Review

*Author for correspondence: Tel.: +90 505 884 2694;

Department of Internal Medicine, Division of Medical Oncology, Ondokuz Mayıs University, Faculty of Medicine, Samsun, 55280, Turkey

Search for more papers by this author

Chiara A Wabl

https://orcid.org/0000-0002-7167-5895

University of California, San Francisco, School of Medicine, San Francisco, CA 94143, USA

Search for more papers by this author

Ozge Gumusay

https://orcid.org/0000-0002-6236-9829

Department of Internal Medicine, Division of Medical Oncology, School of Medicine, Acibadem University, Istanbul, 34752, Turkey

Search for more papers by this author

Published Online:9 Jun 2023https://doi.org/10.2217/imt-2022-0287

View article

Abstract

The impact of checkpoint inhibitors on gastroesophageal cancer treatment has been tremendous in the last 2 years. KEYNOTE-590, CHECKMATE 649 and CheckMate 648 are landmark trials that have introduced immunotherapy to the field as first-line therapy, leading to a paradigm change for advanced esophageal and gastric cancer. Chemotherapy in combination with immunotherapy is now the standard of care for first-line treatment of locally advanced or metastatic adenocarcinoma of the esophagus, esophagogastric junction and stomach. Several new targets and treatments are available for gastroesophageal cancer that are based on the characterization of cancer cells and the tumor microenvironment. Biomarker-based therapy selection is critical to optimize outcomes and minimize toxicities, as well as give insight into the optimal timing and sequence of a patient's treatment course.

Plain language summary

Doctors have found a better treatment for advanced esophageal and stomach cancer. They combined two types of medicines called immune checkpoint inhibitors and chemotherapy. This made more people respond to the treatment and live longer without the cancer getting worse. They use a test called PD-L1 Combined Positive Score to see if the treatment will work but, when looking at the results, there remain challenges and new treatments and tests are still needed for these cancers.

Keywords:

Papers of special note have been highlighted as: •• of considerable interest

References

1. Wagner AD, Syn NL, Moehler M et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst. Rev. 8(8), (2017).
MedlineGoogle Scholar
2. Davidson M, Chau I, Cunningham D et al. Impact of tumour histological subtype on chemotherapy outcome in advanced oesophageal cancer. World J. Gastrointest. Oncol. 9(8), 333–340 (2017).
MedlineGoogle Scholar
3. Lordick F, Kang YK, Chung HC 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. 14(6), 490–499 (2013).
Medline CASGoogle Scholar
4. Catenacci DVT, Tebbutt NC, Davidenko I et al. 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 (2017).
Medline CASGoogle Scholar
5. Shah MA, Bang YJ, Lordick F et al. 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 (2017).
MedlineGoogle Scholar
6. Fuchs CS, Shitara K, Di Bartolomeo M et al. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 20(3), 420–435 (2019).
Medline CASGoogle Scholar
7. Jin Z, Yoon HH. The promise of PD-1 inhibitors in gastro-esophageal cancers: microsatellite instability vs. PD-L1. J. Gastrointest. Oncol. 7(5), 771–788 (2016).
MedlineGoogle Scholar
8. Liu X, Choi MG, Kim K et al. High PD-L1 expression in gastric cancer (GC) patients and correlation with molecular features. Pathol. Res. Pract. 216(4), 152881 (2020).
Medline CASGoogle Scholar
9. Zhou KI, Peterson B, Serritella A et al. Spatial and temporal heterogeneity of PD-L1 expression and tumor mutational burden in gastroesophageal adenocarcinoma at baseline diagnosis and after chemotherapy. Clin. Cancer Res. 26(24), 6453–6463 (2020).
Medline CASGoogle Scholar
10. Schrock AB, Ouyang C, Sandhu J et al. Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer. Ann. Oncol. 30(7), 1096–1103 (2019).
Medline CASGoogle Scholar
11. Samstein RM, Lee CH, Shoushtari AN et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 51(2), 202–206 (2019).
Medline CASGoogle Scholar
12. Hutter C, Zenklusen JC. The Cancer Genome Atlas: creating lasting value beyond its data. Cell 173(2), 283–285 (2018).
Medline CASGoogle Scholar
13. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513(7517), 202–209 (2014).
MedlineGoogle Scholar
14. Nakamura Y, Kawazoe A, Lordick F, Janjigian YY, Shitara K. Biomarker-targeted therapies for advanced-stage gastric and gastro-oesophageal junction cancers: an emerging paradigm. Nat. Rev. Clin. Oncol. 18(8), 473–487 (2021).
MedlineGoogle Scholar
15. Kawazoe A, Kuwata T, Kuboki Y 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 20(3), 407–415 (2017).
Medline CASGoogle Scholar
16. Janjigian YY, Sanchez-Vega F, Jonsson P et al. Genetic predictors of response to systemic therapy in esophagogastric cancer. Cancer Discov. 8(1), 49–58 (2018).
Medline CASGoogle Scholar
17. Kim ST, Cristescu R, Bass AJ et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat. Med. 24(9), 1449–1458 (2018).
Medline CASGoogle Scholar
18. Kwon M, An M, Klempner SJ et al. Determinants of response and intrinsic resistance to PD-1 blockade in microsatellite instability-high gastric cancer. Cancer Discov. 11(9), 2168–2185 (2021).
Medline CASGoogle Scholar
19. Hsiehchen D, Hsieh A, Samstein RM et al. DNA repair gene mutations as predictors of immune checkpoint inhibitor response beyond tumor mutation burden. Cell Rep. Med. 1(3), 100034(2020).
Medline CASGoogle Scholar
20. Sun JM, Shen L, Shah MA et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet 398(10302), 759–771 (2021). •• This study ultimately resulted in the US FDA approval of pembrolizumab in addition to chemotherapy for the first-line treatment of esophageal cancer.
Medline CASGoogle Scholar
21. Metges J-P, Kato K, Sun J-M et al. First-line pembrolizumab plus chemotherapy versus chemotherapy in advanced esophageal cancer: longer-term efficacy, safety, and quality-of-life results from the phase 3 KEYNOTE-590 study. J. Clin. Oncol. 40(Suppl. 4), 241 (2022).
Google Scholar
22. Chau I, Doki Y, Ajani JA et al. Nivolumab (NIVO) plus ipilimumab (IPI) or NIVO plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): first results of the CheckMate 648 study. J. Clin. Oncol. 39(Suppl. 18), LBA4001 (2021).
Google Scholar
23. Doki Y, Ajani JA, Kato K et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N. Engl. J. Med. 386(5), 449–462 (2022). •• First-line treatment of advanced esophageal squamous cell carcinoma with either nivolumab plus chemotherapy or nivolumab plus ipilimumab resulted in a significant overall survival benefit.
Medline CASGoogle Scholar
24. Luo H, Lu J, Bai Y et al. Effect of camrelizumab vs placebo added to chemotherapy on survival and progression-free survival in patients with advanced or metastatic esophageal squamous cell carcinoma: the ESCORT-1st randomized clinical trial. JAMA 326(10), 916–925 (2021).
Medline CASGoogle Scholar
25. Lu Z, Wang J, Shu Y et al. Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial. BMJ 377, e068714 (2022).
MedlineGoogle Scholar
26. Xu R, Wang F, Cui C et al. 1373MO JUPITER-06: a randomized, double-blind, phase III study of toripalimab versus placebo in combination with first-line chemotherapy for treatment naive advanced or metastatic esophageal squamous cell carcinoma (ESCC). Ann. Oncol. 32, S1041 (2021).
CASGoogle Scholar
27. Shen L, Lu Z, Wang J et al. Sintilimab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced or metastatic esophageal squamous cell cancer: first results of the phase III ORIENT-15 study. Ann. Oncol. 32, S1330 (2021).
Google Scholar
28. Janjigian YY, Shitara K, Moehler M et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 398(10294), 27–40 (2021). •• Checkmate 649 was a pivotal trial that resulted in US FDA approval of nivolumab for advanced esophagogastric adenocarcinoma.
Medline CASGoogle Scholar
29. Shitara K, Janjigian YY, Moehler MH et al. Nivolumab (NIVO) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): expanded efficacy, safety, and subgroup analyses from CheckMate 649. J. Clin. Oncol. 40(Suppl. 4), 240 (2022).
Google Scholar
30. Zhao JJ, Yap DWT, Chan YH et al. Low programmed death-ligand 1-expressing subgroup outcomes of first-line immune checkpoint inhibitors in gastric or esophageal adenocarcinoma. J. Clin. Oncol. 40(4), 392–402 (2022).
Medline CASGoogle Scholar
31. Xu J, Jiang H, Pan Y et al. Sintilimab plus chemotherapy (chemo) versus chemo as first-line treatment for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (ORIENT-16): first results of a randomized, double-blind, phase III study. Ann. Oncol. 32, S1331 (2021).
Google Scholar
32. Boku N, Ryu MH, Kato K et al. Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4). Ann. Oncol. 30(2), 250–258 (2019).
Medline CASGoogle Scholar
33. Boku N, Ryu M, Oh D et al. Nivolumab plus chemotherapy versus chemotherapy alone in patients with previously untreated advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer: ATTRACTION-4 (ONO-4538-37) study. Ann. Oncol. 31, S1192 (2020).
Google Scholar
34. Shitara K, Van Cutsem E, Bang YJ et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol. 6(10), 1571–1580 (2020).
MedlineGoogle Scholar
35. Lee KW, Van Cutsem E, Bang YJ et al. Association of tumor mutational burden with efficacy of pembrolizumab ± chemotherapy as first-line therapy for gastric cancer in the phase III KEYNOTE-062 study. Clin. Cancer Res. 28(16), 3489–3498 (2022).
Medline CASGoogle Scholar
36. Rha S, Wyrwicz L, Weber P et al. VP1-2023: pembrolizumab (pembro) plus chemotherapy (chemo) as first-line therapy for advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) cancer: phase III KEYNOTE-859 study. Ann. Oncol. 34(3), 319–320 (2023).
Google Scholar
37. Zhang T, Song X, Xu L et al. The binding of an anti-PD-1 antibody to FcγRI has a profound impact on its biological functions. Cancer Immunol. Immunother. 67(7), 1079–1090 (2018).
Medline CASGoogle Scholar
38. Moehler MH, Kato K, Arkenau H-T et al. Rationale 305: Phase 3 study of tislelizumab plus chemotherapy vs placebo plus chemotherapy as first-line treatment (1L) of advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC).J. Clin. Oncol. 41(Suppl. 4), 286 (2023).
Google Scholar
39. Ajani J, D'Amico T, Bentrem D et al. Esophageal and Esophagogastric Junction Cancers, version 4.2021, NCCN Clinical Practice Guidelines in Oncology. J. Natl Compr. Cancer Netw 17(7), 855–883 (2021).
Google Scholar
40. Ajani JA, D'Amico TA, Bentrem DJ et al. Gastric Cancer, version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J. Natl Compr. Canc. Netw. 20(2), 167–192 (2022).
Medline CASGoogle Scholar
41. Van Cutsem E, Bang YJ, Feng-Yi F et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer 18(3), 476–484 (2015).
Medline CASGoogle Scholar
42. Bang YJ, Van Cutsem E, Feyereislova 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 376(9742), 687–697 (2010).
Medline CASGoogle Scholar
43. Seo S, Ryu MH, Park YS et al. Loss of HER2 positivity after anti-HER2 chemotherapy in HER2-positive gastric cancer patients: results of the GASTric cancer HER2 reassessment study 3 (GASTHER3). Gastric Cancer 22(3), 527–535 (2019).
Medline CASGoogle Scholar
44. Pietrantonio F, Fucà G, Morano F et al. Biomarkers of primary resistance to trastuzumab in HER2-positive metastatic gastric cancer patients: the AMNESIA case-control study. Clin. Cancer Res. 24(5), 1082–1089 (2018).
Medline CASGoogle Scholar
45. Kim J, Fox C, Peng S et al. Preexisting oncogenic events impact trastuzumab sensitivity in ERBB2-amplified gastroesophageal adenocarcinoma. J. Clin. Invest. 124(12), 5145–5158 (2014).
MedlineGoogle Scholar
46. Janjigian YY, Maron SB, Chatila WK et al. First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial. Lancet Oncol. 21(6), 821–831 (2020).
Medline CASGoogle Scholar
47. Varadan V, Gilmore H, Miskimen KL et al. Immune signatures following single dose trastuzumab predict pathologic response to preoperativetrastuzumab and chemotherapy in HER2-positive early breast cancer. Clin. Cancer Res. 22(13), 3249–3259 (2016).
Medline CASGoogle Scholar
48. Taylor C, Hershman D, Shah N et al. Augmented HER-2 specific immunity during treatment with trastuzumab and chemotherapy. Clin. Cancer Res. 13(17), 5133–5143 (2007).
Medline CASGoogle Scholar
49. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer 12(4), 237–251 (2012).
Medline CASGoogle Scholar
50. Kim R, An M, Lee H et al. Early tumor-immune microenvironmental remodeling and response to first-line fluoropyrimidine and platinum chemotherapy in advanced gastric cancer. Cancer Discov. 12(4), 984–1001 (2022).
Medline CASGoogle Scholar
51. Stein A, Paschold L, Tintelnot J et al. Efficacy of ipilimumab vs FOLFOX in combination with nivolumab and trastuzumab in patients with previously untreated ERBB2-positive esophagogastric adenocarcinoma: the AIO INTEGA randomized clinical trial. JAMA Oncol. 8(8), 1150–1158 (2022).
MedlineGoogle Scholar
52. Janjigian YY, Kawazoe A, Yanez PE et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) cancer: initial findings of the global phase 3 KEYNOTE-811 study. J. Clin. Oncol. 39(Suppl. 15), 4013 (2021).
Google Scholar
53. Shitara K, Bang YJ, Iwasa S et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N. Engl. J. Med. 382(25), 2419–2430 (2020).
Medline CASGoogle Scholar
54. Kumagai K, Aida T, Tsuchiya Y, Kishino Y, Kai K, Mori K. Interstitial pneumonitis related to trastuzumab deruxtecan, a human epidermal growth factor receptor 2-targeting Ab-drug conjugate, in monkeys. Cancer Sci. 111(12), 4636–4645 (2020).
Medline CASGoogle Scholar
55. Nordstrom JL, Gorlatov S, Zhang W et al. Anti-tumor activity and toxicokinetics analysis of MGAH22, an anti-HER2 monoclonal antibody with enhanced Fcγ receptor binding properties. Breast Cancer Res. 13(6), R123 (2011).
Medline CASGoogle Scholar
56. Liu L, Yang Y, Burns R et al. Margetuximab mediates greater Fc-dependent anti-tumor activities than trastuzumab or pertuzumab in vitro. Cancer Res. 79(Suppl. 13), 1538 (2019).
Google Scholar
57. Catenacci DVT, Kang YK, Park H et al. Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22-05): a single-arm, phase 1b-2 trial. Lancet Oncol. 21(8), 1066–1076 (2020).
Medline CASGoogle Scholar
58. Meric-Bernstam F, Hamilton EP, Beeram M et al. Zanidatamab (ZW25) in HER2-expressing gastroesophageal adenocarcinoma (GEA): results from a phase I study. J. Clin. Oncol. 39(Suppl. 3), 164 (2021).
Google Scholar
59. Ku G, Elimova E, Denlinger C et al. 1380P Phase (Ph) II study of zanidatamab + chemotherapy (chemo) in first-line (1L) HER2 expressing gastroesophageal adenocarcinoma (GEA). Ann. Oncol. 32, S1044–S1045 (2021).
Google Scholar
60. Kauder SE, Kuo TC, Harrabi O et al. ALX148 blocks CD47 and enhances innate and adaptive antitumor immunity with a favorable safety profile. PLOS ONE 13(8), e0201832 (2018).
MedlineGoogle Scholar
61. Chung H, Lee K, Kim W et al. SO-31 ASPEN-01: a phase 1 study of ALX148, a CD47 blocker, in combination with trastuzumab, ramucirumab and paclitaxel in patients with second-line HER2-positive advanced gastric or gastroesophageal junction cancer. Ann. Oncol. 32, S215–S216 (2021).
Google Scholar
62. Wilke H, Muro K, Van Cutsem E 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. 15(11), 1224–1235 (2014).
Medline CASGoogle Scholar
63. Ku G, Bendell J, Tolcher A et al. 525O A phase I dose escalation study of PRS-343, a HER2/4-1BB bispecific molecule, in patients with HER2-positive malignancies. Ann. Oncol. 31, S462–S463 (2020).
Google Scholar
64. Wiedermann U, Garner-Spitzer E, Chao Y et al. Clinical and immunologic responses to a B-cell epitope vaccine in patients with HER2/neu-overexpressing advanced gastric cancer-results from phase Ib trial IMU.ACS.001. Clin. Cancer Res. 27(13), 3649–3660 (2021).
Medline CASGoogle Scholar
65. Maglakelidze M, Ryspayeva DE, Andric Z et al. HERIZON: A phase 2 study of HER-Vaxx (IMU-131), a HER2-targeting peptide vaccine, plus standard of care chemotherapy in patients with HER2-overexpressing metastatic or advanced gastric/GEJ adenocarcinoma–overall survival analysis. J. Clin Oncol. 41(Suppl. 4), 289 (2023).
Google Scholar
66. Reiss K, Yuan Y, Barton D et al. A phase 1 first in human study of adenovirally transduced anti-HER2 CAR macrophages in subjects with HER2 overexpressing solid tumors: preliminary safety, pharmacokinetics, and TME reprogramming data. J Immunother Cancer. 9(Suppl. 2), A1–A1054 (2021).
Google Scholar
67. Hause RJ, Pritchard CC, Shendure J, Salipante SJ. Classification and characterization of microsatellite instability across 18 cancer types. Nat. Med. 22(11), 1342–1350 (2016).
Medline CASGoogle Scholar
68. Fuchs CS, Doi T, Jang RW et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 4(5), e180013 (2018).
MedlineGoogle Scholar
69. Shitara K, Özgüroğlu M, Bang YJ et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet 392(10142), 123–133 (2018).
Medline CASGoogle Scholar
70. Chao J, Fuchs CS, Shitara K et al. Assessment of pembrolizumab therapy for the treatment of microsatellite instability-high gastric or gastroesophageal junction cancer among patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 clinical trials. JAMA Oncol. 7(6), 895–902 (2021).
MedlineGoogle Scholar
71. Kato K, Ajani JA, Doki Y et al. Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): 29-month (mo) follow-up from CheckMate 648. J. Clin. Oncol. 41(Suppl. 4), 290 (2023).
Google Scholar
72. Catenacci DVT, Moya S, Lomnicki S et al. Personalized Antibodies for Gastroesophageal Adenocarcinoma (PANGEA): a phase II study evaluating an individualized treatment strategy for metastatic disease. Cancer Discov. 11(2), 308–325 (2021).
Medline CASGoogle Scholar
73. Amin M, Lockhart AC. The potential role of immunotherapy to treat colorectal cancer. Exp. Opin. Investig. Drugs 24(3), 329–344 (2015).
Medline CASGoogle Scholar
74. Kang YK, Boku N, Satoh T et al. 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. Lancet 390(10111), 2461–2471 (2017).
Medline CASGoogle Scholar
75. Bang YJ, Ruiz EY, Van Cutsem E et al. Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann. Oncol. 29(10), 2052–2060 (2018).
MedlineGoogle Scholar
76. Weber JS, Kudchadkar RR, Yu B et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J. Clin. Oncol. 31(34), 4311–4318 (2013).
Medline CASGoogle Scholar
77. Zitvogel L, Galluzzi L, Smyth MJ, Kroemer G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 39(1), 74–88 (2013).
Medline CASGoogle Scholar
78. Opzoomer JW, Sosnowska D, Anstee JE, Spicer JF, Arnold JN. Cytotoxic chemotherapy as an immune stimulus: a molecular perspective on turning up the immunological heat on cancer. Front. Immunol. 10, 1654 (2019).
Medline CASGoogle Scholar
79. Kelly RJ, Lee J, Bang YJ et al. Safety and efficacy of durvalumab and tremelimumab alone or in combination in patients with advanced gastric and gastroesophageal junction adenocarcinoma. Clin. Cancer Res. 26(4), 846–854 (2020).
Medline CASGoogle Scholar
80. Janjigian Y, Ajani J, Moehler M et al. LBA7 Nivolumab (NIVO) plus chemotherapy (Chemo) or ipilimumab (IPI) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): checkMate 649 study. Ann. Oncol. 32, S1329–S1330 (2021).
Google Scholar
81. Janjigian YY, Bendell J, Calvo E et al. CheckMate-032 Study: efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer. J. Clin. Oncol. 36(28), 2836–2844 (2018).
Medline CASGoogle Scholar
82. Popovic A, Jaffee EM, Zaidi N. Emerging strategies for combination checkpoint modulators in cancer immunotherapy. J. Clin. Invest. 128(8), 3209–3218 (2018).
MedlineGoogle Scholar
83. Wainberg Z, Matos I, Delord J et al. LBA-5 Phase Ib study of the anti-TIGIT antibody tiragolumab in combination with atezolizumab in patients with metastatic esophageal cancer. Ann. Oncol. 32, S227–S228 (2021).
Google Scholar
84. Dovedi SJ, Elder MJ, Yang C et al. Design and efficacy of a monovalent bispecific PD-1/CTLA4 antibody that enhances CTLA4 blockade on PD-1(+) activated T cells. Cancer Discov. 11(5), 1100–1117 (2021).
Medline CASGoogle Scholar
85. Ji J, Shen L, Gao X et al. A phase Ib/II, multicenter, open-label study of AK104, a PD-1/CTLA-4 bispecific antibody, combined with chemotherapy (chemo) as first-line therapy for advanced gastric (G) or gastroesophageal junction (GEJ) cancer. J. Clin. Oncol. 40(Suppl. 4), 308 (2022).
Google Scholar
86. Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat. Rev. Clin. Oncol. 15(5), 325–340 (2018).
Medline CASGoogle Scholar
87. Chau I, Penel N, Soriano AO et al. Ramucirumab in combination with pembrolizumab in treatment-naïve advanced gastric or GEJ adenocarcinoma: safety and antitumor activity from the phase 1a/b JVDF trial. Cancers (Basel) 12(10), 2985(2020).
Medline CASGoogle Scholar
88. Hara H, Shoji H, Takahari D et al. Phase I/II study of ramucirumab plus nivolumab in patients in second-line treatment for advanced gastric adenocarcinoma (NivoRam study). J. Clin. Oncol. 37(Suppl. 4), 129 (2019).
Google Scholar
89. Bang Y-J, Golan T, Lin C-C et al. Interim safety and clinical activity in patients (pts) with locally advanced and unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma from a multicohort phase I study of ramucirumab (R) plus durvalumab (D). J. Clin. Oncol. 36(Suppl. 4), 92 (2018).
Google Scholar
90. Nakajima TE, Kadowaki S, Minashi K et al. Multicenter phase I/II study of nivolumab combined with paclitaxel plus ramucirumab as second-line treatment in patients with advanced gastric cancer. Clin. Cancer Res. 27(4), 1029–1036 (2021).
Medline CASGoogle Scholar
91. Fukuoka S, Hara H, Takahashi N et al. Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase Ib trial (REGONIVO, EPOC1603). J. Clin. Oncol. 38(18), 2053–2061 (2020).
Medline CASGoogle Scholar
92. Kawazoe A, Fukuoka S, Nakamura Y et al. Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial. Lancet Oncol. 21(8), 1057–1065 (2020).
Medline CASGoogle Scholar
93. Cohen DJ, Tabernero J, Van Cutsem E et al. A randomized phase 3 study evaluating the efficacy and safety of first-line pembrolizumab plus lenvatinib plus chemotherapy versus chemotherapy in patients with advanced/metastatic gastroesophageal adenocarcinoma: LEAP-015. J. Clin. Oncol. 40(Suppl. 4), TPS369 (2022).
Google Scholar
94. Yanez PE, Ben-Aharon I, Rojas C et al. First-line lenvatinib plus pembrolizumab plus chemotherapy versus chemotherapy in advanced/metastatic gastroesophageal adenocarcinoma (LEAP-015): safety run-in results. J. Clin. Oncol. 41(Suppl. 4), 411 (2023).
Google Scholar
95. Chen X, Wang D, Yuan Y et al. Tislelizumab combined with anlotinib and chemotherapy (XELOX) in the treatment of advanced gastric carcinoma: preliminary results of a single-arm, open-label phase I/IIa trial (TALENT study). J. Clin. Oncol. 41(Suppl. 4), 396 (2023).
Google Scholar
96. Sahin U, Koslowski M, Dhaene K et al. Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development. Clin. Cancer Res. 14(23), 7624–7634 (2008).
Medline CASGoogle Scholar
97. Singh P, Toom S, Huang Y. Anti-claudin 18.2 antibody as new targeted therapy for advanced gastric cancer. J. Hematol. Oncol. 10(1), 105 (2017).
MedlineGoogle Scholar
98. Türeci O, Sahin U, Schulze-Bergkamen H et al. A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study. Ann. Oncol. 30(9), 1487–1495 (2019).
MedlineGoogle Scholar
99. Shah MA, Ajani JA, Al-Batran S-E et al. Zolbetuximab + CAPOX versus CAPOX in first-line treatment of claudin18. 2+/HER2-advanced/metastatic gastric or gastroesophageal junction adenocarcinoma: GLOW phase 3 study. J. Clin. Oncol. 40(Suppl. 4), TPS365 (2022).
Google Scholar
100. Qi C, Gong J, Li J et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat. Med. 28(6), 1189–1198 (2022).
Medline CASGoogle Scholar
101. Wainberg ZA, Enzinger PC, Kang Y-K et al. Randomized double-blind placebo-controlled phase 2 study of bemarituzumab combined with modified FOLFOX6 (mFOLFOX6) in first-line (1L) treatment of advanced gastric/gastroesophageal junction adenocarcinoma (FIGHT). J. Clin. Oncol. 39(Suppl. 3), 160 (2021).
Google Scholar

Vol. 15, No. 12

Metrics

Downloaded 229 times

History

Received 26 November 2022

Accepted 11 May 2023

Published online 9 June 2023

Published in print August 2023

Information

Keywords

Author contributions

All authors equally contributed to the conceptualization, research and analysis of the results. CA Wabl and O Gumusay O contributed to the writing of the manuscript.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

PDF download

Advancing immunotherapy in gastroesophageal cancer through rational combinations and biomarkers

Abstract

Plain language summary

References