Skip to main content
SpringerLink
Log in

New therapeutic target molecules for gastric and gastroesophageal junction cancer

  • Invited Review Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Molecularly targeted therapy for receptor tyrosine kinases (RTKs) has faced limitations in gastric and gastroesophageal junction (G/GEJ) cancer except for HER2-targeted agents, possibly due to inappropriate assay selection that has hindered identification of sensitive patients, in addition to coexisting genetic abnormalities as well as intratumoral heterogeneity. Immunohistochemistry of RTKs has, thus, proved largely unsuccessful for patient selection, and detection of RTK gene amplification as a true oncogenic driver is problematic given the small numbers of affected individuals. FGFR2 amplification is associated with poor prognosis in G/GEJ cancer, and immunohistochemistry of the FGFR2b protein isoform has proved effective for the detection of such FGFR2-dependent tumors. Phase III and Ib/III trials of the FGFR2-targeted antibody bemarituzumab for G/GEJ cancer overexpressing FGFR2b are ongoing based on the promising result in a phase II trial, especially in cases with an FGFR2b positivity of ≥ 10%. Challenges to EGFR- and MET-targeted therapies are being tackled with antibody–drug conjugates (ADCs) and bispecific antibodies. CLDN18.2 is expressed in some G/GEJ tumors but lacks oncogenic driver potential, and the CLDN18.2-targeted antibody zolbetuximab prolonged the survival of CLDN18.2-positive G/GEJ cancer patients in phase III trials. Antibody–drug conjugates and ADCs that target CLDN18.2 are also being pursued for treatment of such patients. Similarly, targeting of nondriver molecules such as DKK1, TROP2, and CEACAM5 is under investigation in early-stage clinical trials. This shift in focus from target molecules with driver potential to markers for precise drug delivery should increase the number of possible targets in G/GEJ cancer.

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. Japanese Gastric Cancer A (2022) Japanese Gastric Cancer Treatment Guidelines 2021 (6th edition). Gastric Cancer. https://doi.org/10.1007/s10120-022-01331-8

    Article  Google Scholar 

  2. Lordick F, Kang YK, Chung HC et al (2013) 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 14(6):490–499. https://doi.org/10.1016/s1470-2045(13)70102-5

    Article  CAS  PubMed  Google Scholar 

  3. Waddell T, Chau I, Cunningham D et al (2013) 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 14(6):481–489. https://doi.org/10.1016/S1470-2045(13)70096-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Catenacci DVT, Tebbutt NC, Davidenko I et al (2017) Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 18(11):1467–1482. https://doi.org/10.1016/S1470-2045(17)30566-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Shah MA, Bang YJ, Lordick F et al (2017) Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2-negative, MET-positive gastroesophageal adenocarcinoma: the METGastric randomized clinical trial. JAMA Oncol 3(5):620–627. https://doi.org/10.1001/jamaoncol.2016.5580

    Article  PubMed  Google Scholar 

  6. Schirripa M, Lenz HJ (2016) Biomarker in colorectal cancer. Cancer J 22(3):156–164. https://doi.org/10.1097/ppo.0000000000000190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kawakami H, Okamoto I, Arao T et al (2013) MET amplification as a potential therapeutic target in gastric cancer. Oncotarget 4(1):9–17. https://doi.org/10.18632/oncotarget.718

    Article  PubMed  Google Scholar 

  8. Kawakami H, Okamoto I, Okamoto W et al (2014) Targeting MET amplification as a new oncogenic driver. Cancers 6(3):1540–1552. https://doi.org/10.3390/cancers6031540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kawakami H, Okamoto I (2016) MET-targeted therapy for gastric cancer: the importance of a biomarker-based strategy. Gastric Cancer 19(3):687–695. https://doi.org/10.1007/s10120-015-0585-x

    Article  CAS  PubMed  Google Scholar 

  10. Janjigian YY, Sanchez-Vega F, Jonsson P et al (2018) Genetic predictors of response to systemic therapy in esophagogastric cancer. Cancer Discov 8(1):49–58. https://doi.org/10.1158/2159-8290.Cd-17-0787

    Article  CAS  PubMed  Google Scholar 

  11. Katoh M (2019) Fibroblast growth factor receptors as treatment targets in clinical oncology. Nat Rev Clin Oncol 16(2):105–122. https://doi.org/10.1038/s41571-018-0115-y

    Article  CAS  PubMed  Google Scholar 

  12. Matsumoto K, Arao T, Hamaguchi T et al (2012) FGFR2 gene amplification and clinicopathological features in gastric cancer. Br J Cancer 106(4):727–732. https://doi.org/10.1038/bjc.2011.603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Su X, Zhan P, Gavine PR et al (2014) FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study. Br J Cancer 110(4):967–975. https://doi.org/10.1038/bjc.2013.802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hur JY, Chao J, Kim K et al (2020) High-level FGFR2 amplification is associated with poor prognosis and Lower response to chemotherapy in gastric cancers. Pathol Res Pract 216(4):152878. https://doi.org/10.1016/j.prp.2020.152878

    Article  CAS  PubMed  Google Scholar 

  15. Ahn S, Lee J, Hong M et al (2016) FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival. Modern Pathol 29(9):1095–1103. https://doi.org/10.1038/modpathol.2016.96

    Article  CAS  Google Scholar 

  16. Wainberg ZA, Enzinger PC, Kang YK et al (2022) Bemarituzumab in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma (FIGHT): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet Oncol 23(11):1430–1440. https://doi.org/10.1016/s1470-2045(22)00603-9

    Article  CAS  PubMed  Google Scholar 

  17. Smyth EC, Chao J, Muro K et al (2022) Trial in progress: Phase 3 study of bemarituzumab + mFOLFOX6 versus placebo + mFOLFOX6 in previously untreated advanced gastric or gastroesophageal junction (GEJ) cancer with FGFR2b overexpression (FORTITUDE-101). J Clin Oncol 40(16_suppl):TPS4164. https://doi.org/10.1200/JCO.2022.40.16_suppl.TPS4164

    Article  Google Scholar 

  18. Wainberg ZA, Van Cutsem E, Moehler MH et al (2022) Trial in progress: Phase 1b/3 study of bemarituzumab + mFOLFOX6 + nivolumab versus mFOLFOX6 + nivolumab in previously untreated advanced gastric and gastroesophageal junction (GEJ) cancer with FGFR2b overexpression (FORTITUDE-102). J Clin Oncol 40(16 suppl):TPS4165. https://doi.org/10.1200/JCO.2022.40.16_suppl.TPS4165

    Article  Google Scholar 

  19. Goyal L, Meric-Bernstam F, Hollebecque A et al (2023) Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma. N Engl J Med 388(3):228–239. https://doi.org/10.1056/NEJMoa2206834

    Article  CAS  PubMed  Google Scholar 

  20. Meric-Bernstam F, Bahleda R, Hierro C et al (2022) Futibatinib, an irreversible FGFR1-4 inhibitor, in patients with advanced solid tumors harboring FGF/FGFR aberrations: a phase I dose-expansion study. Cancer Discov 12(2):402–415. https://doi.org/10.1158/2159-8290.CD-21-0697

    Article  CAS  PubMed  Google Scholar 

  21. Zhang L, Yang J, Cai J et al (2013) A subset of gastric cancers with EGFR amplification and overexpression respond to cetuximab therapy. Sci Rep 3:2992. https://doi.org/10.1038/srep02992

    Article  PubMed  PubMed Central  Google Scholar 

  22. Luber B, Deplazes J, Keller G et al (2011) Biomarker analysis of cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric and oesophago-gastric junction cancer: results from a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO). BMC Cancer 11:509. https://doi.org/10.1186/1471-2407-11-509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nakamura Y, Sasaki A, Yukami H et al (2020) Emergence of concurrent multiple EGFR mutations and MET amplification in a patient with EGFR-amplified advanced gastric cancer treated with cetuximab. JCO Precis Oncol. https://doi.org/10.1200/PO.20.00263

    Article  PubMed  PubMed Central  Google Scholar 

  24. Takegawa N, Tsurutani J, Kawakami H et al (2019) [fam-] trastuzumab deruxtecan, antitumor activity is dependent on HER2 expression level rather than on HER2 amplification. Int J Cancer Journal international du cancer 145(12):3414–3424. https://doi.org/10.1002/ijc.32408

    Article  CAS  PubMed  Google Scholar 

  25. Shitara K, Bang YJ, Iwasa S et al (2020) Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med 382(25):2419–2430. https://doi.org/10.1056/NEJMoa2004413

    Article  CAS  PubMed  Google Scholar 

  26. Qiu MZ, Zhang Y, Guo Y et al (2022) Evaluation of safety of treatment with anti-epidermal growth factor receptor antibody Drug conjugate MRG003 in patients with advanced solid tumors: a phase 1 nonrandomized clinical trial. JAMA Oncol 8(7):1042–1046. https://doi.org/10.1001/jamaoncol.2022.0503

    Article  PubMed  PubMed Central  Google Scholar 

  27. Van Cutsem E, Karaszewska B, Kang YK et al (2019) A multicenter phase II study of AMG 337 in patients with MET-amplified gastric/gastroesophageal junction/esophageal adenocarcinoma and other MET-amplified solid tumors. Clin Cancer Res 25(8):2414–2423. https://doi.org/10.1158/1078-0432.Ccr-18-1337

    Article  PubMed  Google Scholar 

  28. Shah MA, Wainberg ZA, Catenacci DV et al (2013) Phase II study evaluating 2 dosing schedules of oral foretinib (GSK1363089), cMET/VEGFR2 inhibitor, in patients with metastatic gastric cancer. PLoS ONE 8(3):e54014. https://doi.org/10.1371/journal.pone.0054014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pant S, Patel M, Kurkjian C et al (2017) A phase II study of the c-Met inhibitor tivantinib in combination with FOLFOX for the treatment of patients with previously untreated metastatic adenocarcinoma of the distal esophagus, gastroesophageal junction, or stomach. Cancer Invest 35(7):463–472. https://doi.org/10.1080/07357907.2017.1337782

    Article  PubMed  Google Scholar 

  30. Lee J, Kim ST, Kim K et al (2019) Tumor genomic profiling guides patients with metastatic gastric cancer to targeted treatment: the VIKTORY umbrella trial. Cancer Discov 9(10):1388–1405. https://doi.org/10.1158/2159-8290.CD-19-0442

    Article  CAS  PubMed  Google Scholar 

  31. Paik PK, Felip E, Veillon R et al (2020) Tepotinib in non-small-cell lung cancer with MET Exon 14 skipping mutations. N Engl J Med 383(10):931–943. https://doi.org/10.1056/NEJMoa2004407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cho BC, Felip E, Spira AI et al (2023) LBA14 Amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Primary results from MARIPOSA, a phase III, global, randomized, controlled trial. Ann Oncol 34:S1306. https://doi.org/10.1016/j.annonc.2023.10.062

    Article  Google Scholar 

  33. Tsukita S, Tanaka H, Tamura A (2019) The claudins: from tight junctions to biological systems. Trends Biochem Sci 44(2):141–152. https://doi.org/10.1016/j.tibs.2018.09.008

    Article  CAS  PubMed  Google Scholar 

  34. Morin PJ (2005) Claudin proteins in human cancer: promising new targets for diagnosis and therapy. Cancer Res 65(21):9603–9606. https://doi.org/10.1158/0008-5472.CAN-05-2782

    Article  CAS  PubMed  Google Scholar 

  35. Moran D, Maurus D, Rohde C et al (2018) Prevalence of CLDN18.2, HER2 and PD-L1 in gastric cancer samples. Ann Oncol 29:32. https://doi.org/10.1093/annonc/mdy269.101

    Article  Google Scholar 

  36. Pellino A, Brignola S, Riello E et al (2021) Association of CLDN18 protein expression with clinicopathological features and prognosis in advanced gastric and gastroesophageal junction adenocarcinomas. J Pers Med 11(11):1095

    Article  PubMed  PubMed Central  Google Scholar 

  37. Kubota Y, Kawazoe A, Mishima S et al (2023) Comprehensive clinical and molecular characterization of claudin 18.2 expression in advanced gastric or gastroesophageal junction cancer. ESMO Open 8(1):100762. https://doi.org/10.1016/j.esmoop.2022.100762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sahin U, Schuler M, Richly H et al (2018) A phase I dose-escalation study of IMAB362 (Zolbetuximab) in patients with advanced gastric and gastro-oesophageal junction cancer. Eur J Cancer 100:17–26. https://doi.org/10.1016/j.ejca.2018.05.007

    Article  CAS  PubMed  Google Scholar 

  39. Sahin U, Türeci Ö, Manikhas G et al (2021) FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol MO 32(5):609–619. https://doi.org/10.1016/j.annonc.2021.02.005

    Article  CAS  Google Scholar 

  40. Shitara K, Lordick F, Bang YJ et al (2023) Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet 401(10389):1655–1668. https://doi.org/10.1016/S0140-6736(23)00620-7

    Article  CAS  PubMed  Google Scholar 

  41. Shah MA, Shitara K, Ajani JA et al (2023) Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med. https://doi.org/10.1038/s41591-023-02465-7

    Article  PubMed  PubMed Central  Google Scholar 

  42. Xu R-h, Wei X, Zhang D et al (2023) A phase 1a dose-escalation, multicenter trial of anti-claudin 18.2 antibody drug conjugate CMG901 in patients with resistant/refractory solid tumors. J Clin Oncol 41(4_suppl):352–352. https://doi.org/10.1200/JCO.2023.41.4_suppl.352

    Article  Google Scholar 

  43. Yk W, Gong J, Sun Y et al (2023) Interim results of a first-in-human phase 1 study of Q-1802, a CLDN18.2/PD-L1 bsABs, in patients with relapsed or refractory solid tumors. J Clin Oncol 41(4 suppl):382–382. https://doi.org/10.1200/JCO.2023.41.4_suppl.382

    Article  Google Scholar 

  44. Qi C, Gong J, Li J et al (2022) Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat Med 28(6):1189–1198. https://doi.org/10.1038/s41591-022-01800-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Liu J, Xiao Q, Xiao J et al (2022) Wnt/beta-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther 7(1):3. https://doi.org/10.1038/s41392-021-00762-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Klempner SJ, Chao J, Uronis HE et al (2022) DKN-01 and tislelizumab ± chemotherapy as a first-line (1L) and second-line (2L) investigational therapy in advanced gastroesophageal adenocarcinoma (GEA): DisTinGuish Trial. J Clin Oncol 40(4_suppl):292–292. https://doi.org/10.1200/JCO.2022.40.4_suppl.292

    Article  Google Scholar 

  47. Klempner SJ, Chao J, Uronis H et al (2022) 1213P DKN-01 and tislelizumab + chemotherapy as first-line (1L) investigational therapy in advanced gastroesophageal adenocarcinoma (GEA): DisTinGuish trial. Ann Oncol 33:S1103–S1104. https://doi.org/10.1016/j.annonc.2022.07.1331

    Article  Google Scholar 

  48. Trerotola M, Cantanelli P, Guerra E et al (2013) Upregulation of Trop-2 quantitatively stimulates human cancer growth. Oncogene 32(2):222–233. https://doi.org/10.1038/onc.2012.36

    Article  CAS  PubMed  Google Scholar 

  49. Cardillo TM, Govindan SV, Sharkey RM et al (2011) Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys. Clin Cancer Res 17(10):3157–3169. https://doi.org/10.1158/1078-0432.Ccr-10-2939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cubas R, Li M, Chen C et al (2009) Trop2: a possible therapeutic target for late stage epithelial carcinomas. Biochem Biophys Acta 1796(2):309–314. https://doi.org/10.1016/j.bbcan.2009.08.001

    Article  CAS  PubMed  Google Scholar 

  51. Bardia A, Hurvitz SA, Tolaney SM et al (2021) Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med 384(16):1529–1541. https://doi.org/10.1056/NEJMoa2028485

    Article  CAS  PubMed  Google Scholar 

  52. Tagawa ST, Balar AV, Petrylak DP et al (2021) TROPHY-U-01: a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol 39(22):2474–2485. https://doi.org/10.1200/jco.20.03489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kushiyama S, Yashiro M, Yamamoto Y et al (2021) Clinicopathologic significance of TROP2 and phospho-TROP2 in gastric cancer. Mol Clin Oncol 14(5):105. https://doi.org/10.3892/mco.2021.2267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Beauchemin N, Arabzadeh A (2013) Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in cancer progression and metastasis. Cancer Metastasis Rev 32(3–4):643–671. https://doi.org/10.1007/s10555-013-9444-6

    Article  CAS  PubMed  Google Scholar 

  55. Thomas J, Klebanov A, John S et al (2023) CEACAMS 1, 5, and 6 in disease and cancer: interactions with pathogens. Genes Cancer 14:12–29. https://doi.org/10.18632/genesandcancer.230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-sayama, 589-8511, Japan

    Hisato Kawakami

Authors
  1. Hisato Kawakami
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hisato Kawakami.

Ethics declarations

Conflict of interest

The author has received consulting or advisory fees from Astellas Pharma Inc. and Daiichi-Sankyo Co. Ltd.; honoraria from Bristol-Myers Squibb Co. Ltd., Ono Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., MSD K.K., Chugai Pharmaceutical Co. Ltd., Daiichi-Sankyo Co. Ltd., Merck Biopharma Co. Ltd., Takeda Pharmaceutical Co. Ltd., Yakult Pharmaceutical Industry, Taiho Pharmaceutical Co. Ltd., and Nippon Kayaku Co. Ltd.; and research funding from Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Kobayashi Pharmaceutical Co. Ltd., and Eisai Co. Ltd.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kawakami, H. New therapeutic target molecules for gastric and gastroesophageal junction cancer. Int J Clin Oncol (2024). https://doi.org/10.1007/s10147-024-02521-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10147-024-02521-3

Keywords

Search

Navigation