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      Correlation between immune-related adverse events and prognosis in patients with various cancers treated with anti PD-1 antibody

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          Abstract

          Background

          Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) are used for the treatment of various cancer types. However, immune-related adverse events (irAEs) occur in patients treated with ICIs. Several small-scale studies have reported the onset of irAEs and therapeutic effects of ICIs. Here we report a large-scale retrospective study covering a wide range of cancers. We evaluated irAEs and the therapeutic effects of ICIs and determined whether irAEs could be predicted.

          Methods

          This study included patients treated with the anti-PD-1 antibodies nivolumab or pembrolizumab at Fujita Health University Hospital between December 2015 and March 2019. We retrospectively reviewed the electronic medical records for age, cancer type, pre-treatment blood test data, presence or absence of irAE onset, type and severity of irAEs, outcome of irAE treatment, response rate, progression-free survival and overall survival.

          Results

          Two hundred-eighty patients received ICIs. The overall incidence of irAEs was 41.1% (115 patients), and the incidence of severe irAEs of grade 3 and higher was 2.8% (eight patients). The most common irAEs were skin disorders, thyroid disorders and interstitial pneumonitis. Patients with irAEs were significantly older than those without irAEs (69.7 versus 66.0 years, P = 0.02). The objective response rate (ORR) in patients with irAEs was 30.4%, which was significantly higher than in patients without irAEs (12.7%; P < 0.01). Both the median overall and progression-free survival were significantly longer in patients with irAEs ( P < 0.01, p < 0.01). Based on the blood test data obtained before ICI therapy, hypothyroidism, thyroid-stimulating hormone levels and thyroglobulin antibody levels were associated with the onset of irAEs. In many patients with irAEs of Common Terminology Criteria for Adverse Events Grade 3 or higher, re-administration of ICIs was difficult, and their outcomes were poor. In contrast, many patients with irAEs of a lower grade were able to resume ICI therapy.

          Conclusion

          Although the onset of irAEs was difficult to be predicted based on pre-treatment tests. It appeared that the continuation of ICI therapy, along with early detection and adequate control of irAEs, might contribute to the improved prognosis of patients.

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          Most cited references 10

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          Profiling Preexisting Antibodies in Patients Treated With Anti–PD-1 Therapy for Advanced Non–Small Cell Lung Cancer

          Administration of anti-programmed cell death protein 1 (anti-PD-1) is now standard therapy in advanced non-small cell lung cancer (NSCLC). However, immune checkpoint inhibitors, including anti-PD-1, have not been assessed in patients with subclinical disease with advanced NSCLC, and no useful clinical biomarkers have been associated with immune-related adverse events (irAEs) among these patients treated with anti-PD-1.
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            Biomarkers for Immune Checkpoint Inhibitor-Mediated Tumor Response and Adverse Events

            In the last decade, inhibitors targeting immune checkpoint molecules such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death-ligand 1 (PD-L1) brought about a major paradigm shift in cancer treatment. These immune checkpoint inhibitors (ICIs) improved the overall survival of a variety of cancer such as malignant melanoma and non-small lung cancer. In addition, numerous clinical trials for additional indication of ICIs including adjuvant and neo-adjuvant therapies are also currently ongoing. Therefore, more and more patients will receive ICIs in the future. However, despite the improved outcome of the cancer treatment by ICIs, the efficacy remains still limited and tumor regression have not been obtained in many cancer patients. In addition, treatment with ICIs is also associated with substantial toxicities, described as immune-related adverse events (irAEs). Therefore, biomarkers to predict tumor response and occurrence of irAEs by the treatment with ICIs are required to avoid overtreatment of ICIs and minimize irAEs development. Whereas, numerous factors have been reported as potential biomarkers for tumor response to ICIs, factors for predicting irAE have been less reported. In this review, we show recent advances in the understanding of biomarkers for tumor response and occurrence of irAEs in cancer patients treated with ICIs.
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              Association Between Immune-Related Adverse Events and Clinical Efficacy in Patients with Melanoma Treated With Nivolumab: A Multicenter Retrospective Study

              Nivolumab, an anti-programmed death 1 antibody, produces antitumor effects by activating host immunity, which also causes immune-related adverse events (irAEs). The aim of this study was to analyze the association between antitumor effect and irAEs induced by nivolumab in patients with melanoma.
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                Author and article information

                Contributors
                mats1025@fujita-hu.ac.jp
                t-hayashi@kinjo-u.ac.jp
                y1571088@kinjo-u.ac.jp
                jeanluc@fujita-hu.ac.jp
                rshiroki@fujita-hu.ac.jp
                nohmiya@fujita-hu.ac.jp
                ksugiura@fujita-hu.ac.jp
                kekawada@fujita-hu.ac.jp
                sawaki@fujita-hu.ac.jp
                kmaeda@fujita-hu.ac.jp
                jobnet.ando57@gmail.com
                iuyama@mac.com
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                14 July 2020
                14 July 2020
                2020
                : 20
                Affiliations
                [1 ]GRID grid.256115.4, ISNI 0000 0004 1761 798X, Department of Surgery Fujita Health University, ; Dengakugakubo 1-98, Kutsukake-cho, Toyoake City, Aichi Japan
                [2 ]GRID grid.411042.2, ISNI 0000 0004 0371 5415, College of Pharmacy, , Kinjo Gakuin University, ; 2-1723 Oomori Moriyama, Nagoya City, Aichi 463-8521 Japan
                [3 ]GRID grid.256115.4, ISNI 0000 0004 1761 798X, Department of Respiratory Medicine Fujita Health University, ; Dengakugakubo 1-98, Kutsukake-cho, Toyoake City, Aichi Japan
                [4 ]GRID grid.256115.4, ISNI 0000 0004 1761 798X, Department of Urology Fujita Health University, ; Dengakugakubo 1-98, Kutsukake-cho, Toyoake City, Aichi Japan
                [5 ]GRID grid.256115.4, ISNI 0000 0004 1761 798X, Department of Gastroenterology Fujita Health University, ; Dengakugakubo 1-98, Kutsukake-cho, Toyoake City, Aichi Japan
                [6 ]GRID grid.256115.4, ISNI 0000 0004 1761 798X, Department of Dermatology Fujita Health University, ; Dengakugakubo 1-98, Kutsukake-cho, Toyoake City, Aichi Japan
                [7 ]GRID grid.256115.4, ISNI 0000 0004 1761 798X, Department of Clinical Oncology Fujita Health University, ; Dengakugakubo 1-98, Kutsukake-cho, Toyoake City, Aichi Japan
                [8 ]GRID grid.256115.4, ISNI 0000 0004 1761 798X, Fujita Health University International Medical Center, ; Dengakugakubo 1-98, Kutsukake-cho, Toyoake City, Aichi Japan
                [9 ]GRID grid.256115.4, ISNI 0000 0004 1761 798X, Department of Pharmacy Fujita Health University, ; Dengakugakubo 1-98, Kutsukake-cho, Toyoake City, Aichi Japan
                Article
                7142
                10.1186/s12885-020-07142-3
                7362440
                32664888
                © The Author(s) 2020

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