Update on targeted therapy and immune therapy for gastric cancer, 2018

Abstract

Gastric cancer (GC) remains one of the most common cancers and serious health problems worldwide. For unresectable or metastatic advanced gastric cancer, chemotherapy treatment is first selected. Although chemotherapy has improved survival in patients with advanced gastric cancer (AGC), the prognosis of these patients remains poor. In recent years, some therapies targeting biological molecules have been reported to prolong the survival of patients with AGC. Since trastuzumab, a monoclonal antibody that targets HER2, was established as standard therapy for unresectable GC in a HER2-positive patient, many other targets have been reported as new therapy targets. Many molecular targeted therapies, such as HER2, VEGFR or EGFR, have been verified as established standard treatments with or without chemotherapy in clinical trials. Furthermore, immunotherapy is expected to be an effective treatment with promising clinical trial data. Especially, immune checkpoint inhibiters, such as PD-1/PD-L1 or CTLA-4, have demonstrated innovative progression in GC therapy. Moreover, ongoing clinical trials including targeted therapy and immunotherapy have shown promising results in improving clinical outcomes, safety, and tolerability. In this article, we review targeting therapies and immunotherapies for GC and summarize future prospective treatments.

Keywords

Gastric cancer / targeted therapy / immunotherapy / immune checkpoint inhibitor

References

[1] Stomach Cancer: Estimated Incidence, Mortality and Prevalence Worldwide in 2012. Available from: http://globocan.iarc.fr/old/FactSheets/cancers/stomach-new.asp [Last accessed on 26 Jun 2018].

[2] Koizumi W,Hara T,Akiya T,Miyashita K,Kobayashi O,Toh Y,Takagi S,Yanaoka K,Takeuchi M.S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial.Lancet Oncol2008;9:215-21

[3] Kang YK,Shin DB,Xiong J,Lichinitser M,Khasanov R,Philco-Salas M,Santamaria J,McCloud PI.Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial.Ann Oncol2009;20:666-73

[4] Bang YJ,Feyereislova A,Shen L,Lordick F,Omuro Y,Aprile G,Hill J,Ruschoff J.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.Lancet2010;376:687-97

[5] Fuchs CS,Yong CJ,Passalacqua R,Safran H,Aprile G,Melichar B,Topuzov E,Chau I,Sivanandan C,Koshiji M,Liepa AM,Schwartz JD.Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial.Lancet2014;383:31-9

[6] Wilke H,Van Cutsem E,Bodoky G,Hironaka S,Lipatov O,Cunningham D,Komatsu Y,Emig M,Ferry D,Schwartz JD.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 Oncol2014;15:1224-35

[7] Kang YK,Satoh T,Chao Y,Chung HC,Muro K,Yeh KH,Oh SC,Tamura T,Hamamoto Y,Chin K,Minashi K,Tsuda M.Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet2017;390:2461-71

[8] Thuss-Patience PC,Ohtsu A,Ajani JA,Mansoor W,Bodoky G,Phillips GDL,Harle-Yge ML,Kang YK.Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study.Lancet Oncol2017;18:640-53

[9] Hecht JR,Qin SK,Xu JM,Jeziorski K,Hoff PM,Salman P,Protsenko SA,Buyse M,Houe V,Kaneko T,Khan-Wasti S,Press MF.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 Oncol2016;34:443-51

[10] Satoh T,Chung HC,Doi T,Tsuji A,Li J,Miwa H,Chung IJ,Feng JF,Kobayashi M,Bang YJ.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 Oncol2014;32:2039-49

[11] Carpenter G.Epidermal growth factor.J Biol Chem1990;265:7709-12

[12] Li S,Jeffrey PD,Kussie P.Structural basis for inhibition of the epidermal growth factor receptor by cetuximab.Cancer Cell2005;7:301-11

[13] Zhang W,Schultheis AM,Nagashima F,Chang HM,Lurje G,Iqbal S,Lenz HJ.FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab.J Clin Oncol2007;25:3712-8

[14] Bokemeyer C,Hartmann JT,Schuch G,Celik I,Koralewski P.Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study.Ann Oncol2011;22:1535-46

[15] Van Cutsem E,Lang I,Nowacki MP,Shchepotin I,Cunningham D,Schlichting M,Celik I,Ciardiello F.Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status.J Clin Oncol2011;29:2011-9

[16] Lordick F,Chung HC,Oh SC,Kurteva G,Moiseyenko VM,Park JO,Celik I,Melezinkova H,Arbeitsgemeinschaft Internistische O.Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial.Lancet Oncol2013;14:490-9

[17] Keating GM.Panitumumab: a review of its use in metastatic colorectal cancer.Drugs2010;70:1059-78

[18] Waddell T,Cunningham D,Okines AF,Wotherspoon A,Middleton G,Ferry D,Crosby T,Smith D,Iveson T,Slater S,Barbachano Y.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 Oncol2013;14:481-9

[19] Talavera A,Gomez-Puerta S,Garrido G,Lopez-Requena A,Johansen RF,Krengel U.Nimotuzumab, an antitumor antibody that targets the epidermal growth factor receptor, blocks ligand binding while permitting the active receptor conformation.Cancer Res2009;69:5851-9

[20] Garrett TP,Lou M,Adams TE,Zhu HJ,Frenkel MJ,Jorissen RN,Burgess AW.Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor alpha.Cell2002;110:763-73

[21] Satoh T,Rha SY,Park SH,Yasui H,Yamaguchi K,Yamada Y,Kim SY,Saitoh S,Morita S,Zhang Q,Kim YH.Randomized phase II trial of nimotuzumab plus irinotecan versus irinotecan alone as second-line therapy for patients with advanced gastric cancer.Gastric Cancer2015;18:824-32 PMCID:PMC4572054

[22] Park DJ,Yoon C.Vascular endothelial growth factor a inhibition in gastric cancer.Gastric Cancer2015;18:33-42

[23] Shih T.Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies.Clin Ther2006;28:1779-802

[24] Ohtsu A,Van Cutsem E,Sawaki A,Lim HY,Wu J,Starnawski M.Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study.J Clin Oncol2011;29:3968-76

[25] Li J,Xu J,Wu C,Liu W,Liu Y,Wang Z,Ouyang X,Ba Y,Lin X,Zheng R,Sun G,Zheng L,Wu J,Yang J,Cheng Y,Chen L,Sun P.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 Oncol2016;34:1448-54

[26] Pavlakis N,Martin AJ,Yip S,Bang YJ,O'Callaghan CJ,Tebbutt NC,Lee J,Lipton LR,Strickland A,Zalcberg JR,Goldstein D.Regorafenib for the treatment of advanced gastric cancer (INTEGRATE): a multinational placebo-controlled phase II trial.J Clin Oncol2016;34:2728-35 PMCID:PMC5019744

[27] Lordick F.Targeting the HGF/MET pathway in gastric cancer.Lancet Oncol2014;15:914-6

[28] Cunningham D,Davidenko I,Murad AM,Jiang Y,Dubey S.RILOMET-1: An international phase III multicenter, randomized, double-blind, placebo-controlled trial of rilotumumab plus epirubicin, cisplatin, and capecitabine (ECX) as first-line therapy in patients with advanced MET-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.J Clin Oncol2013;31 suppl 15:TPS4153

[29] Doi T,Muro K,Jain RK.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 Oncol2015;33 suppl 3:TPS226

[30] Shah MA,Lordick F,Chen M,Bruey JM,McCaffery I,Phan S.Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2-negative, MET-positive gastroesophageal adenocarcinoma: the MET gastric randomized clinical trial.JAMA Oncol2017;3:620-7 PMCID:PMC5824210

[31] Oki E,Tokunaga E,Ueda N,Mashino K,Ikebe M,Maehara Y.Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer.Int J Cancer2005;117:376-80

[32] Doi T,Boku N,Nishina T,Komatsu Y,Ohno N,Robson M.Multicenter phase II study of everolimus in patients with previously treated metastatic gastric cancer.J Clin Oncol2010;28:1904-10

[33] Ohtsu A,Bai YX,Chung HC,Sahmoud T,Yeh KH,Muro K,Ferry D,Al-Batran SE,Costantini C,Lebwohl D.Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study.J Clin Oncol2013;31:3935-43 PMCID:PMC5950503

[34] Lordick F,Al-Batran SE,Manikhas G,Vinnyk Y,Fadeeva N,Dudov A,Pecheniy A,Bondarenko I,Huber C,Türeci Ö.220O Claudin 18.2 - a novel treatment target in the multicenter, randomized, phase II FAST study, a trial of epirubicin, oxaliplatin, and capecitabine (EOX) with or without the anti-CLDN18.2 antibody IMAB362 as 1st line therapy in advanced gastric and gastroesophageal junction (GEJ) cancer..Ann Oncol2016;27 suppl 9:mdw582.001

[35] Shah MA,Wainberg ZA,Smith V,Bendell JC.Results of a phase I study of GS-5745 in combination with mFOLFOX in patients with advanced unresectable gastric / GE junction tumors.J Clin Oncol2016;34 suppl 15:4033

[36] Hodi FS,McDermott DF,Sosman JA,Gonzalez R,Schadendorf D,Akerley W,Lutzky J,Vaubel JM,Hogg D,Lebbe C,Quirt I,Wolchok JD,Tian J,Nichol GM,Urba WJ.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med2010;363:711-23 PMCID:PMC3549297

[37] Higashihara Y,Nagahara A,Konishi M,Serizawa N,Watanabe S.Phase I clinical trial of peptide vaccination with URLC10 and VEGFR1 epitope peptides in patients with advanced gastric cancer.Int J Oncol2014;44:662-8 PMCID:PMC3928476

[38] Sukumar S,Yu Y,Naravula S,Riener R,Necheva AS,Churakova T,Georgiev P,Pinheiro EM,Bailey WJ,McClanahan TK,Beebe AM.Characterization of MK-4166, a clinical agonistic antibody that targets human GITR and inhibits the generation and suppressive effects of T regulatory cells.Cancer Res2017;77:4378-88

[39] Nagase H,Urakawa S,Kawashima A,Takiguchi S,Sato E,Mori M,Wada H.ICOS+ Foxp3+ TILs in gastric cancer are prognostic markers and effector regulatory T cells associated with Helicobacter pylori.Int J Cancer2017;140:686-95

[40] Ueda Y,Kinami S,Yamaguchi A,Tani T,Yamagishi H.A randomized phase III trial of postoperative adjuvant therapy with S-1 alone versus S-1 plus PSK for stage II/IIIA gastric cancer: Hokuriku-Kinki Immunochemo-Therapy Study Group-Gastric Cancer (HKIT-GC)..Jpn J Clin Oncol2006;36:519-22

[41] Janjigian YY,Calvo E,Ascierto PA,Ott PA,Jaeger D,Braud FGD,Tschaika M,Lin CS.CheckMate-032: Phase I/II, open-label study of safety and activity of nivolumab (nivo) alone or with ipilimumab (ipi) in advanced and metastatic (A/M) gastric cancer (GC)..J Clin Oncol2016;34 suppl 15:4010

[42] Muro K,Shankaran V,Catenacci D,Eder JP,Le DT,McRee AJ,Pathiraja K,Emancipator K,Koshiji M.Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial.Lancet Oncol2016;17:717-26

[43] Bang YJ,Kim YH,Di Bartolomeo M,Yamaguchi K,Sanchez T.Efficacy of sequential ipilimumab monotherapy versus best supportive care for unresectable locally advanced/metastatic gastric or gastroesophageal junction cancer.Clin Cancer Res2017;23:5671-8

[44] Janjigian YY,Calvo E,Ascierto PA,Peltola KJ,Evans TRJ,Chau I,Harbison CT,Bendell JC.Nivolumab ± ipilimumab in pts with advanced (adv)/metastatic chemotherapy-refractory (CTx-R) gastric (G), esophageal (E), or gastroesophageal junction (GEJ) cancer: CheckMate 032 study.J Clin Oncol2017;35 suppl 15:4014

[45] Yue EW,Polam P,Douty B,Glass B,Glenn J,Bower M,Leffet L,Bowman KJ,Wei M,Wynn R,Koblish HK,Emm T,Metcalf B.INCB24360 (Epacadostat), a highly potent and selective indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor for immuno-oncology.ACS Med Chem Lett2017;8:486-91 PMCID:PMC5430407

[46] Kodera Y.Neoadjuvant chemotherapy for gastric adenocarcinoma in Japan.Surg Today2017;47:899-907

[47] Ajani JA,Sano T,Fan D.Gastric adenocarcinoma.Nat Rev Dis Primers2017;3:17036

[48] Galluzzi L,Kepp O,Kroemer G.Immunological effects of conventional chemotherapy and targeted anticancer agents.Cancer Cell2015;28:690-714

[49] Wong SS,Ting JC,Fu J,Cristescu R,Gong L,Wang J,Loboda A,Liu X,Jin JG,Kang SY,Park JO,Reinhard C,Kim S.Genomic landscape and genetic heterogeneity in gastric adenocarcinoma revealed by whole-genome sequencing.Nat Commun2014;5:5477

[50] Sugano K,Kuipers EJ,El-Omar EM,Haruma K,Uemura N,faculty members of Kyoto Global Consensus Conference..Kyoto global consensus report on Helicobacter pylori gastritis.Gut2015;64:1353-67 PMCID:PMC4170219

[51] Cancer Genome Atlas Research Network..Comprehensive molecular characterization of gastric adenocarcinoma.Nature2014;513:202-9 PMCID:PMC4170219

[52] Le DT,Wang H,Kemberling H,Skora AD,Azad NS,Biedrzycki B,Zaheer A,Crocenzi TS,Duffy SM,de la Chapelle A,Bhaijee F,Hruban RH,Cuka N,Papadopoulos N,Zhou S,Taube JM,Eshleman JR,Diaz LA, Jr.PD-1 blockade in tumors with mismatch-repair deficiency.N Engl J Med2015;372:2509-20 PMCID:PMC4481136

[53] Le DT,Smith KN,Bartlett BR,Lu S,Wilt C,Wong F,Rucki AA,Donehower R,Fisher GA,Lee JJ,Duffy AG,Eyring AD,Joe A,Holdhoff M,Cope L,Zhou S,Armstrong DK,Fader AN,Housseau F,Xiao N,Papadopoulos N,Eshleman JR,Anders RA.Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.Science2017;357:409-13 PMCID:PMC5576142

[54] Hao NB,Li XQ,Wang RL.The role of miRNA and lncRNA in gastric cancer.Oncotarget2017;8:81572-82 PMCID:PMC5655310