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      A subanalysis of Japanese patients in a randomized, double-blind, placebo-controlled, phase 3 trial of nivolumab for patients with advanced gastric or gastro-esophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2)

      research-article
      1 , 2 , 3 , 4 , 32 , 5 , 33 , 6 , 7 , 8 , 9 , 10 , 34 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 35 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 1 ,
      Gastric Cancer
      Springer Singapore
      Gastric cancer, Gastro-esophageal junction cancer, Japan, Nivolumab

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          Abstract

          Background

          Nivolumab, an anti-programmed death-1 agent, showed survival benefits in Asian patients, including Japanese, with gastric/gastro-esophageal junction (G/GEJ) cancer. We report the analysis of the Japanese subpopulation from ATTRACTION-2 that evaluated nivolumab versus placebo in unresectable advanced or recurrent G/GEJ cancer after ≥ 2 chemotherapy regimens.

          Methods

          Data from the Japanese subpopulation in the randomized, double-blind, placebo-controlled, phase 3 trial were analyzed (data cutoff, February 25, 2017). Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and objective response rate (ORR).

          Results

          Among the overall study population of 493 patients, 226 (nivolumab 152; placebo 74) were enrolled from 28 sites in Japan. In the Japanese subset, median OS was longer with nivolumab versus placebo (5.4 months, 95% CI 4.6–7.4 versus 3.6 months, 95% CI 2.8–5.0). The risk of death was lower in the nivolumab versus placebo group (hazard ratio 0.58, 95% CI 0.42–0.78; p = 0.0002). Incidences of serious adverse events were 23% (35/152) and 25% (18/72) in the nivolumab and placebo groups, respectively. In the Japanese ITT population, 22% of nivolumab-treated and 28% of placebo-treated patients received prior ramucirumab treatment. Overall, clinical activity of nivolumab was observed regardless of prior ramucirumab use. In the nivolumab group, ORR and PFS were numerically higher in patients with prior ramucirumab use than in those without.

          Conclusions

          In the Japanese subpopulation, patients receiving nivolumab had longer OS, similar to the overall population, with a manageable safety profile. The interaction between nivolumab and ramucirumab will be clarified in ongoing clinical trials.

          Electronic supplementary material

          The online version of this article (10.1007/s10120-018-0899-6) contains supplementary material, which is available to authorized users.

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          Most cited references12

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          Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer.

          We evaluated the efficacy and safety of S-1 plus oxaliplatin (SOX) as an alternative to cisplatin plus S-1 (CS) in first-line chemotherapy for advanced gastric cancer (AGC).
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            Clinical Utility of the Combined Positive Score for Programmed Death Ligand-1 Expression and the Approval of Pembrolizumab for Treatment of Gastric Cancer

            Regulatory approval of pembrolizumab for treatment of gastric and gastroesophageal junction (G/GEJ) adenocarcinoma required a reproducible scoring method for use of programmed death ligand-1 (PD-L1) protein expression as a companion diagnostic to identify likely responders to therapy.
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              The parallel lives of angiogenesis and immunosuppression: cancer and other tales.

              Emerging evidence indicates that angiogenesis and immunosuppression frequently occur simultaneously in response to diverse stimuli. Here, we describe a fundamental biological programme that involves the activation of both angiogenesis and immunosuppressive responses, often through the same cell types or soluble factors. We suggest that the initiation of these responses is part of a physiological and homeostatic tissue repair programme, which can be co-opted in pathological states, notably by tumours. This view can help to devise new cancer therapies and may have implications for aseptic tissue injury, pathogen-mediated tissue destruction, chronic inflammation and even reproduction.
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                Author and article information

                Contributors
                +81-3-3542-2511 , nboku@ncc.go.jp
                Journal
                Gastric Cancer
                Gastric Cancer
                Gastric Cancer
                Springer Singapore (Singapore )
                1436-3291
                1436-3305
                1 December 2018
                1 December 2018
                2019
                : 22
                : 2
                : 344-354
                Affiliations
                [1 ]ISNI 0000 0001 2168 5385, GRID grid.272242.3, Division of Gastrointestinal Medical Oncology, , National Cancer Center Hospital, ; 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045 Japan
                [2 ]ISNI 0000 0004 0373 3971, GRID grid.136593.b, Department of Frontier Science for Cancer and Chemotherapy, , Osaka University Graduate School of Medicine, ; Suita, Japan
                [3 ]ISNI 0000 0001 0722 8444, GRID grid.410800.d, Department of Clinical Oncology, , Aichi Cancer Center Hospital, ; Nagoya, Japan
                [4 ]ISNI 0000 0004 0629 2905, GRID grid.414944.8, Department of Gastrointestinal Surgery, , Kanagawa Cancer Center, ; Yokohama, Japan
                [5 ]ISNI 0000 0004 1936 9967, GRID grid.258622.9, Department of Medical Oncology, , Kindai University, Faculty of Medicine, ; Osaka, Japan
                [6 ]ISNI 0000 0004 1936 9959, GRID grid.26091.3c, Keio Cancer Center, School of Medicine, , Keio University, ; Tokyo, Japan
                [7 ]ISNI 0000 0001 0037 4131, GRID grid.410807.a, Department of Gastroenterology, , Cancer Institute Hospital of the Japanese Foundation for Cancer Research, ; Tokyo, Japan
                [8 ]ISNI 0000 0004 1764 921X, GRID grid.418490.0, Clinical Trial Promotion Department, , Chiba Cancer Center, ; Chiba, Japan
                [9 ]GRID grid.417755.5, Department of Gastroenterological Oncology, , Hyogo Cancer Center, ; Akashi, Japan
                [10 ]ISNI 0000 0000 8855 274X, GRID grid.416695.9, Department of Gastroenterology, , Saitama Cancer Center, ; Saitama, Japan
                [11 ]ISNI 0000 0004 1774 9501, GRID grid.415797.9, Division of Gastrointestinal Oncology, , Shizuoka Cancer Center, ; Shizuoka, Japan
                [12 ]GRID grid.470350.5, Department of Gastrointestinal and Medical Oncology, , National Hospital Organization Kyushu Cancer Center, ; Fukuoka, Japan
                [13 ]ISNI 0000 0004 0403 4283, GRID grid.412398.5, Cancer Chemotherapy Center, , Osaka Medical College Hospital, ; Takatsuki, Japan
                [14 ]ISNI 0000 0004 0378 6088, GRID grid.412167.7, Division of Cancer Chemotherapy, , Hokkaido University Hospital Cancer Center, ; Sapporo, Japan
                [15 ]ISNI 0000 0004 0372 3116, GRID grid.412764.2, Department of Clinical Oncology, , St. Marianna University School of Medicine, ; Kawasaki, Japan
                [16 ]GRID grid.489169.b, Department of Medical Oncology, , Osaka International Cancer Institute, ; Osaka, Japan
                [17 ]ISNI 0000 0004 0370 4927, GRID grid.256342.4, Department of Surgical Oncology, , Gifu University Graduate School of Medicine, ; Gifu, Japan
                [18 ]ISNI 0000 0001 2242 4849, GRID grid.177174.3, Department of Surgery and Science, Graduate School of Medical Sciences, , Kyushu University, ; Fukuoka, Japan
                [19 ]ISNI 0000 0004 0618 8403, GRID grid.415740.3, Department of Gastrointestinal Medical Oncology, , National Hospital Organization Shikoku Cancer Center, ; Matsuyama, Japan
                [20 ]ISNI 0000 0004 0466 8016, GRID grid.410843.a, Department of Medical Oncology, , Kobe City Medical Center General Hospital, ; Kobe, Japan
                [21 ]ISNI 0000 0000 8869 7826, GRID grid.415016.7, Department of Clinical Oncology, , Cancer Center Jichi Medical University Hospital, ; Shimotsuke, Japan
                [22 ]ISNI 0000 0000 8962 7491, GRID grid.416751.0, Department of Medical Oncology, , Saku Central Hospital Advanced Care Center, ; Saku, Japan
                [23 ]ISNI 0000 0004 1764 7652, GRID grid.459767.e, Internal Medicine, , Misawa City Hospital, ; Misawa, Japan
                [24 ]GRID grid.415479.a, Department of Medical Oncology, , Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, ; Tokyo, Japan
                [25 ]ISNI 0000 0000 9206 2938, GRID grid.410786.c, Department of Gastroenterology, , Kitasato University School of Medicine, ; Sagamihara, Japan
                [26 ]Medical Oncology, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan
                [27 ]ISNI 0000 0004 1763 9927, GRID grid.415804.c, Medical Oncology, , Shizuoka General Hospital, ; Shizuoka, Japan
                [28 ]ISNI 0000 0004 0615 9100, GRID grid.412002.5, Gastroenterological Surgery, , Kanazawa University Hospital, ; Kanazawa, Japan
                [29 ]ISNI 0000000406229172, GRID grid.59784.37, National Institute of Cancer Research, , National Health Research Institutes, ; Tainan, Taiwan, Republic of China
                [30 ]ISNI 0000 0004 0532 3255, GRID grid.64523.36, Department of Internal Medicine, National Cheng Kung University Hospital, , National Cheng Kung University, ; Tainan, Taiwan, Republic of China
                [31 ]ISNI 0000 0004 0533 4667, GRID grid.267370.7, Department of Oncology, Asan Medical Center, , University of Ulsan College of Medicine, ; Seoul, South Korea
                [32 ]ISNI 0000 0001 2168 5385, GRID grid.272242.3, Present Address: Department of Gastric Surgery, , National Cancer Center Hospital, ; Tokyo, Japan
                [33 ]ISNI 0000 0004 1936 9967, GRID grid.258622.9, Present Address: Department of Medical Oncology, , Kindai University Nara Hospital, ; Ikoma, Japan
                [34 ]ISNI 0000 0001 0037 4131, GRID grid.410807.a, Present Address: Department of Gastroenterology, , Cancer Institute Hospital of the Japanese Foundation for Cancer Research, ; Tokyo, Japan
                [35 ]ISNI 0000 0000 8662 309X, GRID grid.258331.e, Present Address: Department of Medical Oncology, , Kagawa University, ; Takamatsu, Japan
                Article
                899
                10.1007/s10120-018-0899-6
                6394726
                30506519
                9b4a3cc3-810d-43b0-b85f-89c54f844a99
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 22 August 2018
                : 12 November 2018
                Categories
                Original Article
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                © The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2019

                Oncology & Radiotherapy
                gastric cancer,gastro-esophageal junction cancer,japan,nivolumab
                Oncology & Radiotherapy
                gastric cancer, gastro-esophageal junction cancer, japan, nivolumab

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