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      Spotlight on pembrolizumab in the treatment of advanced melanoma

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          Abstract

          Metastatic melanoma is an aggressive cancer with a poor prognosis. Many approved therapies often do not achieve durable responses in patients. This underscores the need for novel therapeutic strategies. Recruiting a robust immune response is an important antineoplastic treatment strategy. Immune checkpoints offer a molecular target for modulating the immune response and a promising therapeutic target in metastatic melanoma. Here we discuss the recent approval of pembrolizumab by the US Food and Drug Administration for the treatment of metastatic melanoma and its impact on future management of the disease.

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          Most cited references 12

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          Treatment of metastatic melanoma: an overview.

          The 10-year survival rate for patients with metastatic melanoma is less than 10%. Although surgery and radiation therapy have a role in the treatment of metastatic disease, systemic therapy is the mainstay of treatment for most patients. Single-agent chemotherapy is well tolerated but is associated with response rates of only 5% to 20%. Combination chemotherapy and biochemotherapy may improve objective response rates but do not extend survival and are associated with greater toxicity. Immunotherapeutic approaches such as high-dose interleukin-2 are associated with durable responses in a small percentage of patients. In this article, we review the treatments for metastatic melanoma including promising investigational approaches.
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            The evolution of checkpoint blockade as a cancer therapy: what's here, what's next?

             D Shin,  Antoni Ribas (2015)
            Unleashing the immune system to fight cancer has become one of the main treatment modalities since the anti-CTLA-4 antibody, ipilimumab was approved for patients with advanced melanoma in 2011. Pembrolizumab and nivolumab, two anti-PD-1 antibodies recently approved for the treatment of patients with metastatic melanoma, are being actively investigated for the treatment of multiple caners including lung, breast, bladder and renal cancers along with other anti-PD-1/L1 antibodies. Early results of combining of anti-CTLA-4 antibody and anti-PD-1 antibody treatment for advanced melanoma patients are showing impressive response rates with manageable toxicity profiles. There are several other checkpoint molecules that are likely potential inhibitory targets. The outcome of blocking some of these negative immune regulators, such as LAG-3 or TIM-3, is being pursued in the clinic or about to enter clinical development. Blockade of these molecules is demonstrating promising preclinical activity alone or when combined with anti-PD-1/L1. Future studies will define bio-markers of these therapies and how to target them alone or in combination with other immunotherapies, chemotherapy, radiotherapy and small molecule inhibitors. Copyright © 2015. Published by Elsevier Ltd.
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              At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy.

              It is increasingly appreciated that cancers are recognized by the immune system, and under some circumstances, the immune system may control or even eliminate tumors. The modulation of signaling via coinhibitory or costimulatory receptors expressed on T cells has proven to be a potent way to amplify antitumor immune responses. This approach has been exploited successfully for the generation of a new class of anticancer therapies, "checkpoint-blocking" antibodies, exemplified by the recently FDA-approved agent, ipilimumab, an antibody that blocks the coinhibitory receptor CTLA-4. Capitalizing on the success of ipilimumab, agents that target a second coinhibitory receptor, PD-1, or its ligand, PD-L1, are in clinical development. Lessons learned from treating patients with CTLA-4 and PD-1 pathway-blocking antibodies will be reviewed, with a focus on concepts likely to inform the clinical development and application of agents in earlier stages of development. See related review At the bench: Preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                04 June 2015
                : 9
                : 2883-2886
                Affiliations
                [1 ]Department of Medicine, Division of Dermatology, Postgraduate Medical Education, University of Toronto, Toronto, ON, Canada
                [2 ]Department of Medicine, Division of Dermatology, St Michael’s Hospital, University of Toronto, Toronto, ON, Canada
                Author notes
                Correspondence: Thanashan Rajakulendran, Division of Dermatology, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Suite M1-700, Toronto, Ontario, M4N 3M5, Canada, Email t.rajakulendran@ 123456mail.utoronto.ca
                David N Adam, Department of Medicine, Division of Dermatology, St Michael’s Hospital, 30 Bond Street, Fourth Floor Cardinal Carter North, Toronto, ON M5B 1W8, Canada, Email david.adam@ 123456utoronto.ca
                Article
                dddt-9-2883
                10.2147/DDDT.S78036
                4461129
                © 2015 Rajakulendran and Adam. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Review

                Pharmacology & Pharmaceutical medicine

                pd-l1, pd-1, immune checkpoint, melanoma, pembrolizumab

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