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• W604097480 abstract "Melanoma accounts for less than 5% of all skin cancers diagnosed in the United States each year, but is the leading cause of skin cancer mortality, with 76,100 new cases diagnosed and 9710 deaths in 2014. Five-year survival for patients with early-stage disease (stage I/II) is 97%, but the prognosis for patients with stage IV melanoma is poor, with 1-year survival rates ranging from 62% to 33%, depending on the location of metastases. While 5 new agents have received FDA approval for the treatment of melanoma since 2011 (ipilimumab, peginterferon alfa-2b, and vemurafenib in 2011; dabrafenib and trametinib in 2013; and the combination of these 2 agents in 2014), treatment of patients with metastatic or relapsed melanoma has remained challenging. Patients without a driver mutation in the MAPK pathway (BRAF in general) are usually first treated with interleukin-2 (IL-2) or ipilimumab, whereas patients with driver mutations (BRAF, C-KIT) are considered for targeted therapies, depending on the extent of their disease and their performance status (PS). Generally, patients with good PS are initially treated with immunotherapy, as they tend to have a better prognosis and relatively slower progression of disease. Tumor-mediated immune suppression and immune evasion is understood as one of the major obstacles to the clinical efficacy of immune-targeted therapies for cancer. Programmed death receptor 1 (PD-1) and its ligands, PD-L1 and PD-L2, are thought to be significant mediators of immunosuppression and the dysfunction of effector lymphocytes within the tumor microenvironment. PD-1 is expressed on activated T cells, and on binding to PD-L1/PD-L2 (expressed by tumor-infiltrating lymphocytes [TILs]/tumor cells and antigen-presenting cells/tumor cells, respectively), downregulates T-cell receptor (TCR) signaling. This induces T-cell anergy and apoptosis, and subsequently, immune suppression. PD-L1 expression is upregulated in multiple cancers, and levels of PD-L1 expression have been shown to predict higher tumor grade and poor prognosis in multiple different malignancies, likely because the PD-1/PD-L1 interaction suppresses TILs. Indeed, some studies have suggested that PD-L1 expression by cancer cells provides them with an “immune shield” and protects them from effector T-cell cytotoxicity. Pembrolizumab (Keytruda; MK-3475, also previously known as lambrolizumab) is a highly selective IgG4 kappa isotype monoclonal antibody against PD-1. The antibody’s highly selective binding to PD-1 blocks the PD-1, PD-L1/PD-L2 axis, thus overcoming this major immune checkpoint inhibitor. On September 4, 2014, pembrolizumab received FDA approval for the treatment of unresectable or metastatic melanoma in patients with disease progression following ipilimumab treatment, and, if BRAF mutation-positive, following treatment with a BRAF inhibitor. Two trials contributed to this drug’s positive regulatory review and approval for therapy of metastatic melanoma. In the KEYNOTE-001 trial, a phase 1 study, 135 patients with advanced melanoma were treated with pembrolizumab at a dosage of 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks. Notably, all patients had measurable metastatic or locally advanced unresectable melanoma. Major exclusion criteria included melanoma of ocular origin, prior treatment with PD-1/PD-L1 blocking agents, current immunosuppressive therapy, infection, or autoimmune disease. A total of 69% of patients in the study population had progressed following treatment with ipilimumab, other immunotherapy, BRAF inhibitor, or chemotherapy, and 31% had not received prior systemic therapy. Using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, the response rate observed across all dosing cohorts was 38% (95% confidence interval [CI], 2544). Importantly, this rate did not differ in patients who had been treated with ipilimumab (38%; 95% CI, 23-55) compared with those who had not (37%; 95% CI, 26-49). The highest response rate (52%) was noted in patients who had been treated with 10 mg/kg every 2 weeks (95% CI, 38-66). Overall, median progression-free survival (PFS) was >7 months, with 81% of paAbstract" @default.
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• W604097480 title "Pembrolizumab: Pharmacology and Therapeutics Review" @default.
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