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Efficacy and safety of ramucirumab-containing chemotherapy in patients with pretreated metastatic gastric neuroendocrine carcinoma
  1. Saori Mishima1,
  2. Akihito Kawazoe1,
  3. Hiroshi Matsumoto1,
  4. Yasutoshi Kuboki1,
  5. Hideaki Bando1,
  6. Takashi Kojima1,
  7. Toshihiko Doi1,
  8. Atsushi Ohtsu1,
  9. Takayuki Yoshino1,
  10. Elizabeth M Nonte2,
  11. Sudhakar Chintharlapalli3,
  12. Aejaz Nasir2,
  13. Takeshi Kuwata4,
  14. Kohei Shitara1
  1. 1 Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
  2. 2 Tailored Therapeutics, Diagnostic & Experimental Pathology, Eli Lilly and Company, Indianapolis, Indiana, USA
  3. 3 Angiogenesis & Tumor Microenvironment Biology, Eli Lilly and Company, Indianapolis, Indiana, USA
  4. 4 Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan
  1. Correspondence to Dr Kohei Shitara; kshitara{at}


Background Ramucirumab (RAM), a monoclonal antibody for vascular endothelial growth factor 2 (VEGFR2), has been effective for advanced gastric adenocarcinoma (AC). However, little is known about the efficacy of RAM-containing chemotherapy (RAM-CTx) in gastric neuroendocrine carcinoma (G-NEC).

Methods We retrospectively analysed and compared the clinical outcomes of patients (pts) with G-NEC receiving RAM-CTx, G-NEC receiving CTx without RAM and AC receiving RAM-CTx in our hospital. G-NEC was defined by neuroendocrine carcinoma features, regardless of the proportion, based on histology and neuroendocrine markers (synaptophysin, chromogranin A or CD56). VEGFR2 expression in tumour vessels was evaluated in archival primary G-NEC tissues by immunohistochemistry using the same anti-VEGFR2 primary antibody and scoring scheme (vascular VEGFR2 H-score) as in the REGARD trial.

Results Seventeen G-NEC receiving RAM-CTx, 13 G-NEC receiving CTx without RAM and 173 AC pts receiving RAM-CTx were analysed. The overall response rate (59% vs 8 % vs 28%), progression-free survival (median 7.7 vs 1.8 vs 3.3 months) and overall survival (median 16.1 vs 8.6 vs 9.6 months) were significantly better in pts with G-NEC receiving RAM-CTx than G-NEC receiving CTx without RAM or AC receiving RAM-CTx. No severe or unexpected adverse events occurred. The median vascular VEGFR2 H-score, based on available G-NEC tissues from 12 pts receiving RAM-CTx, was 220 (range 150–260), which was markedly higher than that reported on AC tissues from the REGARD trial as historical control (median 35, range 0–240).

Conclusions RAM-CTx showed a promising activity without severe or unexpected safety profile in pts with G-NEC. This may in part be explained by higher vascular VEGFR2 expression in G-NEC tissues.

  • gastric neuroendocrine carcinoma
  • ramucirumab
  • VEGFR2

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  • Contributors SM, AK, HM and KS designed the study, collected the data, performed the data analysis and wrote the manuscript. YK, HB, TK, TD, AO and TY were involved in data interpretation and critically reviewing the manuscript. TK, EMN, SC and AN were involved in testing the tumour tissue as well as critically reviewing the manuscript. All authors read and approved the final manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests YK reports personal fees from Taiho Pharmaceutical, personal fees from Bayer, and personal fees from Eli Lilly and Company. HB reports personal fees from Eli Lilly and Company. TY reports personal fees from Taiho Pharmaceutical, personal fees from Eli Lilly and Company and personal fees from Chugai Pharmaceutical. EMN, SC and AN are employees of Eli Lilly and Company. TK reports personal fees from Chugai Pharmaceutical and grants from Daiichi Sankyo. KS reports personal fees from Astellas Pharma, grants and personal fees from Lilly, personal fees from Bristol-Myers Squibb, personal fees from Takeda, personal fees from Pfizer, grants and personal fees from Ono Pharmaceutical, personal fees from Novartis, personal fees from AbbVie, personal fees from Yakult, grants from Dainippon Sumitomo Pharma, grants from MSD, grants from Daiichi Sankyo, grants from Taiho Pharmaceutical and grants from Chugai Pharma, outside the submitted work. The other authors declare that they have no competing interest.

  • Patient consent Obtained.

  • Ethics approval This study was performed under an institutional review board waiver in accordance with the Japanese ethical guidelines for epidemiological research. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and informed consent.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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