Gastric Cancer

, Volume 22, Issue 4, pp 793–802 | Cite as

Predictive factors for hyperprogressive disease during nivolumab as anti-PD1 treatment in patients with advanced gastric cancer

  • Akinori Sasaki
  • Yoshiaki Nakamura
  • Saori Mishima
  • Akihito Kawazoe
  • Yasutoshi Kuboki
  • Hideaki Bando
  • Takashi Kojima
  • Toshihiko Doi
  • Atsushi Ohtsu
  • Takayuki Yoshino
  • Takeshi Kuwata
  • Tetsuo Akimoto
  • Kohei ShitaraEmail author
Original Article



Hyperprogressive disease (HPD) during treatment with anti-programmed death-1/programmed death-ligand 1 monoclonal antibodies has anecdotally been reported in some types of cancers, but is not well-characterized in patients with advanced gastric cancer (AGC).


Total 62 AGC patients treated with nivolumab in a single institution from September 2017 to April 2018 were enrolled in this study. Tumor responses were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1, and HPD was defined as ≥ two fold increase in tumor growth rate. Clinicopathological and molecular characteristics associated with HPD were also investigated.


Thirteen of 62 patients (21%) developed HPD after nivolumab treatment. Overall survival (OS) and progression-free survival (PFS) were significantly shorter in patients with HPD than in patients without HPD (median OS: 2.3 months vs. not reached, P < 0.001; median PFS: 0.7 months vs. 2.4 months, P < 0.001). Liver metastases (77% vs. 41%), Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or 2 (77% vs. 29%), and a large sum of target lesion diameters at baseline (median 104.2 mm vs. 44.9 mm) were significantly associated with HPD. Absolute neutrophil count (ANC) and C-reactive protein (CRP) level significantly increased in the first 4 weeks in only patients with HPD.


HPD was observed in AGC patients treated with nivolumab and correlated with some clinicopathological characteristics. Elevations in ANC and CRP levels upon treatment might indicate HPD.


Nivolumab PD-1 inhibitor Gastric cancer Hyperprogressive disease 



Anti-programmed death-1


Programmed death-ligand 1


Monoclonal antibodies


Hyperprogressive disease


Advanced gastric cancer


Overall survival


Progression-free survival


Eastern Cooperative Oncology Group performance status


Absolute neutrophil count


C-reactive protein


Human epidermal growth factor receptor 2


Mismatch repair


Epstein–Barr virus




Fluorescence in situ hybridization


Tumor cell


Immune cell


Combined positive score


Anti-mutL homolog 1


Anti-mutS homolog 2


Anti-postmeiotic segregation increased 2


Anti-mutS homolog 6


EBV-encoded RNA


Tumor mutation burden




Neutrophil-to-lymphocyte ratio


Lactate dehydrogenase


Tumor growth kinetics


TGK ratio


Hazard ratio


Confidence interval


Partial response


Stable disease


Progressive disease


Mitogen-activated protein kinase


Myeloid-derived suppressor cell


Author contributions

AS, YN, SM, AK, and KS designed the study, collected data, performed data analysis, and wrote manuscript. YK, HB, TD, TY, TK, and TA were involved in data interpretation and critically reviewing the manuscript. TK was involved in testing tumor tissue as well as critically reviewing the manuscript. All authors read and approved the final manuscript.


This study was supported by a research funding from National Cancer Center Hospital East (none apply).

Compliance with ethical standards

Ethics approval and consent to participate

All procedures followed in this study were in accordance with the Declaration of Helsinki of 1964 and later versions and the Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects. Informed consent for it was obtained from all patients for their being included in the study.

Consent for publication

This is not applicable for this study.

Conflict of interest

AS has nothing to disclose. YN reports personal fees from Chugai. SM has nothing to disclose. AK reports research funding from Ono, Sumitomo Dainippon, and Taiho. YK reports consulting or advisory role for Takeda; personal fees from Bayer, Lilly, and Taiho; and research funding from Astra Zeneca, Daiichi Sankyo, Incyte, Taiho, and Takeda. HB reports research funding from Astra Zeneca and Sysmex. TK reports personal fees from MSD; and research funding from Astellas, Bristol-Myers Squibb, MSD, Oncolys BioPharma, Ono, Shionogi. TD reports consulting or advisory role for Amgen, Chugai, Daiichi Sankyo, Kyowa Hakko Kirin, Lilly, MSD, Sumitomo Dainippon, and Taiho; and research funding from Abbvie, Astellas, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chugai, Daiichi Sankyo, Janssen, Kyowa Hakko Kirin, Lilly, Merck Serono, MSD, Novartis, Pfizer, Quintiles, Sumitomo Group, Takeda, and Taiho. AO reports personal fees from Bristol-Myers Squibb, Chugai, Ono, and Taiho. TY consulting or advisory role for Chugai, Lilly, Merck Serono, and Sanofi; and research funding from Chugai, GlaxoSmithKline, MSD, Nippon Boehringer Ingelheim, Sanofi, and Sumitomo Dainippon. TK consulting or advisory role for ThermoFisher Inc; personal fees from Chugai and Roche Diagnostics; and research funding from Daiichi Sankyo. TA has nothing to disclose. KS reports consulting or advisory role for Astellas, Bristol-Myers Squibb, Lilly, Ono, Pfizer, and Takeda; personal fees from AbbVie, Novartis, and Yakult; and research funding from Chugai, Daiichi Sankyo, Lilly, MSD, Ono, Sumitomo Dainippon, and Taiho.

Supplementary material

10120_2018_922_MOESM1_ESM.docx (23 kb)
Supplementary material 1 (DOCX 23 KB)
10120_2018_922_MOESM2_ESM.docx (19 kb)
Supplementary material 2 (DOCX 18 KB)
10120_2018_922_MOESM3_ESM.docx (14 kb)
Supplementary material 3 (DOCX 14 KB)


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Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2019

Authors and Affiliations

  • Akinori Sasaki
    • 1
    • 2
  • Yoshiaki Nakamura
    • 1
  • Saori Mishima
    • 1
  • Akihito Kawazoe
    • 1
  • Yasutoshi Kuboki
    • 1
  • Hideaki Bando
    • 1
  • Takashi Kojima
    • 1
  • Toshihiko Doi
    • 1
  • Atsushi Ohtsu
    • 1
  • Takayuki Yoshino
    • 1
  • Takeshi Kuwata
    • 3
  • Tetsuo Akimoto
    • 2
    • 4
  • Kohei Shitara
    • 1
    Email author
  1. 1.Department of Gastroenterology and Gastrointestinal OncologyNational Cancer Center Hospital EastKashiwaJapan
  2. 2.Courses of Advanced Clinical Research of CancerJuntendo University Graduate School of MedicineTokyoJapan
  3. 3.Department of Pathology and Clinical LaboratoriesNational Cancer Center Hospital EastKashiwaJapan
  4. 4.Department of Radiation OncologyNational Cancer Center Hospital EastKashiwaJapan

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