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Does immunotherapy change the treatment paradigm in metastatic gastric cancer?

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Abstract

Gastric cancer represents one of the leading causes of cancer-related death worldwide. Even if the last decade has witnessed an improvement in surgical and systemic treatments, with an increase of overall life expectancy, survival rates still remain unsatisfactory, especially for patients with metastatic disease. Systemic therapies represent the gold standard in the management of stage IV gastric cancer. In this scenario, the availability of effective second and third lines has represented for a long time the only hope to offer an overall survival improvement to these patients. Recently, the advent of immune checkpoint inhibitors has involved also gastric cancer with encouraging efficacy data in the metastatic setting, becoming integral part of the management of selected patients.

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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. 2018;68(6):394–424.

    Article  PubMed  Google Scholar 

  2. SEER Cancer statistics: survival by stage in stomach cancer. Available from: https://seer.cancer.gov/statfacts/html/stomach.html. Accessed 6 June 2022.

  3. Van Cutsem E, Sagaert X, Topal B, Haustermans K, Prenen H. Gastric cancer. Lancet. 2016;388(10060):2654–64.

    Article  PubMed  Google Scholar 

  4. Wagner AD, Syn NL, Moehler M, Grothe W, Yong WP, Tai BC, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. 2017;29(8):CD004064.

    Google Scholar 

  5. Bang YJ, Van Cutsem E, 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  PubMed  CAS  Google Scholar 

  6. Okines AFC, Norman AR, McCloud P, Kang YK, Cunningham D. Meta-analysis of the REAL-2 and ML17032 trials: evaluating capecitabine-based combination chemotherapy and infused 5-fluorouracil-based combination chemotherapy for the treatment of advanced oesophago-gastric cancer. Ann Oncol. 2009;20(9):1529–34.

    Article  PubMed  CAS  Google Scholar 

  7. Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, et al. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009;20(4):666–73.

    Article  PubMed  Google Scholar 

  8. Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, et al. Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358(1):36–46.

    Article  PubMed  CAS  Google Scholar 

  9. Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. Ramucirumab monotherapy 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  PubMed  CAS  Google Scholar 

  10. Wilke H, Muro K, Van Cutsem E, 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  PubMed  CAS  Google Scholar 

  11. Mansoor W, Arkenau HT, Alsina M, Shitara K, Thuss-Patience P, Cuffe S, et al. Trifluridine/tipiracil in patients with metastatic gastroesophageal junction cancer: a subgroup analysis from the phase 3 TAGS study. Gastric Cancer. 2021;24:970–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Pasquini G, Vasile E, Caparello C, Vivaldi C, Musettini G, Lencioni M, et al. Third-line chemotherapy with irinotecan plus 5-fluorouracil in Caucasian metastatic gastric cancer patients. Oncology. 2016;91(6):311–6.

    Article  PubMed  CAS  Google Scholar 

  13. Erdem GU, Bozkaya Y, Ozdemir NY, Demirci NS, Yazici O, Zengin N. 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) as a third-line chemotherapy treatment in metastatic gastric cancer, after failure of fluoropyrimidine, platinum, anthracycline, and taxane. Bosn J Basic Med Sci. 2018;18(2):170–7.

    PubMed  PubMed Central  CAS  Google Scholar 

  14. 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  PubMed  CAS  Google Scholar 

  15. Van Cutsem E, Bang YJ, Mansoor W, Petty RD, Chao Y, Cunningham D, 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. 2017;28(6):1316–24.

    Article  PubMed  Google Scholar 

  16. Catenacci DVT, Tebbutt NC, Davidenko I, Murad AM, Al-Batran SE, Ilson DH, 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. 2017;18(11):1467–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. 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  PubMed  PubMed Central  CAS  Google Scholar 

  18. Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, 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. 2020;6(10):1571–80.

    Article  PubMed  Google Scholar 

  19. Shitara K, Özgüroğlu M, Bang YJ, Di Bartolomeo M, Mandalà M, Ryu MH, 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. 2018;392(10142):123–33.

    Article  PubMed  CAS  Google Scholar 

  20. Wainberg ZA, Shitara K, Van Cutsem E, Wyrwicz L, Lee KW, Kudabaet I, et al. Pembrolizumab with or without chemotherapy versus chemotherapy alone for patients with PD-L1–positive advanced gastric or gastroesophageal junction adenocarcinoma: Update from the phase 3 KEYNOTE-062 trial. Presented at 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium. January 20–22, 2022. Abstract 243.

  21. Tabernero J, Bang YJ, Van Cutsem E, Fuchs CS, Janjigian YY, Bhagia P, et al. KEYNOTE-859: a Phase III study of pembrolizumab plus chemotherapy in gastric/gastroesophageal junction adenocarcinoma. Future Oncol. 2021;17(22):2847–55.

    Article  PubMed  CAS  Google Scholar 

  22. Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, 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. 2017;390(10111):2461–71.

    Article  PubMed  CAS  Google Scholar 

  23. Kang YK, Chen LT, Ryu MH, Oh DY, Oh SC, Chung HC, et al. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022;23(2):234–47.

    Article  PubMed  CAS  Google Scholar 

  24. Moehler M, Shitara K, Garrido M, Salman P, Shen L, Wyrwicz L, et al. LBA6_PR Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): first results of the CheckMate 649 study. Ann Oncol. 2020;31:S1191. https://doi.org/10.1016/j.annonc.2020.08.2296.

    Article  Google Scholar 

  25. Moehler M, Shitara K, Garrido M, Salman P, Shen L, Wyrwicz L, et al. First-line (1L) nivolumab (NIVO) plus chemotherapy (chemo) versus chemo in advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): expanded efficacy and safety data from CheckMate 649. J Clin Oncol 39, 2021 (suppl 15; abstr 4002)

  26. Shitara K, Janjigian YY, Moehler M, Garrido M, Gallardo C, Shen L, 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. 2022. https://doi.org/10.1200/JCO.2022.40.4_suppl.240.

    Article  PubMed  Google Scholar 

  27. Chung HC, Bang YJ, Fuchs SC, Qin SK, Satoh T, Shitara K, et al. First-line pembrolizumab/placebo plus trastuzumab and chemotherapy in HER2-positive advanced gastric cancer: KEYNOTE-811. Future Oncol. 2021;17(5):491–501. https://doi.org/10.2217/fon-2020-0737.

    Article  PubMed  CAS  Google Scholar 

  28. Fuchs CS, Özgüroğlu M, Bang YJ, Di Bartolomeo M, Mandala M, Ryu MH, et al. Pembrolizumab versus paclitaxel for previously treated PD-L1-positive advanced gastric or gastroesophageal junction cancer: 2-year update of the randomized phase 3 KEYNOTE-061 trial. Gastric Cancer. 2022;25(1):197–206.

    Article  PubMed  CAS  Google Scholar 

  29. Nakajima TE, Kadowaki S, Minashi K, Nishina T, Yamanaka T, Hayashi Y, 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. 2021;27(4):1029–36.

    Article  PubMed  CAS  Google Scholar 

  30. Chen LT, Kang YK, Satoh T, Chao Y, Kato K, Chung HC, et al. A phase III study of nivolumab (Nivo) in previously treated advanced gastric or gastric esophageal junction (G/GEJ) cancer (ATTRACTION-2): three-year update data. J Clin Oncol. 2020. https://doi.org/10.1200/JCO.2020.38.4_suppl.383.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Muro K, Chung HC, Shankaran V, Geva R, Catenacci D, Gupta S, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol. 2016;17(6):717–26.

    Article  PubMed  CAS  Google Scholar 

  32. Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, 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. 2018;4(5):e180013.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Zhao JJ, Yap DWT, Chan YH, Tan BKJ, Teo CB, Syn NL, et al. Low programmed death-ligand 1-expressing subgroup outcomes of first-line immune checkpoint inhibitors in gastric or esophageal adenocarcinoma. J Clin Oncol. 2022;40(4):392–402.

    Article  PubMed  CAS  Google Scholar 

  34. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–9.

    Article  Google Scholar 

  35. Martinez-Ciarpaglini C, Fleitas-Kanonnikoff T, Gambardella V, Llorca M, Mongort C, Mengual R, et al. Assessing molecular subtypes of gastric cancer: microsatellite unstable and Epstein-Barr virus subtypes. Methods for detection and clinical and pathological implications. ESMO Open. 2019;4(3):e000470.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Lin SJ, Gagnon-Bartsch JA, Tan IB, Earle S, Ruff L, Pettinger K, et al. Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas. Gut. 2015;64(11):1721–31.

    Article  PubMed  CAS  Google Scholar 

  37. Murphy G, Pfeiffer R, Camargo MC, Rabkin CS. Meta-analysis shows that prevalence of Epstein-Barr virus-positive gastric cancer differs based on sex and anatomic location. Gastroenterology. 2009;137:824–33.

    Article  PubMed  Google Scholar 

  38. Mansoor W, Roeland EJ, Chaudhry A, Liepa AM, Wei R, Knoderer H, et al. Early weight loss as a prognostic factor in patients with advanced gastric cancer: analyses from REGARD, RAINBOW, and RAINFALL Phase III studies. Oncologist. 2021;26(9):e1538–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Lu Z, Fang Y, Liu C, Zhang X, Xin X, He Y, et al. Early interdisciplinary supportive care in patients with previously untreated metastatic esophagogastric cancer: a phase III randomized controlled trial. J Clin Oncol. 2021;39(7):748–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Baldessari C, Guaitoli G, Valoriani F, Bonacini R, Marcheselli R, Reverberi L. Impact of body composition, nutritional and inflammatory status on outcome of non-small cell lung cancer patients treated with immunotherapy. Clin Nutr ESPEN. 2021;43:64–75.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132, Milan, Italy

    Silvia Camera, Nicole Liscia, Silvia Foti, Elena Mazza & Stefano Cascinu

  2. Gastrointestinal Surgery Unit, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132, Milan, Italy

    Lavinia Barbieri, Andrea Cossu, Francesco Puccetti, Ugo Elmore & Riccardo Rosati

  3. Medical Oncology Unit, University Hospital and University of Cagliari, 09042, Cagliari, Italy

    Mario Scartozzi

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  1. Silvia Camera
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Contributions

Conception and design: SC, EM, SC. Literature search, data analysis and manuscript drafting: SC, NL, EM, SC. Critical revision and final approval of the manuscript: All authors.

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Correspondence to Silvia Camera.

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Stefano Cascinu reports the following disclosures: advisory board and speakers’ bureau: Lilly, Daiichi-Sankyo, Servier, MSD, BMS. Mario Scartozzi reports the following disclosures: advisory board and speakers’ bureau: Lilly, Servier, MSD, BMS. The other authors have no conflict of interest to declare.

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Camera, S., Liscia, N., Foti, S. et al. Does immunotherapy change the treatment paradigm in metastatic gastric cancer?. Med Oncol 39, 224 (2022). https://doi.org/10.1007/s12032-022-01819-4

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