Skip to main content
SpringerLink
Log in

New targets in gastric cancer

  • review
  • Published:
memo - Magazine of European Medical Oncology Aims and scope Submit manuscript

Abstract

Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. Since the effectiveness of current therapeutic options for the treatment of advanced (inoperable locally advanced, recurrent, or metastatic) disease is limited the need for novel effective treatment options is obvious. During last 2 decades, molecular-targeted therapy emerged as a new promising treatment modality and showed pronounced success in many tumor types. But in GC the only targeted agent approved until recently was trastuzumab for human epidermal growth factor receptor (HER) 2-positive advanced disease. Recently ramucirumab has emerged as new treatment option for second-line therapy of advanced GC. Clinical research data on novel targeted drugs hold promise for further improvement in GC patients’ outcomes. Currently the most studied targets in GC are HER family receptors, vascular endothelial growth factor proangiogenic pathway, and PI3K/Akt/mTOR axis. Also hepatocyte growth factor/mesenchymal epithelial transition factor, fibroblast growth factor receptor (FGFR) pathways and some other promising targets have emerged recently. This review is focused at the current progress in clinical research of targeted drugs for GC with the accent on recent studies and future perspectives.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. 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. 2014;136(5):359–86.

  2. Waddell T, Verheij M, Allum W, Cunningham D, Cervantes A, Arnold D. Gastric cancer: ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Suppl. 6):vi57–63.

    PubMed  Google Scholar 

  3. Roskoski R, Jr. The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res. 2014;79:34–74.

    Article  CAS  PubMed  Google Scholar 

  4. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008;19(9):1523–9.

    Article  CAS  PubMed  Google Scholar 

  5. Bang YJ, Van CE, 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(9742):687–97.

    Article  CAS  PubMed  Google Scholar 

  6. Hecht JR, Bang YJ, Qin S, Chung HC, Xu JM, Park JO, et al. Lapatinib in combination with capecitabine plus oxaliplatin (CapeOx) in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma (AC): The TRIO-013/LOGiC Trial. J Clin Oncol. 2013;31 (suppl; abstr LBA4001).

  7. 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(19):2039–49.

    Article  CAS  PubMed  Google Scholar 

  8. 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(6):481–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. 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(6):490–9.

    Article  CAS  PubMed  Google Scholar 

  10. Satoh T, Lee KH, Rha SY, Sasaki Y, Park SH, Komatsu Y, et al. Randomized phase II trial of nimotuzumab plus irinotecan versus irinotecan alone as second-line therapy for patients with advanced gastric cancer. Gastric Cancer. 2014. [Epub ahead of print].

  11. Wang L, Yuan H, Li Y, Han Y. The role of HER3 in gastric cancer. Biomed Pharmacother. 2014;68(6):809–12.

    Article  CAS  PubMed  Google Scholar 

  12. Ohtsu A, Shah MA, Van CE, 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, placebo-controlled phase III study. J Clin Oncol. 2011;29(30):3968–76.

    Article  CAS  PubMed  Google Scholar 

  13. Van Cutsem E, de Haas S, Kang YK, Ohtsu A, Tebbutt NC, Ming XJ, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol. 2012 ;30(17):2119–27.

    Article  PubMed  Google Scholar 

  14. Morishita A, Gong J, Masaki T. Targeting receptor tyrosine kinases in gastric cancer. World J Gastroenterol. 2014;20(16):4536–45.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. Ramucirumabmonotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31–9.

    Article  CAS  PubMed  Google Scholar 

  16. Wilke H, Muro K, Van CE, 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(11):1224–35.

    Article  CAS  PubMed  Google Scholar 

  17. Qin S. Phase III study of apatinib in advanced gastric cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2014;32:5s (suppl; abstr 4003).

  18. Yoon HH, Bendell JC, Braiteh FS, Firdaus I, Philip PA, Cohn AL, et al. Ramucirumab (RAM) plus FOLFOX as front-line therapy (Rx) for advanced gastric or esophageal adenocarcinoma (GE-AC): randomized, double-blind, multicenter phase 2 trial. J Clin Oncol. 2014;32:5 s (suppl; abstr 4004).

  19. 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(11):1904–10.

    Article  CAS  PubMed  Google Scholar 

  20. 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(31):3935–43.

    Article  CAS  PubMed  Google Scholar 

  21. Ramanathan RK, McDonough SL, Kennecke HF, Iqbal S, Baranda JC, Seery TE, et al. A phase II study of MK-2206, an allosteric inhibitor of AKT as second-line therapy for advanced gastric and gastroesophageal junction (GEJ) cancer: A SWOG Cooperative Group Trial (S1005). J Clin Oncol. 2014;32:5s (suppl; abstr 4041).

    Article  Google Scholar 

  22. Peng Z, Zhu Y, Wang Q, Gao J, Li Y, Li Y, et al. Prognostic significance of MET amplification and expression in gastric cancer: a systematic review with meta-analysis. PLoS One. 2014;9(1):e84502.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Salgia R, Patel P, Bothos J, Yu W, Eppler S, Hegde P, et al. Phase I dose-escalation study of onartuzumab as a single agent and in combination with bevacizumab in patients with advanced solid malignancies. Clin Cancer Res. 2014;20(6):1666–75.

    Article  CAS  PubMed  Google Scholar 

  24. 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(9):1007–18.

    Article  CAS  PubMed  Google Scholar 

  25. Hale MD, Oliner KS, Tang R, Vallone JG, Klement I, Webster S, et al. Evaluation of MET staining in gastric/gastroesophageal junction (G/GEJ) tumor samples as a biomarker for rilotumumab benefit. Ann Oncol. 2014;25(Suppl 4):iv58–84. doi:10.1093/annonc/mdu326.

    Google Scholar 

  26. Hong DS, LoRusso P, Hamid O, Beaupre D, Janku F, Khan R, et al. First-in-human study of AMG 337, a highly selective oral inhibitor of MET, in adult patients (pts) with advanced solid tumors. J Clin Oncol. 2014;32:5s (suppl; abstr 2508).

    Article  Google Scholar 

  27. Kilgour E, Su X, Zhan P, Gavine P, Morgan S, Womack C, et al. Prevalence and prognostic significance of FGF receptor 2 (FGFR2) gene amplification in Caucasian and Korean gastric cancer cohorts. J Clin Oncol. 2012;30 (suppl; abstr 4124).

  28. Arkenau HT, Saggese M, Hollebecque A, Mathewson A, Lemech CR, Landers D, et al. A phase 1 expansion cohort of the fibroblast growth factor receptor (FGFR) inhibitor AZD4547 in patients (pts) with advanced gastric (GC) and gastroesophageal (GOJ) cancer. J Clin Oncol. 2014;32:5s (suppl; abstr 2620).

    Article  Google Scholar 

  29. Ralph C, Elkord E, Burt DJ, O’Dwyer JF, Austin EB, Stern PL, et al. Modulation of lymphocyte regulation for cancer therapy: a phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma. Clin Cancer Res. 2010;16(5):1662–72.

    Article  CAS  PubMed  Google Scholar 

  30. Muro K, Bang Y, Shankaran V, Geva R, Catenacci DV, Gupta S, et al. A phase 1b study of pembrolizumab (Pembro; MK-3475) in patients (pts) with advanced gastric cancer. Ann Oncol. 2014;25(5):1–41. doi:10.1093/annonc/mdu438.

    Google Scholar 

  31. Schuler MH, Zvirbule Z, Lordick F, Krilova A, Helbig U, Schulze-Bergkamen U, et al. Safety, tolerability, and efficacy of the first-in-class antibody IMAB362 targeting claudin 18.2 in patients with metastatic gastroesophageal adenocarcinomas. J Clin Oncol. 2013;31 (suppl; abstr 4080).

  32. Zambrano CC, Almhanna K, Messersmith WA, Ahnert JR, Ryan DP, Faris JE, et al. MLN0264, an investigational antiguanylylcyclase C (GCC) antibody-drug conjugate (ADC), in patients (pts) with advanced gastrointestinal (GI) malignancies: phase I study. J Clin Oncol. 2014;32:5s (suppl; abstr 3546).

    Article  Google Scholar 

  33. Bang YJ, Im SA, Lee KW, Cho JY, Song EK, Lee KH, et al. Olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer: A randomized, double-blind phase II study. J Clin Oncol. 2013;31 (suppl; abstr 4013).

  34. Hitron M, Stephenson J, Chi KN, Edenfield WJ, Leggett D, Li Y, et al. A phase 1b study of the cancer stem cell inhibitor BBI608 administered with paclitaxel in patients with advanced malignancies. J Clin Oncol. 2014;32:5s (suppl; abstr 2530).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Diagnostic and Treatment Center of International Institute of Biological Systems, Karla Marksa str. 43, 197758, Pesochny, Saint-Petersburg, Russian Federation

    Nikita M. Volkov MD, PhD

Authors
  1. Nikita M. Volkov MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nikita M. Volkov MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Volkov, N. New targets in gastric cancer. memo 8, 92–100 (2015). https://doi.org/10.1007/s12254-015-0205-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12254-015-0205-9

Keywords

Search

Navigation