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Association Between Immune-Related Adverse Events and the Prognosis of Patients with Advanced Gastric Cancer Treated with Nivolumab

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Abstract

Background

Little is known about the association between immune-related adverse events (irAEs) and the efficacy and survival outcomes of nivolumab in patients with advanced gastric cancer (AGC).

Objective

The present study examined the association between irAEs and the prognosis of patients with AGC treated with nivolumab.

Patients and Methods

From July 2017 to November 2020, patients who had been diagnosed with advanced unresected gastric cancer and treated with nivolumab at our institution were included in this analysis. We compared the clinical and survival outcomes between the irAE and non-irAE groups. We also evaluated the factors associated with better survival in patients treated with nivolumab.

Results

A total of 52 patients were included in the present study, and irAEs were observed in 13 (25%). Among the patients with measurable lesions (n = 29), the disease control rates were significantly higher in the irAE group than in the non-irAE group (88 vs. 24%; P = 0.0033). At the 8- and 12-week landmark analyses, the median overall survival (OS) in the irAE group was significantly longer than that in the non-irAE group, whereas the median progression-free survival was comparable between the groups. A multivariate analysis by Cox proportional hazard regression at the 8-week landmark revealed that the development of irAEs (hazard ratio 0.18; 95% confidence interval 0.0099–0.86) alone was positively associated with a longer OS.

Conclusions

The development of irAEs might be associated with survival outcomes with nivolumab treatment in patients with AGC.

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References

  1. Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008;9(3):215–21. https://doi.org/10.1016/s1470-2045(08)70035-4.

    Article  CAS  PubMed  Google Scholar 

  2. Yamada Y, Higuchi K, Nishikawa K, Gotoh M, Fuse N, Sugimoto N, et al. Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer. Ann Oncol. 2015;26(1):141–8. https://doi.org/10.1093/annonc/mdu472.

    Article  CAS  PubMed  Google Scholar 

  3. 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. https://doi.org/10.1016/s0140-6736(17)31827-5.

    Article  CAS  PubMed  Google Scholar 

  4. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2014 (ver. 4). Gastric Cancer. 2017;20(1):1–19. https://doi.org/10.1007/s10120-016-0622-4.

    Article  Google Scholar 

  5. Ogata T, Satake H, Ogata M, Hatachi Y, Inoue K, Hamada M, et al. Neutrophil-to-lymphocyte ratio as a predictive or prognostic factor for gastric cancer treated with nivolumab: a multicenter retrospective study. Oncotarget. 2018;9(77):34520–7. https://doi.org/10.18632/oncotarget.26145.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ota Y, Takahari D, Suzuki T, Osumi H, Nakayama I, Oki A, et al. Changes in the neutrophil-to-lymphocyte ratio during nivolumab monotherapy are associated with gastric cancer survival. Cancer Chemother Pharmacol. 2020;85(2):265–72. https://doi.org/10.1007/s00280-019-04023-w.

    Article  CAS  PubMed  Google Scholar 

  7. Yamada T, Hayashi T, Inokuchi Y, Hayashi K, Watanabe H, Komori K, et al. Impact of the neutrophil-to-lymphocyte ratio on the survival of patients with gastric cancer treated with nivolumab monotherapy. Target Oncol. 2020;15(3):317–25. https://doi.org/10.1007/s11523-020-00716-y.

    Article  PubMed  Google Scholar 

  8. Namikawa T, Yokota K, Tanioka N, Fukudome I, Iwabu J, Munekage M, et al. Systemic inflammatory response and nutritional biomarkers as predictors of nivolumab efficacy for gastric cancer. Surg Today. 2020;50(11):1486–95. https://doi.org/10.1007/s00595-020-02048-w.

    Article  CAS  PubMed  Google Scholar 

  9. Kurosaki T, Kawakami H, Mitani S, Kawabata R, Takahama T, Nonagase Y, et al. Glasgow Prognostic Score (GPS) and tumor response as biomarkers of nivolumab monotherapy in third- or later-line setting for advanced gastric cancer. Vivo. 2020;34(4):1921–9. https://doi.org/10.21873/invivo.11989.

    Article  CAS  Google Scholar 

  10. Masuda K, Shoji H, Nagashima K, Yamamoto S, Ishikawa M, Imazeki H, et al. Correlation between immune-related adverse events and prognosis in patients with gastric cancer treated with nivolumab. BMC Cancer. 2019;19(1):974. https://doi.org/10.1186/s12885-019-6150-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ksienski D, Wai ES, Croteau N, Fiorino L, Brooks E, Poonja Z, et al. Efficacy of nivolumab and pembrolizumab in patients with advanced non-small-cell lung cancer needing treatment interruption because of adverse events: a retrospective multicenter analysis. Clin Lung Cancer. 2019;20(1):e97–106. https://doi.org/10.1016/j.cllc.2018.09.005.

    Article  CAS  PubMed  Google Scholar 

  12. Mouri A, Kaira K, Yamaguchi O, Shiono A, Miura Y, Hashimoto K, et al. Clinical difference between discontinuation and retreatment with nivolumab after immune-related adverse events in patients with lung cancer. Cancer Chemother Pharmacol. 2019;84(4):873–80. https://doi.org/10.1007/s00280-019-03926-y.

    Article  CAS  PubMed  Google Scholar 

  13. Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res. 2016;22(4):886–94. https://doi.org/10.1158/1078-0432.Ccr-15-1136.

    Article  CAS  PubMed  Google Scholar 

  14. Okada N, Kawazoe H, Takechi K, Matsudate Y, Utsunomiya R, Zamami Y, et al. Association between immune-related adverse events and clinical efficacy in patients with melanoma treated with nivolumab: a multicenter retrospective study. Clin Ther. 2019;41(1):59–67. https://doi.org/10.1016/j.clinthera.2018.11.004.

    Article  CAS  PubMed  Google Scholar 

  15. Otsuka M, Sugihara S, Mori S, Hamada K, Sasaki Y, Yoshikawa S, et al. Immune-related adverse events correlate with improved survival in patients with advanced mucosal melanoma treated with nivolumab: a single-center retrospective study in Japan. J Dermatol. 2020;47(4):356–62. https://doi.org/10.1111/1346-8138.15246.

    Article  CAS  PubMed  Google Scholar 

  16. Suo A, Chan Y, Beaulieu C, Kong S, Cheung WY, Monzon JG, et al. Anti-PD1-induced immune-related adverse events and survival outcomes in advanced melanoma. Oncologist. 2020;25(5):438–46. https://doi.org/10.1634/theoncologist.2019-0674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Haratani K, Hayashi H, Chiba Y, Kudo K, Yonesaka K, Kato R, et al. Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol. 2018;4(3):374–8. https://doi.org/10.1001/jamaoncol.2017.2925.

    Article  PubMed  Google Scholar 

  18. Sato K, Akamatsu H, Murakami E, Sasaki S, Kanai K, Hayata A, et al. Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab. Lung Cancer. 2018;115:71–4. https://doi.org/10.1016/j.lungcan.2017.11.019.

    Article  PubMed  Google Scholar 

  19. Toi Y, Sugawara S, Kawashima Y, Aiba T, Kawana S, Saito R, et al. Association of immune-related adverse events with clinical benefit in patients with advanced non-small-cell lung cancer treated with nivolumab. Oncologist. 2018;23(11):1358–65. https://doi.org/10.1634/theoncologist.2017-0384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ricciuti B, Genova C, De Giglio A, Bassanelli M, Dal Bello MG, Metro G, et al. Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab: long-term outcomes from a multi-institutional analysis. J Cancer Res Clin Oncol. 2019;145(2):479–85. https://doi.org/10.1007/s00432-018-2805-3.

    Article  CAS  PubMed  Google Scholar 

  21. Baldini E, Lunghi A, Cortesi E, Turci D, Signorelli D, Stati V, et al. Immune-related adverse events correlate with clinical outcomes in NSCLC patients treated with nivolumab: the Italian NSCLC expanded access program. Lung Cancer. 2020;140:59–64. https://doi.org/10.1016/j.lungcan.2019.12.014.

    Article  PubMed  Google Scholar 

  22. Hosoya K, Fujimoto D, Morimoto T, Kumagai T, Tamiya A, Taniguchi Y, et al. Association between early immune-related adverse events and clinical outcomes in patients with non-small cell lung cancer treated with immune checkpoint inhibitors. Clin Lung Cancer. 2020;21(4):e315–28. https://doi.org/10.1016/j.cllc.2020.01.003.

    Article  CAS  PubMed  Google Scholar 

  23. Naqash AR, Ricciuti B, Owen DH, Florou V, Toi Y, Cherry C, et al. Outcomes associated with immune-related adverse events in metastatic non-small cell lung cancer treated with nivolumab: a pooled exploratory analysis from a global cohort. Cancer Immunol Immunother. 2020;69(7):1177–87. https://doi.org/10.1007/s00262-020-02536-5.

    Article  CAS  PubMed  Google Scholar 

  24. Arigami T, Matsushita D, Okubo K, Yanagita S, Ehi K, Sasaki K, et al. Response rate and prognostic impact of salvage chemotherapy after nivolumab in patients with advanced gastric cancer. Oncology. 2020;98(9):630–6. https://doi.org/10.1159/000507219.

    Article  CAS  PubMed  Google Scholar 

  25. Diehl A, Yarchoan M, Hopkins A, Jaffee E, Grossman SA. Relationships between lymphocyte counts and treatment-related toxicities and clinical responses in patients with solid tumors treated with PD-1 checkpoint inhibitors. Oncotarget. 2017;8(69):114268–80. https://doi.org/10.18632/oncotarget.23217.

    Article  PubMed  PubMed Central  Google Scholar 

  26. 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. https://doi.org/10.1016/s1470-2045(16)00175-3.

    Article  CAS  PubMed  Google Scholar 

  27. Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127(8):2930–40. https://doi.org/10.1172/jci91190.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Nozoe T, Ninomiya M, Maeda T, Matsukuma A, Nakashima H, Ezaki T. Prognostic nutritional index: a tool to predict the biological aggressiveness of gastric carcinoma. Surg Today. 2010;40(5):440–3. https://doi.org/10.1007/s00595-009-4065-y.

    Article  PubMed  Google Scholar 

  29. Jeong JH, Lim SM, Yun JY, Rhee GW, Lim JY, Cho JY, et al. Comparison of two inflammation-based prognostic scores in patients with unresectable advanced gastric cancer. Oncology. 2012;83(5):292–9. https://doi.org/10.1159/000342376.

    Article  PubMed  Google Scholar 

  30. Li QQ, Lu ZH, Yang L, Lu M, Zhang XT, Li J, et al. Neutrophil count and the inflammation-based glasgow prognostic score predict survival in patients with advanced gastric cancer receiving first-line chemotherapy. Asian Pac J Cancer Prev. 2014;15(2):945–50. https://doi.org/10.7314/apjcp.2014.15.2.945.

    Article  PubMed  Google Scholar 

  31. Bass A, et al. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202–9. https://doi.org/10.1038/nature13480.

    Article  CAS  Google Scholar 

  32. Derks S, Liao X, Chiaravalli AM, Xu X, Camargo MC, Solcia E, et al. Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers. Oncotarget. 2016;7(22):32925–32. https://doi.org/10.18632/oncotarget.9076.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med. 2017;377(25):2500–1. https://doi.org/10.1056/NEJMc1713444.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Matsumoto T, Yamamoto Y, Kuriona Y, Okazaki U, Kimura S, Miura K, et al. Efficacy and safety of nivolumab for advanced gastric cancer patients with poor performance statuses. BMC Cancer. 2020;20(1):684. https://doi.org/10.1186/s12885-020-07176-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine, Hiroshima City Hiroshima Citizens Hospital, 7-33 Moto-machi, Naka-ku, Hiroshima, 730-8518, Japan

    Yoshiyasu Kono, Koji Miyahara, Tetsu Hirata, Yuka Obayashi, Tatsuhiro Gotoda & Yuki Moritou

  2. Department of Surgery, Hiroshima City Hiroshima Citizens Hospital, 7-33 Moto-machi, Naka-ku, Hiroshima, 730-8518, Japan

    Yasuhiro Choda, Michihiro Ishida & Tetsushi Kubota

  3. Department of Endoscopy, Hiroshima City Hiroshima Citizens Hospital, 7-33 Moto-machi, Naka-ku, Hiroshima, 730-8518, Japan

    Masahiro Nakagawa

  4. Department of Pharmacy, Hiroshima City Hiroshima Citizens Hospital, 7-33 Moto-machi, Naka-ku, Hiroshima, 730-8518, Japan

    Keiji Seo

  5. Department of Oncology, Hiroshima City Hiroshima Citizens Hospital, 7-33 Moto-machi, Naka-ku, Hiroshima, 730-8518, Japan

    Yoshiko Okikawa & Yasuo Iwamoto

  6. Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan

    Yoshiyasu Kono & Hiroyuki Okada

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  1. Yoshiyasu Kono
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  2. Yasuhiro Choda
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Corresponding author

Correspondence to Yoshiyasu Kono.

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Funding

No external funding was used in the preparation of this manuscript.

Conflict of interest

Yoshiyasu Kono, Yasuhiro Choda, Masahiro Nakagawa, Koji Miyahara, Michihiro Ishida, Tetsushi Kubota, Keiji Seo, Tetsu Hirata, Yuka Obayashi, Tatsuhiro Gotoda, Yuki Moritou, Yoshiko Okikawa, Yasuo Iwamoto, Hiroyuki Okada have no conflicts of interest that are directly relevant to the content of this article.

Ethics approval

This retrospective chart review study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The Human Investigation Committee (IRB) of Hiroshima City Hiroshima Citizens Hospital approved this study.

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Informed consent was acquired by the opt-out method.

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Not applicable.

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable.

Author contributions

YK conceived and designed the work and drafted the manuscript. MI, TK, KS, TH, YO, TG, YM, YO, and YI acquired, analyzed or interpreted the data for the work. YC, MN, and KM revised it critically for important intellectual content. MN and HO provided final approval of the version to be published.

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Kono, Y., Choda, Y., Nakagawa, M. et al. Association Between Immune-Related Adverse Events and the Prognosis of Patients with Advanced Gastric Cancer Treated with Nivolumab. Targ Oncol 16, 237–248 (2021). https://doi.org/10.1007/s11523-021-00790-w

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