We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine
Published Online:https://doi.org/10.2217/pgs-2020-0090

Advanced esophago-gastric (OG) adenocarcinomas have a high mortality rate and new therapeutic options are urgently required. Despite recent advances in understanding the molecular characteristics of OG cancers, tumor heterogeneity poses a challenge in developing new therapeutics capable of improving patient outcomes. Consequently, chemotherapy remains the mainstay of systemic treatment, with the HER2 being the only predictive biomarker routinely targeted in clinical practice. Recent data indicate that immunotherapy will be incorporated into first-line chemotherapy, but further research is required to refine patient selection. This review will summarize the clinical strategies being evaluated to utilize our knowledge of predictive biomarkers with reference to novel therapeutics, and discuss the barriers to implementing precision oncology in OG adenocarcinoma.

References

  • 1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68(6), 394–424 (2018).
  • 2. Wagner AD, Syn NLX, Moehler M et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst. Rev. 8(8), CD004064 (2017).
  • 3. 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-esophageal junction cancer (ToGA): a Phase III, open-label, randomized controlled trial. Lancet 376(9742), 687–697 (2010).
  • 4. 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-esophageal junction adenocarcinoma (RAINBOW): a double-blind, randomized Phase III trial. Lancet Oncol. 15(11), 1224–1235 (2014).
  • 5. Oh DY, Bang YJ. HER2-targeted therapies – a role beyond breast cancer. Nat. Rev. Clin. Oncol. 17(1), 33–48 (2020).
  • 6. Kreutzfeldt J, Rozeboom B, Dey N, De P. The trastuzumab era: current and upcoming targeted HER2+ breast cancer therapies. Am. J. Cancer Res. 10(4), 1045 (2020).
  • 7. Van Cutsem E, Bang YJ, Feng-yi F et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastresophageal junction cancer. Gastric Cancer. 18(3), 476–484 (2015).
  • 8. Hecht JR, Bang YJ, Qin SK et al. Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2-positive advanced or metastatic gastric, esophageal, or gastresophageal adenocarcinoma: TRIO-013/LOGiC – a randomized Phase III trial. J. Clin. Oncol. 34(5), 443–451 (2016).
  • 9. Tabernero J, Hoff PM, Shen L et al. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-esophageal junction cancer (JACOB): final analysis of a double-blind, randomized, placebo-controlled Phase III study. Lancet Oncol. 19(10), 1372–1384 (2018).
  • 10. Shah MA, Xu R hua, Bang YJ et al. HELOISE: Phase IIIb randomized multicenter study comparing standard-of-care and higher-dose trastuzumab regimens combined with chemotherapy as first-line therapy in patients with human epidermal growth factor receptor 2–positive metastatic gastric or gast. J. Clin. Oncol. 35(22), 2558–2567 (2017).
  • 11. Janjigian YY, Maron SB, Chatila WK et al. First-line pembrolizumab and trastuzumab in HER2-positive esophageal, gastric, or gastro-esophageal junction cancer: an open-label, single-arm, Phase II trial. Lancet Oncol. 2(20), 1–11 (2020).
  • 12. Satoh T, Doi T, Ohtsu A 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. 32(19), 2039–2049 (2014).
  • 13. Thuss-Patience PC, Shah MA, Ohtsu A et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma (GATSBY): an international randomized, open-label, adaptive, Phase II/III study. Lancet Oncol. 18(5), 640–653 (2017).
  • 14. Makiyama A, Sukawa Y, Kashiwada T et al. Randomized, Phase II study of trastuzumab beyond progression in patients with HER2-positive advanced gastric or gastresophageal junction cancer: WJOG7112G (T-ACT Study). J. Clin. Oncol. JCO.19.03077 38(17), 1919–1927 (2020).
  • 15. Park H, Uronis H, Kang Y-K et al. Determinants of response of HER2+ gastric cancer (GC) vs gastresophageal junction adenocarcinoma (GEJ) to margetuximab (M) plus pembrolizumab (P) post trastuzumab (T). Ann. Oncol. 30, v485 (2019).
  • 16. Shitara K, Bang Y-J, Iwasa S et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-positive advanced gastric or gastresophageal junction (GEJ) adenocarcinoma: a randomized, Phase II, multicenter, open-label study (DESTINY-Gastric01). J. Clin. Oncol. 38(Suppl. 15), 4513 (2020).
  • 17. Yamaguchi K, Bang Y-J, Iwasa S et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-low, advanced gastric or gastresophageal junction (GEJ) adenocarcinoma: results of the exploratory cohorts in the Phase II, multicenter, open-label DESTINY-Gastric01 study. Ann. Oncol. 31, S899–S900 (2020).
  • 18. Bartley AN, Washington MK, Ventura CB et al. HER2 testing and clinical decision making in gastresophageal adenocarcinoma guideline from the College of American Pathologists, American Society for clinical Pathology, and American Society of Clinical Oncology. Am. J. Clin. Pathol. 146(6), 647–669 (2016).
  • 19. Lee HE, Park KU, Yoo SB et al. Clinical significance of intratumoral HER2 heterogeneity in gastric cancer. Eur. J. Cancer 49(6), 1448–1457 (2013).
  • 20. Saeki H, Oki E, Kashiwada T et al. Re-evaluation of HER2 status in patients with HER2-positive advanced or recurrent gastric cancer refractory to trastuzumab (KSCC1604). Eur. J. Cancer 105, 41–49 (2018).
  • 21. Pietrantonio F, Fuca 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).
  • 22. Gambardella V, Fleitas T, Tarazona N et al. Towards precision oncology for HER2 blockade in gastresophageal adenocarcinoma. Ann. Oncol. 30(8), 1254–1264 (2019).
  • 23. Ogitani Y, Aida T, Hagihara K et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin. Cancer Res. 22(20), 5097–5108 (2016).
  • 24. Ogitani Y, Hagihara K, Oitate M, Naito H, Agatsuma T. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody–drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci. 107(7), 1039–1046 (2016).
  • 25. Shitara K, Iwata H, Takahashi S et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, Phase I study. Lancet Oncol. 20(6), 827–836 (2019).
  • 26. Shitara K, Bang Y-J, Iwasa S et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N. Engl. J. Med. 382, 2419–2430 (2020).
  • 27. Doi T, Shitara K, Naito Y et al. Safety, pharmacokinetics, and antitumor activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody–drug conjugate, in patients with advanced breast and gastric or gastro-esophageal tumors: a Phase I dose-escalation study. Lancet Oncol. 18(11), 1512–1522 (2017).
  • 28. Iwata TN, Ishii C, Ishida S, Ogitani Y, Wada T, Agatsuma T. A HER2-targeting antibody-drug conjugate, trastuzumab deruxtecan (DS-8201a), enhances antitumor immunity in a mouse model. Mol. Cancer Ther. 17(7), 1494–1503 (2018).
  • 29. Arnould L, Gelly M, Penault-Llorca F et al. Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism? Br. J. Cancer 94(2), 259–267 (2006).
  • 30. Stagg J, Loi S, Divisekera U et al. Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc. Natl Acad. Sci. USA 108(17), 7142–7147 (2011).
  • 31. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer. 12(4), 237–251 (2012).
  • 32. Janjigian YY, Maron SB, Chatila WK et al. First-line pembrolizumab and trastuzumab in HER2-positive esophageal, gastric, or gastro-esophageal junction cancer: an open-label, single-arm, Phase II trial. Lancet Oncol. 2(20), 1–11 (2020).
  • 33. Bang YJ, Giaccone G, Im SA et al. First-in-human Phase I study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors. Ann. Oncol. 28(4), 855–861 (2017).
  • 34. Park H, Uronis H, Kang Y-K et al. Determinants of response of HER2+ gastric cancer (GC) vs gastresophageal junction adenocarcinoma (GEJ) to margetuximab (M) plus pembrolizumab (P) post trastuzumab (T). Ann. Oncol. 30, v485 (2019).
  • 35. Brief NIN. ZW25 effective in HER2-positive cancers. Cancer Discov. 9(1), 8 (2019).
  • 36. Meric-Bernstam F, Beeram M, Mayordomo JI et al. Single agent activity of ZW25, a HER2-targeted bispecific antibody, in heavily pretreated HER2-expressing cancers. J. Clin. Oncol. 36(Suppl. 15), 2500 (2018).
  • 37. Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat. Rev. Cancer 10(2), 116–129 (2010).
  • 38. Babina IS, Turner NC. Advances and challenges in targeting FGFR signalling in cancer. Nat. Rev. Cancer 17(5), 318–332 (2017).
  • 39. Deng N, Goh LK, Wang H et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut 61(5), 673–684 (2012).
  • 40. Liu YJ, Shen D, Yin X et al. HER2, MET and FGFR2 oncogenic driver alterations define distinct molecular segments for targeted therapies in gastric carcinoma. Br. J. Cancer 110(5), 1169–1178 (2014).
  • 41. Kunii K, Davis L, Gorenstein J et al. FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival. Cancer Res. 68(7), 2340–2348 (2008).
  • 42. Matsumoto K, Arao T, Hamaguchi T et al. FGFR2 gene amplification and clinicopathological features in gastric cancer. Br. J. Cancer 106(4), 727–732 (2012).
  • 43. Jung EJ, Jung EJ, Min SY, Kim MA, Kim WH. Fibroblast growth factor receptor 2 gene amplification status and its clinicopathologic significance in gastric carcinoma. Hum. Pathol. 43(10), 1559–1566 (2012).
  • 44. Xie L, Su X, Zhang L et al. FGFR2 gene amplification in gastric cancer predicts sensitivity to the selective FGFR inhibitor AZD4547. Clin. Cancer Res. 19(9), 2572–2583 (2013).
  • 45. Van Cutsem E, Bang YJ, Mansoor W et al. A randomized, open-label study of the efficacy and safety of AZD4547 monotherapy versus paclitaxel for the treatment of advanced gastric adenocarcinoma with FGFR2 polysomy or gene amplification. Ann. Oncol. 28(6), 1316–1324 (2017).
  • 46. Smyth EC, Turner NC, Pearson A et al. Phase II study of AZD4547 in FGFR amplified tumors: gastresophageal cancer (GC) cohort pharmacodynamic and biomarker results. J. Clin. Oncol. 34(Suppl. 4), 154 (2016).
  • 47. Pearson A, Smyth E, Babina IS et al. High-level clonal FGFR amplification and response to FGFR inhibition in a translational clinical trial. Cancer Discov. 6(8), 838–851 (2016).
  • 48. Kuboki Y, Matsubara N, Bando H et al. First-in-human (FIH) study of TAS-120, a highly selective covalent oral fibroblast growth receptor (FGFR) inhibitor, in patients (pts) with advanced solid tumors. Ann. Oncol. 28(Suppl. 5), v122–v141 (2017).
  • 49. Catenacci DVT, Rha SY, Bang Y-J et al. Updated antitumor activity and safety of FPA144, an ADCC-enhanced, FGFR2b isoform-specific monoclonal antibody, in patients with FGFR2b+ gastric cancer. J. Clin. Oncol. 35(Suppl. 15), 4067 (2017).
  • 50. Tejani MA, Cheung E, Eisenberg PD et al. Phase I results from the Phase I/3 FIGHT study evaluating bemarituzumab and mFOLFOX6 in advanced gastric/GEJ cancer (GC). J. Clin. Oncol. 37(Suppl. 4), 91 (2019).
  • 51. Catenacci DVT, Tesfaye A, Tejani M et al. Bemarituzumab with modified FOLFOX6 for advanced FGFR2-positive gastresophageal cancer: FIGHT Phase III study design. Futur. Oncol. 15(18), 2073–2082 (2019).
  • 52. McSheehy P, Bachmann F, Forster-Gross N et al. The FGFR-inhibitor derazantinib (DZB) is active in PDX-models of GI-cancer with specific aberrations in FGFR. J. Clin. Oncol. 38(Suppl. 4), 421 (2020).
  • 53. Hall TG, Yu Y, Eathiraj S et al. Preclinical activity of ARQ 087, a novel inhibitor targeting FGFR dysregulation. PLoS ONE 11(9), 3–5 (2016).
  • 54. Peranzoni E, Lemoine J, Vimeux L et al. Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti–PD-1 treatment. Proc. Natl Acad. Sci. USA 115(17), E4041–E4050 (2018).
  • 55. Zhu Y, Knolhoff BL, Meyer MA et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 74(18), 5057–5069 (2014).
  • 56. Basilea. Basilea reports activity of derazantinib in preclinical models of gastric cancer at ASCO Gastrointestinal Cancers Symposium. (2020). https://www.basilea.com/news/news/basilea-reports-activity-of-derazantinib-in-preclinical-models-of-gastric-cancer-at-asco-gastrointestinal-cancers-symposium?type=1546938654
  • 57. Mori M, Sawada N, Kokai Y, Satoh M. Role of tight junctions in the occurrence of cancer invasion and metastasis. Med. Electron Microsc. 32(4), 193–198 (1999).
  • 58. 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).
  • 59. Bass AJ, Thorsson V, Shmulevich I et al. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513(7517), 202–209 (2014).
  • 60. Singh P, Toom S, Huang Y. Anti-claudin 18.2 antibody as new targeted therapy for advanced gastric cancer. J. Hematol. Oncol. 10(1), 1–5 (2017).
  • 61. Kreuzberg M, Mitnacht-Kraus R, Sahin U, Türeci Ö. Preclinical characterization of IMAB362-VCMMAE, an anti-CLDN18.2 antibody–drug conjugate. Ann. Oncol. 28(Suppl. 5), v122–v141 (2017).
  • 62. Türeci O, Sahin U, Schulze-Bergkamen H et al. A multicenter, 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).
  • 63. Sahin U, Türeci, Manikhas G et al. FAST: a randomized Phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-esophageal adenocarcinoma. Ann. Oncol. 32(5), 609–619 (2021).
  • 64. Shah MA, Ajani JA, Al-Batran S-E et al. Phase III study of first-line zolbetuximab + CAPOX versus placebo + CAPOX in Claudin 18.2+/HER2-advanced or metastatic gastric or gastresophageal junction adenocarcinoma: GLOW. J. Clin. Oncol. 38(Suppl. 15), TPS4648–TPS4648 (2020).
  • 65. Iveson T, Donehower RC, Davidenko I et al. Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or esophagogastric junction adenocarcinoma: an open-label, dose de-escalation Phase Ib study and a double-blind, randomized Phase II study. Lancet Oncol. 15(9), 1007–1018 (2014).
  • 66. 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-esophageal junction cancer (RILOMET-1): a randomized, double-blind, placebo-controlled, Phase III trial. Lancet Oncol. 18(11), 1467–1482 (2017).
  • 67. Doi T, Kang Y-K, Muro K, Jiang Y, Jain RK, Lizambri R. A Phase III, 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 gastresophageal junction (G). J. Clin. Oncol. 33(Suppl. 3), TPS226–TPS226 (2015).
  • 68. Shah MA, Bang YJ, Lordick F et al. Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2-negative, MET-positive gastresophageal adenocarcinoma: the METGastric randomized clinical trial. JAMA Oncol. 3(5), 620–627 (2017).
  • 69. Zang DY, Sohn S-H, Kim B et al. Tepotinib inhibits the epithelial-mesenchymal transition and tumor growth of gastric cancers via increasing GSK3β, ECAD, MUC5AC, and MUC6. J. Clin. Oncol. 38 (Suppl. 15), e16562–e16562 (2020).
  • 70. Li J, Guo Y, Xue J et al. First-in-human (FIH) Phase I study of GST-HG161, a potent and highly selective c-met inhibitor, in patients with advanced solid tumor. J. Clin. Oncol. 38(Suppl. 15), e16126–e16126 (2020).
  • 71. Kim HS, Kim MA, Hodgson D et al. Concordance of ATM (ataxia telangiectasia mutated) immunohistochemistry between biopsy or metastatic tumor samples and primary tumors in gastric cancer patients. Pathobiology 80(3), 127–137 (2013).
  • 72. Bang YJ, Im SA, Lee KW et al. Randomized, double-blind Phase II trial with prospective classification by ATM protein level to evaluate the efficacy and tolerability of olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer. J. Clin. Oncol. 33(33), 3858–3865 (2015).
  • 73. Bang YJ, Xu RH, Chin K et al. Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): a double-blind, randomized, placebo-controlled, Phase III trial. Lancet Oncol. 18(12), 1637–1651 (2017).
  • 74. Smyth E. Missing a GOLDen opportunity in gastric cancer. Lancet Oncol. 18, 1561–1563 (2017).
  • 75. Alexandrov LB, Nik-Zainal S, Wedge DC et al. Signatures of mutational processes in human cancer. Nature 500(7463), 415–421 (2013).
  • 76. Alexandrov LB, Nik-Zainal S, Siu HC, Leung SY, Stratton MR. A mutational signature in gastric cancer suggests therapeutic strategies. Nat. Commun. 6, 1–7 (2015).
  • 77. Secrier M, Li X, De Silva N et al. Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance. Nat. Genet. 48(10), 1131–1141 (2016).
  • 78. Mamdani H, Mehta R, Fountzilas C, Radovich M, Perkins S, Jalal SI. A Phase II study evaluating safety and efficacy of niraparib in patients with previously treated homologous recombination (HR) defective or loss of heterozygosity (LOH) high-metastatic esophageal/GEJ/proximal gastric adenocarcinoma: a big ten cancer research consortium study. J. Clin. Oncol. 38(Suppl.4), TPS472–TPS472 (2020).
  • 79. Moehler M, Shitara K, Garrido M et al. Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastresophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): first results of the CheckMate 649 study. Ann. Oncol. 31, S1191 (2020).
  • 80. Boku N, Ryu MH, Oh D-Y et al. Nivolumab plus chemotherapy versus chemotherapy alone in patients with previously untreated advanced or recurrent gastric/gastresophageal junction (G/GEJ) cancer: ATTRACTION-4 (ONO-4538-37) study. Ann. Oncol. 31, S1192 (2020).
  • 81. Kato K, Sun J-M, Shah MA et al. Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: the Phase III KEYNOTE-590 study. Ann. Oncol. 31, S1192–S1193 (2020).
  • 82. Tabernero J, Van Cutsem E, Bang Y-J et al. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastresophageal junction (G/GEJ) adenocarcinoma: the Phase III KEYNOTE-062 study. J. Clin. Oncol. 37(Suppl. 18), LBA4007–LBA4007 (2019).
  • 83. Wang F, Wei XL, Wang FH et al. Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD-1 antibody in Phase Ib/II clinical trial NCT02915432. Ann. Oncol. 30(9), 1479–1486 (2019).
  • 84. Moehler MH, Dvorkin M, Ozguroglu M et al. Results of the JAVELIN Gastric 100 Phase III trial: avelumab maintenance following first-line (1L) chemotherapy (CTx) vs continuation of CTx for HER2- advanced gastric or gastresophageal junction cancer (GC/GEJC). J. Clin. Oncol. 39(9), 966–977 (2020).
  • 85. Shitara K, Özgüroğlu M, Bang YJ et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-esophageal junction cancer (KEYNOTE-061): a randomized, open-label, controlled, Phase III trial. Lancet 392(10142), 123–133 (2018).
  • 86. Metges J, François E, Shah M et al. The Phase III KEYNOTE-181 study: pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer. Ann. Oncol. 30(July), iv130 (2019).
  • 87. 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 gastresophageal junction adenocarcinoma. Clin. Cancer Res. 26(4), 846–854 (2020).
  • 88. Kang YK, Boku N, Satoh T et al. Nivolumab in patients with advanced gastric or gastro-esophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomized, double-blind, placebo-controlled, Phase III trial. Lancet 390(10111), 2461–2471 (2017).
  • 89. Fuchs CS, Doi T, Jang RW et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastresophageal junction cancer: Phase II clinical KEYNOTE-059 trial. JAMA Oncol. 4(5), 1–8 (2018).
  • 90. Bang YJ, Yañez Ruiz E, Van Cutsem E et al. Phase III, randomized trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-esophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann. Oncol. 29(10), 2052–2060 (2018).
  • 91. 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).
  • 92. Muro K, Chung HC, Shankaran V et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicenter, open-label, Phase Ib trial. Lancet Oncol. 17(6), 717–726 (2016).
  • 93. Le DT, Uram JN, Wang H et al. PD-1 blockade in tumors with mismatch repair deficiency. N. Engl. J. Med. 372(26), 2509–2520 (2015).
  • 94. Amonkar M, Lorenzi M, Zhang J, Mehta S, Liaw K-L. Structured literature review (SLR) and meta-analyses of the prevalence of microsatellite instability high (MSI-H) and deficient mismatch repair (dMMR) in gastric, colorectal, and esophageal cancers. J. Clin. Oncol. 37(Suppl. 15), e15074–e15074 (2019).
  • 95. 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).
  • 96. Kulangara K, Zhang N, Corigliano E et al. Clinical utility of the combined positive score for programmed death ligand-1 expression and the approval of pembrolizumab for treatment of gastric cancer. Arch. Pathol. Lab. Med. 143(3), 330–337 (2019).
  • 97. Fuchs CS, Özgüroğlu M, Bang Y-J et al. Pembrolizumab versus paclitaxel for previously treated patients with PD-L1–positive advanced gastric or gastresophageal junction cancer (GC): update from the Phase III KEYNOTE-061 trial. J. Clin. Oncol. 38(Suppl. 15), 4503 (2020).
  • 98. Wainberg ZA, Fuchs CS, Tabernero J et al. Efficacy of pembrolizumab (pembro) monotherapy versus chemotherapy for PD-L1–positive (CPS ≥10) advanced G/GEJ cancer in the Phase II KEYNOTE-059 (cohort 1) and Phase III KEYNOTE-061 and KEYNOTE-062 studies. J. Clin. Oncol. 38(Suppl. 4), 427 (2020).
  • 99. Hagi T, Kurokawa Y, Kawabata R et al. Multicenter biomarker cohort study on the efficacy of nivolumab treatment for gastric cancer. Br. J. Cancer 123(6), 965–972 (2020).
  • 100. Kulangara K, Zhang N, Corigliano E et al. Clinical utility of the combined positive score for programmed death ligand-1 expression and the approval of pembrolizumab for treatment of gastric cancer. Arch. Pathol. Lab. Med. 143(3), 330–337 (2019).
  • 101. Krigsfeld GS, Prince EA, Pratt J et al. Analysis of real-world PD-L1 IHC 28-8 and 22C3 pharmDx assay utilisation, turnaround times and analytical concordance across multiple tumor types. J. Clin. Pathol. 73(10), 656–664 (2020).
  • 102. Zhou KI, Peterson B, Serritella A, Reizine N, Wang Y, Catenacci DVT. Evaluation of spatiotemporal heterogeneity of tumor mutational burden (TMB) in gastresophageal adenocarcinoma (GEA) at baseline diagnosis and after chemotherapy. J. Clin. Oncol. 38(Suppl. 15), 4546–4546 (2020).
  • 103. Bass AJ, Thorsson V, Shmulevich I et al. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513(7517), 202–209 (2014).
  • 104. 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).
  • 105. Ayers M, Lunceford J, Nebozhyn M et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J. Clin. Invest. 127(8), 2930–2940 (2017).
  • 106. Higgs BW, Morehouse CA, Streicher K et al. Interferon gamma messenger RNA Signature in tumor biopsies predicts outcomes in patients with non–small cell lung carcinoma or urothelial cancer treated with durvalumab. Clin. Cancer Res. 24(16), 3857–3866 (2018).
  • 107. Lei M, Siemers N, Pandya D et al. Analyses of PD-L1 and inflammatory gene expressionassociation with efficacy of nivolumab + ipilimumab ingastric cancer/gastroesophageal junction cancer. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-20-2790 (2021) (Epub ahead of print).
  • 108. Cristescu R, Lee J, Nebozhyn M et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat. Med. 21(5), 449–456 (2015).
  • 109. Greally M, Chou JF, Chatila WK et al. Clinical and molecular predictors of response to immune checkpoint inhibitors in patients with advanced esophagogastric cancer. Clin. Cancer Res. 25(20), 6160–6169 (2019).
  • 110. 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).
  • 111. Goodman AM, Kato S, Bazhenova L et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol. Cancer Ther. 16(11), 2598–2608 (2017).
  • 112. Campesato LF, Barroso-Sousa R, Jimenez L et al. Comprehensive cancer-gene panels can be used to estimate mutational load and predict clinical benefit to PD-1 blockade in clinical practice. Oncotarget 6(33), 34221–34227 (2015).
  • 113. Marabelle A, Fakih MG, Lopez J et al. Association of tumor mutational burden with outcomes in patients with select advanced solid tumors treated with pembrolizumab in KEYNOTE-158. Ann. Oncol. 30, v477–v478 (2019).
  • 114. Fuchs CS, Özgüroğlu M, Bang Y-J et al. The association of molecular biomarkers with efficacy of pembrolizumab versus paclitaxel in patients with gastric cancer (GC) from KEYNOTE-061. J. Clin. Oncol. 38(Suppl. 15), 4512 (2020).
  • 115. Shitara K, Özgüroğlu M, Bang Y-J et al. The association of tissue tumor mutational burden (tTMB) using the Foundation Medicine genomic platform with efficacy of pembrolizumab versus paclitaxel in patients (pts) with gastric cancer (GC) from KEYNOTE-061. J. Clin. Oncol. 38(Suppl. 15), 4537 (2020).
  • 116. Galon J, Costes A, Sanchez-Cabo F et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795), 1960–1964 (2006).
  • 117. Solinas C, Pusole G, Demurtas L et al. Tumor infiltrating lymphocytes in gastrointestinal tumors: controversies and future clinical implications. Crit. Rev. Oncol. Hematol. 110, 106–116 (2017).
  • 118. Challoner BR, von Loga K, Woolston A et al. Computational image analysis of T-cell infiltrates in resectable gastric cancer: association with survival and molecular subtypes. JNCI J. Natl Cancer Inst. 113(1), 88–98 (2020).
  • 119. Wang M, Huang YK, Kong JCH et al. High-dimensional analyses reveal a distinct role of T-cell subsets in the immune microenvironment of gastric cancer. Clin. Transl. Immunol. 9(5), e1127 (2020).
  • 120. Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature 541(7637), 321–330 (2017).
  • 121. Herbst RS, Soria JC, Kowanetz M et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515(7528), 563–567 (2014).
  • 122. Tumeh PC, Harview CL, Yearley JH et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528), 568–571 (2014).
  • 123. Kim T, Lee D, Oh D et al. The analysis of T cell subsets and clinical efficacy of immune checkpoint blockades in patients with advanced gastric cancer using multiplex immunohistochemistry. Ann. Oncol. 30(October), v253 (2019).
  • 124. Cho J, Chang YH, Heo YJ et al. Four distinct immune microenvironment subtypes in gastric adenocarcinoma with special reference to microsatellite instability. ESMO Open 3(3), e000326 (2018).
  • 125. Giampieri R, Maccaroni E, Mandolesi A et al. Mismatch repair deficiency may affect clinical outcome through immune response activation in metastatic gastric cancer patients receiving first-line chemotherapy. Gastric Cancer. 20(1), 156–163 (2017).
  • 126. Lauren P. The two main histological types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol. Microbiol. Scand. 64, 31–49 (1965).
  • 127. Tae Kim S, Lee J, Hong M et al. Development of mesenchymal subtype gene signature for clinical application in gastric cancer. Oncotarget 8(39), 66305–66315 (2017).
  • 128. Lee J, Kim ST, Kim K et al. Tumor genomic profiling guides patients with metastatic gastric cancer to targeted treatment: the viktory umbrella trial. Cancer Discov. 9(10), 1388–1405 (2019).
  • 129. Catenacci DVT, Peterson B, Chase L et al. Personalized antibodies for gastresophageal adenocarcinoma (PANGEA): secondary and final primary efficacy analyses. J. Clin. Oncol. 38(Suppl. 15), 4561 (2020).
  • 130. Pectasides E, Stachler MD, Derks S et al. Genomic heterogeneity as a barrier to precision medicine in gastresophageal adenocarcinoma. Cancer Discov. 8(1), 37–48 (2018).
  • 131. Davidson M, Barber LJ, Woolston A et al. Detecting and tracking circulating tumor DNA copy number profiles during first line chemotherapy in esophagogastric adenocarcinoma. Cancers (Basel). 11(5), 736 (2019).
  • 132. 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 randomized, open-label Phase III trial. Lancet Oncol. 14(6), 490–499 (2013).
  • 133. Waddell T, Chau I, Cunningham D et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced esophagogastric cancer (REAL3): a randomized, open-label Phase III trial. Lancet Oncol. 14(6), 481–489 (2013).
  • 134. Dutton SJ, Ferry DR, Blazeby JM et al. Gefitinib for esophageal cancer progressing after chemotherapy (COG): a Phase III, multicenter, double-blind, placebo-controlled randomized trial. Lancet Oncol. 15(8), 894–904 (2014).
  • 135. Maron SB, Alpert L, Kwak HA et al. Targeted therapies for targeted populations: anti-EGFR treatment for EGFR-amplified gastresophageal adenocarcinoma. Cancer Discov. 8(6), 696–713 (2018).