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      Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials : A Systematic Review and Meta-analysis

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          Abstract

          Programmed cell death (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have been increasingly used in cancer therapy. Understanding the treatment-related adverse events of these drugs is critical for clinical practice.

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          Most cited references 34

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          Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial.

          Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy.
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            Is Open Access

            Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort

            Purpose Treatment with pembrolizumab, an anti–programmed death-1 antibody, at 10 mg/kg administered once every 2 weeks, displayed durable antitumor activity in programmed death-ligand 1 (PD-L1) –positive recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 trial. Results from the expansion cohort, in which patients with HNSCC, irrespective of biomarker status, received a fixed dose of pembrolizumab at a less frequent dosing schedule, are reported. Patients and Methods Patients with R/M HNSCC, irrespective of PD-L1 or human papillomavirus status, received pembrolizumab 200 mg intravenously once every 3 weeks. Imaging was performed every 8 weeks. Primary end points were overall response rate (ORR) per central imaging vendor (Response Evaluation Criteria in Solid Tumors v1.1) and safety. Secondary end points included progression-free survival, overall survival, and association of response and PD-L1 expression. Patients who received one or more doses of pembrolizumab were included in analyses. Results Of 132 patients enrolled, median age was 60 years (range, 25 to 84 years), 83% were male, and 57% received two or more lines of therapy for R/M disease. ORR was 18% (95% CI, 12 to 26) by central imaging vendor and 20% (95% CI, 13 to 28) by investigator review. Median duration of response was not reached (range, ≥ 2 to ≥ 11 months). Six-month progression-free survival and overall survival rates were 23% and 59%, respectively. By using tumor and immune cells, a statistically significant increase in ORR was observed for PD-L1–positive versus –negative patients (22% v 4%; P = .021). Treatment-related adverse events of any grade and grade ≥ 3 events occurred in 62% and 9% of patients, respectively. Conclusion Fixed-dose pembrolizumab 200 mg administered once every 3 weeks was well tolerated and yielded a clinically meaningful ORR with evidence of durable responses, which supports further development of this regimen in patients with advanced HNSCC.
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              Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure.

              Classical Hodgkin lymphoma (HL) frequently exhibits genetic alterations leading to overexpression of the programmed death-1 (PD-1) ligands, suggesting a possible vulnerability to PD-1 blockade. The phase Ib study KEYNOTE-013 (NCT01953692) tested the safety and efficacy of the anti-PD-1 antibody pembrolizumab in patients with hematologic malignancies. Based on its genetics, HL was included as an independent cohort.
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                Author and article information

                Journal
                JAMA Oncology
                JAMA Oncol
                American Medical Association (AMA)
                2374-2437
                April 25 2019
                Affiliations
                [1 ]Division of Hematology, Mayo Clinic, Rochester, Minnesota
                [2 ]Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota
                [3 ]Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston
                [4 ]Department of Public Health Sciences, Pennsylvania State College of Medicine, Hershey
                [5 ]Medical School of Nanjing University, Nanjing, China
                [6 ]The Comprehensive Cancer Centre of Drum Tower Hospital, Clinical Cancer Institute of Nanjing University, Nanjing, China
                [7 ]Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston
                [8 ]Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
                [9 ]West Cancer Center, The University of Tennessee, Memphis
                [10 ]Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston
                Article
                10.1001/jamaoncol.2019.0393
                6487913
                31021376
                © 2019

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