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Keitaro Shimozaki,1 Yasutaka Sukawa,1 Noriko Beppu,2 Isao Kurihara,3 Shigeaki Suzuki,4 Ryuichi Mizuno,5 Takeru Funakoshi,6 Shinnosuke Ikemura,7,8 Kai Tsugaru,1 Kazuhiro Togasaki,1 Kenta Kawasaki,1 Kenro Hirata,1 Hideyuki Hayashi,8 Yasuo Hamamoto,8 Hiromasa Takaishi,8 Takanori Kanai1 1Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; 2Department of Pharmacy, Keio University Hospital, Tokyo, Japan; 3Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; 4Department of Neurology, Keio University School of Medicine, Tokyo, Japan; 5Department of Urology, Keio University School of Medicine, Tokyo, Japan; 6Department of Dermatology, Keio University School of Medicine, Tokyo, Japan; 7Division of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; 8Keio Cancer Center, Keio University School of Medicine, Tokyo, JapanCorrespondence: Yasutaka Sukawa Tel +81-3-3353-1211Fax +81-3-5363-6247Email sukawa@keio.jpPurpose: Immune checkpoint inhibitors (ICIs) have been approved for various types of cancer; however, they cause a broad spectrum of immune-related adverse events (irAEs). The association between the development of irAEs and the clinical benefit remains uncertain. We aimed to evaluate the association of irAEs and the treatment efficacy in real-world practice.Patients and Methods: We conducted a retrospective study on patients with recurrent or metastatic non-small-cell lung cancer, malignant melanoma, renal cell carcinoma, or gastric cancer who received anti-PD-1/PD-L1 antibodies (nivolumab, pembrolizumab, or atezolizumab) at the Keio University Hospital between September 2014 and January 2019. We recorded treatment-related AEs from medical records and graded them using the Common Terminology Criteria for Adverse Events version 4. We performed an overall survival (OS) analysis using a Cox proportional hazards model and the shared frailty model.Results: Of 212 patients eligible for this study, 108 experienced irAEs and 42 developed multiple irAEs. The median OS was significantly longer in the irAEs than in the no-irAE group (28.1 months vs 12.7 months; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.33– 0.73; P = 0.0004). Moreover, the OS of patients with multiple irAEs was significantly longer than that of patients with a single irAE (42.3 months vs 18.8 months; HR, 0.473; 95% CI, 0.346– 0.647; P < 0.0001).Conclusion: Our single-center retrospective study revealed a significant tendency associating the development of multiple irAEs with favorable prognoses.Keywords: immune checkpoint inhibitors, programmed cell death 1, prognosis

Kazuhiro Togasaki, Yasutaka Sukawa, Takanori Kanai, Hiromasa Takaishi Department of Internal Medicine, Division of Gastroenterology and Hepatology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan Abstract: Standard treatment options for patients with advanced gastric cancer (GC) offer limited efficacy and are associated with some toxicity, which necessitates the development of more effective therapies for improving the treatment outcomes for this disease. Immunotherapy involving immune checkpoint inhibitors (ICIs) which inhibit the programmed death 1 (PD-1)/programmed death ligand 1 interaction has emerged as a new treatment option. Nivolumab, a human IgG4 monoclonal antibody inhibitor of PD-1, has demonstrated promising clinical activity and induced durable responses in patients with advanced GC. Nivolumab has recently been approved for treating patients with pretreated advanced GC in Japan. In the present review, we summarized current evidence of the clinical efficacy of ICIs in a variety of solid tumors and reported our experience in patients with GC who were treated with nivolumab and the interesting features that were observed in these cases. Certain ICI-specific clinical features such as pseudo- and hyper-progression of tumor and hyper-response to subsequent chemotherapy have been reported in several cancer types. Lastly, we discussed the present scenario regarding research on biomarkers for assessing the clinical benefits of ICI therapies. Keywords: nivolumab, pembrolizumab, avelumab, pseudoprogression, hyperprogression, hypersensitivity, microbiome