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http://dx.doi.org/10.5230/jgc.2018.18.e3

Novel Systemic Therapies for Advanced Gastric Cancer  

Kim, Hong Jun (Division of Oncology/Hematology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine)
Oh, Sang Cheul (Division of Oncology/Hematology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine)
Publication Information
Journal of Gastric Cancer / v.18, no.1, 2018 , pp. 1-19 More about this Journal
Abstract
Gastric cancer (GC) is the second leading cause of cancer mortality and the fourth most commonly diagnosed malignant diseases. While continued efforts have been focused on GC treatment, the introduction of trastuzumab marked the beginning of a new era of target-specific treatments. Considering the diversity of mutations in GC, satisfactory results obtained from various target-specific therapies were expected, yet most of them were unsuccessful in controlled clinical trials. There are several possible reasons underlying the failures, including the absence of patient selection depending on validated predictive biomarkers, the inappropriate combination of drugs, and tumor heterogeneity. In contrast to targeted agents, immuno-oncologic agents are designed to regulate and boost immunity, are not target-specific, and may overcome tumor heterogeneity. With the successful establishment of predictive biomarkers, including Epstein-Barr virus pattern, microsatellite instability status, and programmed death-ligand 1 (PD-L1) expression, as well as ideal combination regimens, a new frontier in the immuno-oncology of GC treatment is on the horizon. Since the field of immuno-oncology has witnessed innovative, practice-changing successes in other cancer types, several trials on GC are ongoing. Among immuno-oncologic therapies, immune checkpoint inhibitors are the mainstay of clinical trials performed on GC. In this article, we review target-specific agents currently used in clinics or are undergoing clinical trials, and highlight the future clinical application of immuno-oncologic agents in inoperable GC.
Keywords
Stomach neoplasms; Immunotherapy; Therapeutics;
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1 Derks S, Liao X, Xu X, Camargo MC, Chiaravalli AM, Solcia E, et al. PD-L1 expression in Epstein-Barr virus-infected gastric cancers. J Clin Oncol 2016;34 suppl:abstr 4052.
2 Kang BW, Seo AN, Yoon S, Bae HI, Jeon SW, Kwon OK, et al. Prognostic value of tumor-infiltrating lymphocytes in Epstein-Barr virus-associated gastric cancer. Ann Oncol 2016;27:494-501.   DOI
3 Forman D, Burley V. Gastric cancer: global pattern of the disease and an overview of environmental risk factors. Best Pract Res Clin Gastroenterol 2006;20:633-649.   DOI
4 Niwa T, Tsukamoto T, Toyoda T, Mori A, Tanaka H, Maekita T, et al. Inflammatory processes triggered by Helicobacter pylori infection cause aberrant DNA methylation in gastric epithelial cells. Cancer Res 2010;70:1430-1440.   DOI
5 Anderson KM, Czinn SJ, Redline RW, Blanchard TG. Induction of CTLA-4-mediated anergy contributes to persistent colonization in the murine model of gastric Helicobacter pylori infection. J Immunol 2006;176:5306-5313.   DOI
6 Stromberg E, Lundgren A, Edebo A, Lundin S, Svennerholm AM, Lindholm C. Increased frequency of activated T-cells in the Helicobacter pylori-infected antrum and duodenum. FEMS Immunol Med Microbiol 2003;36:159-168.   DOI
7 Das S, Suarez G, Beswick EJ, Sierra JC, Graham DY, Reyes VE. Expression of B7-H1 on gastric epithelial cells: its potential role in regulating T cells during Helicobacter pylori infection. J Immunol 2006;176:3000-3009.   DOI
8 Okazaki T, Chikuma S, Iwai Y, Fagarasan S, Honjo T. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol 2013;14:1212-1218.   DOI
9 Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A 2010;107:4275-4280.   DOI
10 Selby M, Engelhardt J, Lu LS, Quigley M, Wang C, Chen B, et al. Antitumor activity of concurrent blockade of immune checkpoint molecules CTLA-4 and PD-1 in preclinical models. J Clin Oncol 2013;31 suppl:abstr 3061.
11 Das R, Verma R, Sznol M, Boddupalli CS, Gettinger SN, Kluger H, et al. Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo. J Immunol 2015;194:950-959.   DOI
12 Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369:122-133.   DOI
13 Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015;372:2006-2017.   DOI
14 Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. Updated results from a phase III trial of nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naive patients (pts) with advanced melanoma (MEL)(CheckMate 067). J Clin Oncol 2016;34 suppl:abstr 9505.
15 Atkins MB, Gupta S, Choueiri TK, McDermott DF, Puzanov I, Tarazi J, et al. Phase Ib dose-finding study of axitinib plus pembrolizumab in treatment-naive patients with advanced renal cell carcinoma. J Immunother Cancer 2015;3:P353.
16 Bendell JC, Kim TW, Goh BC, Wallin J, Oh DY, Han SW, et al. Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). J Clin Oncol 2016;34 suppl:abstr 3502.
17 Kim KC, Koh YW, Chang HM, Kim TH, Yook JH, Kim BS, et al. Evaluation of HER2 protein expression in gastric carcinomas: comparative analysis of 1414 cases of whole-tissue sections and 595 cases of tissue microarrays. Ann Surg Oncol 2011;18:2833-2840.   DOI
18 Lee J, Ou SH. Towards the goal of personalized medicine in gastric cancer-time to move beyond HER2 inhibition. Part I: targeting receptor tyrosine kinase gene amplification. Discov Med 2013;15:333-341.
19 Lee J, Ou SH. Towards the goal of personalized medicine in gastric cancer-time to move beyond HER2 inhibition. Part II: targeting gene mutations and gene amplifications and the angiogenesis pathway. Discov Med 2013;16:7-14.
20 Catenacci DV, Ang A, Liao WL, Shen J, O'Day E, Loberg RD, et al. MET tyrosine kinase receptor expression and amplification as prognostic biomarkers of survival in gastroesophageal adenocarcinoma. Cancer 2017;123:1061-1070.   DOI
21 Mittendorf EA, Wu Y, Scaltriti M, Meric-Bernstam F, Hunt KK, Dawood S, et al. Loss of HER2 amplification following trastuzumab-based neoadjuvant systemic therapy and survival outcomes. Clin Cancer Res 2009;15:7381-7388.   DOI
22 Stahl P, Seeschaaf C, Lebok P, Kutup A, Bockhorn M, Izbicki JR, et al. Heterogeneity of amplification of HER2, EGFR, CCND1 and MYC in gastric cancer. BMC Gastroenterol 2015;15:7.   DOI
23 Yamamoto H, Watanabe Y, Maehata T, Morita R, Yoshida Y, Oikawa R, et al. An updated review of gastric cancer in the next-generation sequencing era: insights from bench to bedside and vice versa. World J Gastroenterol 2014;20:3927-3937.
24 Swain SM, Kim SB, Cortes J, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2013;14:461-471.
25 Karabacak NM, Zheng Y, Emmons E, Koulopoulos M, Haber DA, Toner M, et al. Single cell signaling analysis reveals circulating tumor cell markers of drug susceptibility and tumor heterogeneity. 2017 AACR Annual Meeting; 2017 Apr 1-5; Washington, D.C. Philadelphia (PA): American Association for Cancer Research; 2017. p. 4953.
26 Jemal A, Center MM, DeSantis C, Ward EM. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev 2010;19:1893-1907.   DOI
27 Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-E386.
28 Hofmann M, Stoss O, Shi D, Buttner R, Van De Vijver M, Kim W, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 2008;52:797-805.   DOI
29 Agus DB, Akita RW, Fox WD, Lewis GD, Higgins B, Pisacane PI, et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2002;2:127-137.
30 Yamashita-Kashima Y, Iijima S, Yorozu K, Furugaki K, Kurasawa M, Ohta M, et al. Pertuzumab in combination with trastuzumab shows significantly enhanced antitumor activity in HER2-positive human gastric cancer xenograft models. Clin Cancer Res 2011;17:5060-5070.   DOI
31 Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007;357:1810-1820.
32 Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer 2006;118:3030-3044.   DOI
33 Oh CM, Won YJ, Jung KW, Kong HJ, Cho H, Lee JK, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2013. Cancer Res Treat 2016;48:436-450.   DOI
34 Mizrak Kaya D, Harada K, Shimodaira Y, Amlashi FG, Lin Q, Ajani JA. Advanced gastric adenocarcinoma: optimizing therapy options. Expert Rev Clin Pharmacol 2017;10:263-271.
35 Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet 2012;379:315-321.
36 Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376:687-697.
37 Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 2014;15:1224-1235.
38 Li J, Qin S, Xu J, Xiong J, Wu C, Bai Y, et al. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol 2016;34:1448-1454.   DOI
39 Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733-2743.   DOI
40 Amir E, Ocana A, Seruga B, Freedman O, Clemons M. Lapatinib and HER2 status: results of a metaanalysis of randomized phase III trials in metastatic breast cancer. Cancer Treat Rev 2010;36:410-415.   DOI
41 Hecht JR, Bang YJ, Qin SK, Chung HC, Xu JM, Park JO, et al. Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC--a randomized phase III trial. J Clin Oncol 2016;34:443-451.
42 Satoh T, Xu RH, Chung HC, Sun GP, Doi T, Xu JM, et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN-a randomized, phase III study. J Clin Oncol 2014;32:2039-2049.   DOI
43 Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 2000;19:3159-3167.
44 Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature 2013;500:415-421.   DOI
45 Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med 2015;21:449-456.   DOI
46 Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2:127-137.   DOI
47 Okines A, Cunningham D, Chau I. Targeting the human EGFR family in esophagogastric cancer. Nat Rev Clin Oncol 2011;8:492-503.   DOI
48 Burstein HJ. The distinctive nature of HER2-positive breast cancers. N Engl J Med 2005;353:1652-1654.
49 Tan M, Yu D. Molecular mechanisms of erbB2-mediated breast cancer chemoresistance. Adv Exp Med Biol 2007;608:119-129.
50 Ruschoff J, Hanna W, Bilous M, Hofmann M, Osamura RY, Penault-Llorca F, et al. HER2 testing in gastric cancer: a practical approach. Mod Pathol 2012;25:637-650.   DOI
51 Holbro T, Hynes NE. ErbB receptors: directing key signaling networks throughout life. Annu Rev Pharmacol Toxicol 2004;44:195-217.
52 Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177-182.   DOI
53 Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol 2008;19:1523-1529.   DOI
54 Pavlakis N, Sjoquist KM, Martin AJ, Tsobanis E, Yip S, Kang YK, et al. Regorafenib for the treatment of advanced gastric cancer (INTEGRATE): a multinational placebo-controlled phase II trial. J Clin Oncol 2016;34:2728-2735.
55 Janjigian YY, Viola-Villegas N, Holland JP, Divilov V, Carlin SD, Gomes-DaGama EM, et al. Monitoring afatinib treatment in HER2-positive gastric cancer with 18F-FDG and 89Zr-trastuzumab PET. J Nucl Med 2013;54:936-943.   DOI
56 Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat 2011;128:347-356.   DOI
57 Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012;367:1783-1791.   DOI
58 Hynes NE, Stern DF. The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta 1994;1198:165-184.
59 Fujimoto-Ouchi K, Sekiguchi F, Yasuno H, Moriya Y, Mori K, Tanaka Y. Antitumor activity of trastuzumab in combination with chemotherapy in human gastric cancer xenograft models. Cancer Chemother Pharmacol 2007;59:795-805.   DOI
60 Carneiro F, Sobrinho-Simoes M. The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas. Cancer 2000;88:238-239.   DOI
61 Janjigian YY, Tang LH, Coit DG, Kelsen DP, Francone TD, Weiser MR, et al. MET expression and amplification in patients with localized gastric cancer. Cancer Epidemiol Biomarkers Prev 2011;20:1021-1027.   DOI
62 Iveson T, Donehower RC, Davidenko I, Tjulandin S, Deptala A, Harrison M, et al. Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: an open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study. Lancet Oncol 2014;15:1007-1018.
63 Cunningham D, Tebbutt NC, Davidenko I, Murad AM, Al-Batran SE, Ilson DH, et al. Phase III, randomized, double-blind, multicenter, placebo (P)-controlled trial of rilotumumab (R) plus epirubicin, cisplatin and capecitabine (ECX) as first-line therapy in patients (pts) with advanced METpositive (pos) gastric or gastroesophageal junction (G/GEJ) cancer: RILOMET-1 study. J Clin Oncol 2015;33 suppl:abstr 4000.
64 Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer 2001;37 Suppl 4:S9-S15.
65 Han SW, Oh DY, Im SA, Park SR, Lee KW, Song HS, et al. Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advanced gastric cancer. Br J Cancer 2009;100:298.   DOI
66 Lordick F, Luber B, Lorenzen S, Hegewisch-Becker S, Folprecht G, Woll E, et al. Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Br J Cancer 2010;102:500.   DOI
67 Moehler M, Mueller A, Trarbach T, Lordick F, Seufferlein T, Kubicka S, et al. Cetuximab with irinotecan, folinic acid and 5-fluorouracil as first-line treatment in advanced gastroesophageal cancer: a prospective multi-center biomarker-oriented phase II study. Ann Oncol 2011;22:1358-1366.   DOI
68 Barok M, Tanner M, Koninki K, Isola J. Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer. Cancer Lett 2011;306:171-179.   DOI
69 Kang YK, Shah MA, Ohtsu A, Van Cutsem E, Ajani JA, van der Horst T, et al. A randomized, openlabel, multicenter, adaptive phase 2/3 study of trastuzumab emtansine (T-DM1) versus a taxane (TAX) in patients (pts) with previously treated HER2-positive locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (LA/MGC/GEJC). J Clin Oncol 2016;34 suppl:abstr 5.
70 Kim MA, Lee HS, Lee HE, Jeon YK, Yang HK, Kim WH. EGFR in gastric carcinomas: prognostic significance of protein overexpression and high gene copy number. Histopathology 2008;52:738-746.
71 Pinto C, Di Fabio F, Siena S, Cascinu S, Rojas Llimpe F, Ceccarelli C, et al. Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Ann Oncol 2007;18:510-517.
72 Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005;438:820.
73 Doi T, Kang YK, Muro K, Jiang Y, Jain RK, Lizambri R. A phase 3, multicenter, randomized, double-blind, placebo-controlled study of rilotumumab in combination with cisplatin and capecitabine (CX) as first-line therapy for Asian patients (pts) with advanced MET-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: the RILOMET-2 trial. J Clin Oncol 2015;33 suppl:abstr TPS226.
74 Kim C, Lee JL, Ryu MH, Chang HM, Kim TW, Lim HY, et al. A prospective phase II study of cetuximab in combination with XELOX (capecitabine and oxaliplatin) in patients with metastatic and/or recurrent advanced gastric cancer. Invest New Drugs 2011;29:366-373.   DOI
75 Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol 2013;14:490-499.   DOI
76 Waddell T, Chau I, Cunningham D, Gonzalez D, Okines AF, Okines C, et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol 2013;14:481-489.   DOI
77 Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer 2013;13:871.   DOI
78 Ohtsu A, Ajani JA, Bai YX, Bang YJ, Chung HC, Pan HM, et al. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol 2013;31:3935-3943.   DOI
79 Shah MA, Bang YJ, Lordick F, Tabernero J, Chen M, Hack SP, et al. METGastric: a phase III study of onartuzumab plus mFOLFOX6 in patients with metastatic HER2-negative (HER2-) and MET-positive (MET+) adenocarcinoma of the stomach or gastroesophageal junction (GEC). J Clin Oncol 2015;33 suppl:abstr 4012.
80 Doi T, Muro K, Boku N, Yamada Y, Nishina T, Takiuchi H, et al. Multicenter phase II study of everolimus in patients with previously treated metastatic gastric cancer. J Clin Oncol 2010;28:1904-1910.   DOI
81 Bang YJ, Van Cutsem E, Mansoor W, Petty R, Chao Y, Cunningham D, et al. A randomized, open-label phase II study of AZD4547 (AZD) versus Paclitaxel (P) in previously treated patients with advanced gastric cancer (AGC) with Fibroblast Growth Factor Receptor 2 (FGFR2) polysomy or gene amplification (amp): SHINE study. J Clin Oncol 2015;33 suppl:abstr 4014.
82 Helwick C, Goodman A. At ESMO 2016, Many Phase III Trials Fail to Meet Primary Endpoints. Huntington (NY): The ASCO Post; 2016.
83 Chen J, Zhou SJ, Zhang Y, Zhang GQ, Zha TZ, Feng YZ, et al. Clinicopathological and prognostic significance of galectin-1 and vascular endothelial growth factor expression in gastric cancer. World J Gastroenterol 2013;19:2073-2079.   DOI
84 Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9:669-676.
85 Okines AF, Reynolds AR, Cunningham D. Targeting angiogenesis in esophagogastric adenocarcinoma. Oncologist 2011;16:844-858.   DOI
86 Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol 2006;7:359-371.
87 Peggs KS, Quezada SA, Chambers CA, Korman AJ, Allison JP. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med 2009;206:1717-1725.   DOI
88 Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 2004;22:329-360.
89 Palucka AK, Coussens LM. The basis of oncoimmunology. Cell 2016;164:1233-1247.   DOI
90 Harris TJ, Drake CG. Primer on tumor immunology and cancer immunotherapy. J Immunother Cancer 2013;1:12.   DOI
91 Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014;515:568-571.   DOI
92 Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014;383:31-39.   DOI
93 Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebocontrolled phase III study. J Clin Oncol 2011;29:3968-3976.   DOI
94 Shen L, Li J, Xu J, Pan H, Dai G, Qin S, et al. Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study). Gastric Cancer 2015;18:168-176.   DOI
95 Youssoufian H, Hicklin DJ, Rowinsky EK. monoclonal antibodies to the vascular endothelial growth factor receptor-2 in cancer therapy. Clin Cancer Res 2007;13:5544s-5548s.   DOI
96 Huynh H, Ong R, Zopf D. Antitumor activity of the multikinase inhibitor regorafenib in patient-derived xenograft models of gastric cancer. J Exp Clin Cancer Res 2015;34:132.   DOI
97 Kang YK, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, et al. Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer (AGC): a double-blinded, randomized, phase III trial. J Clin Oncol 2017;35 suppl:abstr 2.
98 Goode EF, Smyth EC. Immunotherapy for gastroesophageal cancer. J Clin Med 2016;5:84.
99 Burstein HJ, Krilov L, Aragon-Ching JB, Baxter NN, Chiorean EG, Chow WA, et al. Clinical cancer advances 2017: annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol 2017;35:1341-1367.   DOI
100 Muro K, Chung HC, Shankaran V, Geva R, Catenacci D, Gupta S, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol 2016;17:717-726.   DOI
101 Arzimanoglou II, Gilbert F, Barber HR. Microsatellite instability in human solid tumors. Cancer 1998;82:1808-1820.   DOI
102 Colli LM, Machiela MJ, Myers TA, Jessop L, Yu K, Chanock SJ. Burden of nonsynonymous mutations among TCGA cancers and candidate immune checkpoint inhibitor responses. Cancer Res 2016;76:3767-3772.
103 Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-2454.
104 Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509-2520.   DOI
105 Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016;27:1386-1422.   DOI
106 Shankaran V, Muro K, Bang YJ, Geva R, Catenacci DV, Gupta S, et al. Correlation of gene expression signatures and clinical outcomes in patients with advanced gastric cancer treated with pembrolizumab (MK-3475). J Clin Oncol 2015;33 suppl:abstr 3026.
107 Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014;513:202-209.   DOI
108 ClinicalTrials.gov (US). An investigational immuno-therapy study of nivolumab, and nivolumab in combination with other anti-cancer drugs, in colon cancer that has come back or has spread (CheckMate142) [Internet]. Bethesda (MD): National Library of Medicine; 2014 [cited 2016 Jul 31]. Available from: https://clinicaltrials.gov/ct2/show/NCT02060188.
109 Ribas A, Robert C, Hodi FS, Wolchok JD, Joshua AM, Hwu WJ, et al. Association of response to programmed death receptor 1 (PD-1) blockade with pembrolizumab (MK-3475) with an interferoninflammatory immune gene signature. J Clin Oncol 2015;33 suppl:abstr 3001.
110 Murphy G, Pfeiffer R, Camargo MC, Rabkin CS. Meta-analysis shows that prevalence of Epstein-Barr virus-positive gastric cancer differs based on sex and anatomic location. Gastroenterology 2009;137:824-833.   DOI
111 Bae JM, Kim EH. Epstein-Barr Virus and gastric cancer risk: a meta-analysis with meta-regression of casecontrol studies. J Prev Med Public Health 2016;49:97.   DOI
112 Derks S, Liao X, Chiaravalli AM, Xu X, Camargo MC, Solcia E, et al. Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers. Oncotarget 2016;7:32925.
113 Kawazoe A, Kuwata T, Kuboki Y, Shitara K, Nagatsuma AK, Aizawa M, et al. Clinicopathological features of programmed death ligand 1 expression with tumor-infiltrating lymphocyte, mismatch repair, and Epstein-Barr virus status in a large cohort of gastric cancer patients. Gastric Cancer 2017;20:407-415.   DOI