis in melanoma and as targets for combination therapy with selective BRAF inhibitors. 2012

Lai, Fritz / Jin, Lei / Gallagher, Stuart / Mijatov, Branka / Zhang, Xu Dong / Hersey, Peter. ·Oncology and Immunology Unit, University of Newcastle, Newcastle, Australia. ·Adv Pharmacol · Pubmed #22959022.

ABSTRACT: HDACs are viewed as enzymes used by cancer cells to inhibit tumor suppressor mechanisms. In particular, we discuss their role as suppressors of apoptosis in melanoma cells and as mediators of resistance to selective BRAF inhibitors. Synergistic increases in apoptosis are seen when pan-HDAC inhibitors are combined with selective BRAF inhibitors. Moreover, cell lines from patients with acquired resistance to Vemurafenib undergo PLX4720 induced apoptosis when combined with pan-HDAC inhibitors. The mechanisms of upregulation of HDACs and the mechanisms involved in HDACi reversal of resistance to apoptosis are as yet poorly understood.

11 Review Update on melanoma and non-melanoma skin cancer. Annual Skin Cancer Conference 2011, Hamilton Island, Australia, 5–6 August 2011. 2011

Zalaudek, Iris / Whiteman, David / Rosendahl, Cliff / Menzies, Scott W / Green, Adèle C / Hersey, Peter / Argenziano, Giuseppe. ·Department of Dermatology, Medical University of Graz, Graz, Austria. iris.zalaudek@meduni-graz.at ·Expert Rev Anticancer Ther · Pubmed #22117149.

ABSTRACT: In this article, we will summarize some of the highlights of the third annual conference on skin cancer, with special emphasis on the the recent advances regarding melanoma and non-melanoma skin cancer epidemiology, diagnosis and treatment. Topics were particularly addressed to a newly developing medical branch in Australia, namely that of Primary Care Skin Cancer Practitioners, and focused on strategies to improve primary and secondary prevention and early detection of melanoma and non-melanoma skin cancer using dermoscopy. Controversies related to skin cancer screening programs and recent progresses for treating advanced melanoma were additionally discussed. Yet, besides its scientific goals, the conference aimed also to encourage research originating in primary care and relevant to primary care.

12 Review Biology and clinical applications of CD40 in cancer treatment. 2010

Fonsatti, Ester / Maio, Michele / Altomonte, Maresa / Hersey, Peter. ·Division of Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. ·Semin Oncol · Pubmed #21074067.

ABSTRACT: CD40 is a costimulatory molecule widely expressed by immune cells and by neoplastic cells of different histotypes. Engagement of surface CD40 mediates different effects depending on cell type and microenvironment. In particular, CD40 expression on immune cells regulates humoral and cellular immunity, while it has apoptotic and antiproliferative activity on selected neoplastic cells. Thus, CD40 targeting may indirectly affect tumor growth through the activation of immune cells and/or directly by mediating cytotoxic effects on neoplastic cells. Preliminary findings emerging from clinical trials indicate that antibodies to CD40 can induce immune modulation and clinical responses in cancer patients.

13 Review Immunotherapy of melanoma. 2010

Hersey, Peter. ·Sydney and Newcastle Melanoma Units, Newcastle, New South Wales, Australia. peter.hersey@newcastle.edu.au ·Asia Pac J Clin Oncol · Pubmed #20482529.

ABSTRACT: A number of studies have shown that melanoma is a particularly immunogenic tumour, at least in the early stages of its development. A range of clinical phenomena also suggests that immune responses play an important role in the natural history of the disease, including the total or partial regression of primary melanomas associated with lymphoid infiltrates. Immunization with a variety of vaccines can increase immune responses to melanoma, but whether this is of therapeutic benefit remains unclear. Various trials of melanoma vaccines have shown benefits but their significance has been marginal to date. Two trials have actually shown an adverse effect on survival. Stimulation of immune responses by blocking down-regulatory mechanisms in the immune system has evolved as a potential therapeutic approach following studies that have shown that immune responses are finely regulated by a series of receptors and ligands on lymphocytes and antigen presenting cells. The best studied of these approaches is the blockade of the cytotoxic T-lymphocyte antigen 4 receptor on T cells, which allows the generation of more effector cells for longer periods. Agents targeting this receptor have shown promising results and continue to be studied.

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

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

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

15 Clinical Trial Durable Complete Response After Discontinuation of Pembrolizumab in Patients With Metastatic Melanoma. 2018

Robert, Caroline / Ribas, Antoni / Hamid, Omid / Daud, Adil / Wolchok, Jedd D / Joshua, Anthony M / Hwu, Wen-Jen / Weber, Jeffrey S / Gangadhar, Tara C / Joseph, Richard W / Dronca, Roxana / Patnaik, Amita / Zarour, Hassane / Kefford, Richard / Hersey, Peter / Zhang, Jin / Anderson, James / Diede, Scott J / Ebbinghaus, Scot / Hodi, F Stephen. ·Caroline Robert, Gustave Roussy Cancer Campus and Paris Sud University, Villejuif Paris-Sud, France · Antoni Ribas, University of California, Los Angeles · Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles · Adil Daud, University of California, San Francisco, San Francisco, CA · Jedd D. Wolchok, Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, NY · Anthony M. Joshua, The Princess Margaret Cancer Centre, Toronto, Ontario, Canada · 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 W. Joseph, Mayo Clinic Cancer Center-Florida, Jacksonville, FL · Tara C. Gangadhar, Abramson Cancer Center at the University of Pennsylvania, Philadelphia · Hassane Zarour, UPMC Hillman Cancer Center, Pittsburgh, PA · Roxana Dronca, Mayo Clinic, Rochester, MN · Richard Kefford, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead · Melanoma Institute Australia, Wollstonecraft · and Macquarie University, MQ Health, Health Sciences Centre · Peter Hersey, University of Sydney, Sydney, New South Wales, Australia · Jin Zhang, James Anderson, Scott J. Diede, and Scot Ebbinghaus, Merck & Co., Inc., Kenilworth, NJ · F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA. ·J Clin Oncol · Pubmed #29283791.

ABSTRACT: Purpose Pembrolizumab provides durable antitumor activity in metastatic melanoma, including complete response (CR) in about 15% of patients. Data are limited on potential predictors of CR and patient disposition after pembrolizumab discontinuation after CR. We describe baseline characteristics and long-term follow-up in patients who experienced CR with pembrolizumab in the KEYNOTE-001 study ( ClinicalTrials.gov identifier: NCT01295827). Patients and Methods Patients with ipilimumab-naive or -treated advanced/metastatic melanoma received one of three dose regimens of pembrolizumab. Eligible patients who received pembrolizumab for ≥ 6 months and at least two treatments beyond confirmed CR could discontinue therapy. Response was assessed every 12 weeks by central Response Evaluation Criteria in Solid Tumors version 1.1. For this analysis, CR was defined per investigator assessment, immune-related response criteria, and potential predictors of CR were evaluated using univariate and multivariate analyses. Results Of 655 treated patients, 105 (16.0%) achieved CR after median follow-up of 43 months. At data cutoff, 92 patients (87.6%) had CR, with median follow-up of 30 months from first CR. Fourteen (13.3%) patients continued to receive treatment for a median of ≥ 40 months. Pembrolizumab was discontinued by 91 patients (86.7%), including 67 (63.8%) who proceeded to observation without additional anticancer therapy. The 24-month disease-free survival rate from time of CR was 90.9% in all 105 patients with CR and 89.9% in the 67 patients who discontinued pembrolizumab after CR for observation. Tumor size and programmed death-ligand 1 status were among the baseline factors independently associated with CR by univariate analysis. Conclusion Patients with metastatic melanoma can have durable complete remission after discontinuation of pembrolizumab, and the low incidence of relapse after median follow-up of approximately 2 years from discontinuation provides hope for a cure for some patients. The mechanisms underlying durable CR require further investigation.

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

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

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

17 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.

18 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.

19 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.

20 Clinical Trial Dynamics of chemokine, cytokine, and growth factor serum levels in BRAF-mutant melanoma patients during BRAF inhibitor treatment. 2014

Wilmott, James S / Haydu, Lauren E / Menzies, Alexander M / Lum, Trina / Hyman, Jessica / Thompson, John F / Hersey, Peter / Kefford, Richard F / Scolyer, Richard A / Long, Georgina V. ·Melanoma Institute Australia, Sydney, New South Wales 2060, Australia; ·J Immunol · Pubmed #24489105.

ABSTRACT: The purpose of this study is to profile the changes in the serum levels of a range of chemokines, cytokines, and growth and angiogenic factors in MAPK inhibitor-treated metastatic melanoma patients and to correlate these changes with clinical outcome and changes in melanoma tissue biopsies taken from the same patients. Forty-two chemokine, cytokine, angiogenic, and growth factors were measured in the sera of 20 BRAF inhibitor-treated and four combination BRAF and MEK inhibitor-treated metastatic melanoma patients using a multiplex chemokine assay. The changes were correlated with Ki-67 and CD8(+) tumor-infiltrating lymphocytes in the tumor biopsies taken at the same time points, as well as clinical outcome, including response rate, progression-free survival, and overall survival. Serum levels of IFN-γ, CCL4, and TNF-α were significantly increased, whereas CXCL8 significantly decreased from pretreatment (PRE) to early during treatment (EDT) serum samples. The decrease in serum CXCL8 levels from PRE to EDT significantly correlated with decreases in markers of melanoma proliferation (Ki-67) and increases in cytotoxic tumor-infiltrating T cells in corresponding tumor biopsies. In addition, a greater fold reduction in CXCL8 serum levels from PRE to EDT serum samples was associated with decreased overall survival. These results suggest that BRAF inhibition causes decreased CXCL8 secretion from melanoma cells and induce an immune response against the tumor associated with increased IFN-γ, CCL4, and TNF-α. Further studies are needed to determine if CXCL8 is predictive of response and to confirm the functions of these chemokine and cytokine in BRAF-mutant melanoma under BRAF inhibition.

21 Clinical Trial Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. 2013

Hamid, Omid / Robert, Caroline / Daud, Adil / Hodi, F Stephen / Hwu, Wen-Jen / Kefford, Richard / Wolchok, Jedd D / Hersey, Peter / Joseph, Richard W / Weber, Jeffrey S / Dronca, Roxana / Gangadhar, Tara C / Patnaik, Amita / Zarour, Hassane / Joshua, Anthony M / Gergich, Kevin / Elassaiss-Schaap, Jeroen / Algazi, Alain / Mateus, Christine / Boasberg, Peter / Tumeh, Paul C / Chmielowski, Bartosz / Ebbinghaus, Scot W / Li, Xiaoyun Nicole / Kang, S Peter / Ribas, Antoni. ·Angeles Clinic and Research Institute, Los Angeles, CA, USA. ·N Engl J Med · Pubmed #23724846.

ABSTRACT: BACKGROUND: The programmed death 1 (PD-1) receptor is a negative regulator of T-cell effector mechanisms that limits immune responses against cancer. We tested the anti-PD-1 antibody lambrolizumab (previously known as MK-3475) in patients with advanced melanoma. METHODS: We administered lambrolizumab intravenously at a dose of 10 mg per kilogram of body weight every 2 or 3 weeks or 2 mg per kilogram every 3 weeks in patients with advanced melanoma, both those who had received prior treatment with the immune checkpoint inhibitor ipilimumab and those who had not. Tumor responses were assessed every 12 weeks. RESULTS: A total of 135 patients with advanced melanoma were treated. Common adverse events attributed to treatment were fatigue, rash, pruritus, and diarrhea; most of the adverse events were low grade. The confirmed response rate across all dose cohorts, evaluated by central radiologic review according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was 38% (95% confidence interval [CI], 25 to 44), with the highest confirmed response rate observed in the cohort that received 10 mg per kilogram every 2 weeks (52%; 95% CI, 38 to 66). The response rate did not differ significantly between patients who had received prior ipilimumab treatment and those who had not (confirmed response rate, 38% [95% CI, 23 to 55] and 37% [95% CI, 26 to 49], respectively). Responses were durable in the majority of patients (median follow-up, 11 months among patients who had a response); 81% of the patients who had a response (42 of 52) were still receiving treatment at the time of analysis in March 2013. The overall median progression-free survival among the 135 patients was longer than 7 months. CONCLUSIONS: In patients with advanced melanoma, including those who had had disease progression while they had been receiving ipilimumab, treatment with lambrolizumab resulted in a high rate of sustained tumor regression, with mainly grade 1 or 2 toxic effects. (Funded by Merck Sharp and Dohme; ClinicalTrials.gov number, NCT01295827.).

22 Clinical Trial Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. 2013

Trunzer, Kerstin / Pavlick, Anna C / Schuchter, Lynn / Gonzalez, Rene / McArthur, Grant A / Hutson, Thomas E / Moschos, Stergios J / Flaherty, Keith T / Kim, Kevin B / Weber, Jeffrey S / Hersey, Peter / Long, Georgina V / Lawrence, Donald / Ott, Patrick A / Amaravadi, Ravi K / Lewis, Karl D / Puzanov, Igor / Lo, Roger S / Koehler, Astrid / Kockx, Mark / Spleiss, Olivia / Schell-Steven, Annette / Gilbert, Houston N / Cockey, Louise / Bollag, Gideon / Lee, Richard J / Joe, Andrew K / Sosman, Jeffrey A / Ribas, Antoni. ·Vanderbilt-Ingram Cancer Center, 777 Preston Research Building, Nashville, TN 37232-6307, USA. jeff.sosman@vanderbilt.edu ·J Clin Oncol · Pubmed #23569304.

ABSTRACT: PURPOSE To assess pharmacodynamic effects and intrinsic and acquired resistance mechanisms of the BRAF inhibitor vemurafenib in BRAF(V600)-mutant melanoma, leading to an understanding of the mechanism of action of vemurafenib and ultimately to optimization of metastatic melanoma therapy. METHODS In the phase II clinical study NP22657 (BRIM-2), patients received oral doses of vemurafenib (960 mg twice per day). Serial biopsies were collected to study changes in mitogen-activated protein kinase (MAPK) signaling, cell-cycle progression, and factors causing intrinsic or acquired resistance by immunohistochemistry, DNA sequencing, or somatic mutation profiling. Results Vemurafenib inhibited MAPK signaling and cell-cycle progression. An association between the decrease in extracellular signal-related kinase (ERK) phosphorylation and objective response was observed in paired biopsies (n = 22; P = .013). Low expression of phosphatase and tensin homolog showed a modest association with lower response. Baseline mutations in MEK1(P124) coexisting with BRAF(V600) were noted in seven of 92 samples; their presence did not preclude objective tumor responses. Acquired resistance to vemurafenib associated with reactivation of MAPK signaling as observed by elevated ERK1/2 phosphorylation levels in progressive lesions and the appearance of secondary NRAS(Q61) mutations or MEK1(Q56P) or MEK1(E203K) mutations. These two activating MEK1 mutations had not previously been observed in vivo in biopsies of progressive melanoma tumors. CONCLUSION Vemurafenib inhibits tumor proliferation and oncogenic BRAF signaling through the MAPK pathway. Acquired resistance results primarily from MAPK reactivation driven by the appearance of secondary mutations in NRAS and MEK1 in subsets of patients. The data suggest that inhibition downstream of BRAF should help to overcome acquired resistance.

23 Clinical Trial Improved survival with MEK inhibition in BRAF-mutated melanoma. 2012

Flaherty, Keith T / Robert, Caroline / Hersey, Peter / Nathan, Paul / Garbe, Claus / Milhem, Mohammed / Demidov, Lev V / Hassel, Jessica C / Rutkowski, Piotr / Mohr, Peter / Dummer, Reinhard / Trefzer, Uwe / Larkin, James M G / Utikal, Jochen / Dreno, Brigitte / Nyakas, Marta / Middleton, Mark R / Becker, Jürgen C / Casey, Michelle / Sherman, Laurie J / Wu, Frank S / Ouellet, Daniele / Martin, Anne-Marie / Patel, Kiran / Schadendorf, Dirk / Anonymous13130727. ·Massachusetts General Hospital Cancer Center, Boston, USA. kflaherty@partners.org ·N Engl J Med · Pubmed #22663011.

ABSTRACT: BACKGROUND: Activating mutations in serine-threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population. METHODS: In this phase 3 open-label trial, we randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio. Patients received trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive trametinib. Progression-free survival was the primary end point, and overall survival was a secondary end point. RESULTS: Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the trametinib group, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32 to 0.92; P=0.01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group and were managed with dose interruption and dose reduction; asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed. CONCLUSIONS: Trametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline; METRIC ClinicalTrials.gov number, NCT01245062.).

24 Clinical Trial Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. 2012

Sosman, Jeffrey A / Kim, Kevin B / Schuchter, Lynn / Gonzalez, Rene / Pavlick, Anna C / Weber, Jeffrey S / McArthur, Grant A / Hutson, Thomas E / Moschos, Stergios J / Flaherty, Keith T / Hersey, Peter / Kefford, Richard / Lawrence, Donald / Puzanov, Igor / Lewis, Karl D / Amaravadi, Ravi K / Chmielowski, Bartosz / Lawrence, H Jeffrey / Shyr, Yu / Ye, Fei / Li, Jiang / Nolop, Keith B / Lee, Richard J / Joe, Andrew K / Ribas, Antoni. ·Vanderbilt-Ingram Cancer Center, Nashville, TN 37232-6307, USA. jeff.sosman@vanderbilt.edu ·N Engl J Med · Pubmed #22356324.

ABSTRACT: BACKGROUND: Approximately 50% of melanomas harbor activating (V600) mutations in the serine-threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600-mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial. METHODS: We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600-mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point. RESULTS: A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients. CONCLUSIONS: Vemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600-mutant metastatic melanoma. In this study with a long follow-up, the median overall survival was approximately 16 months. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00949702.).

25 Clinical Trial Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. 2012

Kirkwood, John M / Bastholt, Lars / Robert, Caroline / Sosman, Jeff / Larkin, James / Hersey, Peter / Middleton, Mark / Cantarini, Mireille / Zazulina, Victoria / Kemsley, Karin / Dummer, Reinhard. ·Departments of Medicine and Dermatology, University of Pittsburgh, PA 15213, USA. KirkwoodJM@upmc.edu ·Clin Cancer Res · Pubmed #22048237.

ABSTRACT: PURPOSE: To compare the efficacy and tolerability of the mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase (MEK) 1/2 inhibitor selumetinib versus temozolomide in chemotherapy-naive patients with unresectable stage III/IV melanoma. EXPERIMENTAL DESIGN: This phase II, open-label, multicenter, randomized, parallel-group study examined the effect of 100 mg oral selumetinib twice daily in 28-day cycles versus oral temozolomide (200 mg/m(2)/d for 5 days, then 23 days off-treatment). The primary endpoint was progression-free survival. RESULTS: Two hundred patients were randomized. Progression-free survival did not differ significantly between selumetinib and temozolomide (median time to event 78 and 80 days, respectively; hazard ratio, 1.07; 80% confidence interval, 0.86-1.32). Objective response was observed in six (5.8%) patients receiving selumetinib and nine (9.4%) patients in the temozolomide group. Among patients with BRAF mutations, objective responses were similar between selumetinib and temozolomide groups (11.1% and 10.7%, respectively). However, five of the six selumetinib partial responders were BRAF mutated. Frequently reported adverse events with selumetinib were dermatitis acneiform (papular pustular rash; 59.6%), diarrhea (56.6%), nausea (50.5%), and peripheral edema (40.4%), whereas nausea (64.2%), constipation (47.4%), and vomiting (44.2%) were reported with temozolomide. CONCLUSIONS: No significant difference in progression-free survival was observed between patients with unresectable stage III/IV melanoma unselected for BRAF/NRAS mutations, who received therapy with selumetinib or temozolomide. Five of six patients with partial response to selumetinib had BRAF mutant tumors.

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