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      Pneumonitis and pneumonitis-related death in cancer patients treated with programmed cell death-1 inhibitors: a systematic review and meta-analysis

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          Abstract

          Purpose

          We conducted a meta-analysis of published clinical trials to determine the relationship between the risks of pneumonitis and pneumonitis-related death and programmed cell death-1 (PD-1) inhibitor treatment in patients with cancer.

          Materials and methods

          We examined clinical trials from the Medline and Google Scholar databases. Data from original studies and review articles were also cross-referenced and evaluated. Randomized Phase II and Phase III trials of pembrolizumab and nivolumab treatment in patients with cancer were eligible for the analysis. Information about the participants, all-grade and high-grade pneumonitis, and pneumonitis-related death was extracted from each study and analyzed.

          Results

          After the exclusion of ineligible studies, 12 clinical trials were included in the analysis. The odds ratio (OR) for all-grade pneumonitis after PD-1 inhibitor treatment was 4.59 (95% confidence interval [CI]: 2.51–8.37; P<0.00001), and the OR for high-grade pneumonitis after PD-1 inhibitor treatment was 3.83 (95% CI: 1.54–9.48; P=0.004). The OR for pneumonitis-related death after PD-1 inhibitor treatment was 2.47 (95% CI: 0.41–14.81; P=0.32). Moreover, the OR for all-grade pneumonitis after nivolumab/ipilimumab combination therapy versus nivolumab monotherapy was 3.54 (95% CI: 1.52–8.23; P=0.003), and that for high-grade pneumonitis after nivolumab/ipilimumab combination therapy versus nivolumab monotherapy was 2.35 (95% CI: 0.45–12.13; P=0.31). Treated cancer appeared to have no effect on the risk of pneumonitis.

          Conclusion

          Our data showed that PD-1 inhibitors were associated with increased risks of all-grade and high-grade pneumonitis compared with chemotherapy or placebo controls in patients with cancer. However, we noted no significant difference between patients treated with a PD-1 inhibitor and patients treated with control regimens with respect to the risk of pneumonitis-related death.

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          Most cited references 10

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          Cancer immunotherapy: moving beyond current vaccines.

          Great progress has been made in the field of tumor immunology in the past decade, but optimism about the clinical application of currently available cancer vaccine approaches is based more on surrogate endpoints than on clinical tumor regression. In our cancer vaccine trials of 440 patients, the objective response rate was low (2.6%), and comparable to the results obtained by others. We consider here results in cancer vaccine trials and highlight alternate strategies that mediate cancer regression in preclinical and clinical models.
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            Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial.

            Endogenous or iatrogenic antitumour immune responses can improve the course of follicular lymphoma, but might be diminished by immune checkpoints in the tumour microenvironment. These checkpoints might include effects of programmed cell death 1 (PD1), a co-inhibitory receptor that impairs T-cell function and is highly expressed on intratumoral T cells. We did this phase 2 trial to investigate the activity of pidilizumab, a humanised anti-PD1 monoclonal antibody, with rituximab in patients with relapsed follicular lymphoma. We did this open-label, non-randomised trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Adult (≥18 years) patients with rituximab-sensitive follicular lymphoma relapsing after one to four previous therapies were eligible. Pidilizumab was administered at 3 mg/kg intravenously every 4 weeks for four infusions, plus eight optional infusions every 4 weeks for patients with stable disease or better. Starting 17 days after the first infusion of pidilizumab, rituximab was given at 375 mg/m(2) intravenously weekly for 4 weeks. The primary endpoint was the proportion of patients who achieved an objective response (complete response plus partial response according to Revised Response Criteria for Malignant Lymphoma). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00904722. We enrolled 32 patients between Jan 13, 2010, and Jan 20, 2012. Median follow-up was 15.4 months (IQR 10.1-21.0). The combination of pidilizumab and rituximab was well tolerated, with no autoimmune or treatment-related adverse events of grade 3 or 4. The most common adverse events of grade 1 were anaemia (14 patients) and fatigue (13 patients), and the most common adverse event of grade 2 was respiratory infection (five patients). Of the 29 patients evaluable for activity, 19 (66%) achieved an objective response: complete responses were noted in 15 (52%) patients and partial responses in four (14%). The combination of pidilizumab plus rituximab is well tolerated and active in patients with relapsed follicular lymphoma. Our results suggest that immune checkpoint blockade is worthy of further study in follicular lymphoma. National Institutes of Health, Leukemia and Lymphoma Society, Cure Tech, and University of Texas MD Anderson Cancer Center. Copyright © 2014 Elsevier Ltd. All rights reserved.
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              Incidence of Programmed Cell Death 1 Inhibitor-Related Pneumonitis in Patients With Advanced Cancer: A Systematic Review and Meta-analysis.

              Programmed cell death 1 (PD-1) inhibitor-related pneumonitis is a rare but clinically serious and potentially life-threatening adverse event. Little is known about its incidence across different tumor types and treatment regimens.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2017
                25 September 2017
                : 13
                : 1259-1271
                Affiliations
                [1 ]First Department of Medical Oncology
                [2 ]Department of Graduate Administration, Chinese PLA General Hospital, Beijing
                [3 ]Health Bureau of the 75709 Army, Central Theater of the Chinese PLA, Wuhan, China
                Author notes
                Correspondence: Yi Hu, First Department of Medical Oncology, Chinese PLA General Hospital, 28 Fuxing Road, Haidian, Beijing 100853, China, Tel +86 139 1103 1186, Fax +86 10 6693 9272, Email huyi0401@ 123456aliyun.com
                [*]

                These authors contributed equally to this work

                Article
                tcrm-13-1259
                10.2147/TCRM.S143939
                5626381
                © 2017 Cui et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Medicine

                immune mediated pneumonitis, nivolumab, pd-1 inhibitors, pembrolizumab

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