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Clinical Studies

Three-year outcomes of preoperative chemoradiotherapy plus nivolumab in microsatellite stable and microsatellite instability-high locally advanced rectal cancer

British Journal of Cancer volume 131, pages 283–289 (2024)Cite this article

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Abstract

Background

Preoperative chemoradiotherapy (CRT) followed by surgery is the standard treatment for locally advanced rectal cancer (LARC). We reported the short-term outcomes of the VOLTAGE trial that investigated the safety and efficacy of preoperative CRT followed by nivolumab and surgery. Here, we present the 3-year outcomes of this trial.

Methods

Thirty-nine patients with microsatellite stable (MSS) LARC and five patients with microsatellite instability-high (MSI-H) LARC underwent CRT (50.4 Gy) followed by five doses of nivolumab (240 mg) and surgery. The 3-year relapse-free survival (RFS), overall survival (OS), and associations with biomarkers were evaluated.

Results

The 3-year RFS rates in patients with MSS and MSI-H were 79.5% and 100%, respectively, and the 3-year OS rates were 97.4% and 100%, respectively. Of the MSS patients, those with pre-CRT PD-L1 positivity, pre-CRT high CD8 + T cell/effector regulatory T cell (eTreg) ratio, pre-CRT high expression of Ki-67, CTLA-4, and PD-1 had a trend toward better 3-year RFS than those without.

Conclusions

Three-year outcomes of patients with MSI-H were better than those of patients with MSS. PD-L1 positivity, elevated CD8/eTreg ratio, and high expression of Ki-67, CTLA-4, and PD-1 could be positive predictors of prognosis in patients with MSS.

Clinical trial registration

ClinicalTrials.gov Identifier: NCT02948348.

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Fig. 1: Study flowchart.
Fig. 2: Estimation of survival rates in microsatellite stable and microsatellite instability-high patients and relapse-free survival by response in microsatellite stable patients.
Fig. 3: Swimmer’s plot of overall survival.
Fig. 4: Estimation of relapse-free survival by biomarkers in microsatellite stable patients.

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Data availability

The data generated in this study are available upon request from the corresponding author.

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Acknowledgements

This investigator-initiated trial was funded by Ono Pharmaceutical Co. Ltd. We would like to express special thanks to all the participating patients, their families, all participating investigators, members of the Data and Safety Monitoring Board (Atsushi Sato [Hirosaki University], Keiji Koda [Teikyo University Chiba Medical Centre], and Koji Oba [Tokyo University]), and technical assistants (Miyuki Nakai, Chie Haijima, Megumi Hoshino, Kumiko Yoshida, Tomoka Takaku, Konomi Onagawa, Megumi Takemura, Yumi Osada, Miho Ozawa, and Yuka Nakamura).

Funding

The VOLTAGE study is an investigator-initiated investigational new drug (IND) clinical trial. A research grant and nivolumab were provided by Ono Pharmaceutical Co., Ltd. (Osaka, Japan).

Author information

Author notes

  1. These authors contributed equally: Yuichiro Tsukada, Hideaki Bando, Koji Inamori.

Authors and Affiliations

  1. Department of Colorectal Surgery, National Cancer Center Hospital East, Kashiwa, 277-8577, Japan

    Yuichiro Tsukada, Koji Inamori & Masaaki Ito

  2. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, 277-8577, Japan

    Hideaki Bando, Daisuke Kotani & Takayuki Yoshino

  3. Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo/Kashiwa, 104-0045/277-8587, Japan

    Koji Inamori, Yosuke Togashi, Shohei Koyama & Hiroyoshi Nishikawa

  4. Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, 277-8587, Japan

    Masashi Wakabayashi, Makoto Fukui & Akihiro Sato

  5. Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, 060-8648, Japan

    Satoshi Yuki

  6. Department of Cancer chemotherapy, Hokkaido University Hospital Cancer Center, Sapporo, 060-8648, Japan

    Yoshito Komatsu

  7. Department of Gastroenterological Surgery, Hokkaido University Hospital, Sapporo, 060-8648, Japan

    Shigenori Homma & Akinobu Taketomi

  8. Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, 540-0006, Japan

    Mamoru Uemura & Takeshi Kato

  9. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan

    Mamoru Uemura

  10. Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Kashiwa, 277-8587, Japan

    Naoki Nakamura

  11. Department of Radiation Oncology, St. Marianna University Hospital, Kawasaki, 216-8511, Japan

    Naoki Nakamura

  12. Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, 277-8587, Japan

    Motohiro Kojima

  13. Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan

    Hiroshi Kawachi

  14. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, M5G 1×5, Canada

    Richard Kirsch

  15. Division of Molecular Pathology, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, 252-0374, Japan

    Tsutomu Yoshida

  16. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, 466–8550, Japan

    Hiroyoshi Nishikawa

Authors
  1. Yuichiro Tsukada
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  2. Hideaki Bando
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  3. Koji Inamori
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  4. Masashi Wakabayashi
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  5. Yosuke Togashi
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  6. Shohei Koyama
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  7. Daisuke Kotani
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  8. Satoshi Yuki
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  9. Yoshito Komatsu
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  10. Shigenori Homma
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  11. Akinobu Taketomi
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  12. Mamoru Uemura
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  13. Takeshi Kato
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  14. Makoto Fukui
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  15. Naoki Nakamura
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  16. Motohiro Kojima
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  17. Hiroshi Kawachi
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  18. Richard Kirsch
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  19. Tsutomu Yoshida
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  20. Akihiro Sato
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  21. Hiroyoshi Nishikawa
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  22. Masaaki Ito
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  23. Takayuki Yoshino
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Contributions

Y Tsukada: Conceptualization, Resources, Investigation, Visualization, Writing – original draft. H Bando: Conceptualization, Resources, Investigation, Writing – original draft. K Inamori: Resources, Investigation, Visualization. M Wakabayashi: Data curation, Formal analysis, Methodology, Software, Visualization, Writing – original draft. Y Togashi: Investigation, Writing – review & editing. S Koyama: Resources, Writing – review & editing. D Kotani: Resources, Writing – review & editing. S Yuki: Resources, Investigation, Writing – review & editing. Y Komatsu: Resources, Investigation, Writing – review & editing. S Homma: Resources, Investigation, Writing – review & editing. A Taketomi: Resources, Investigation, Writing – review & editing. M Uemura: Resources, Investigation, Writing – review & editing. T Kato: Resources, Investigation, Writing – review & editing. M Fukui: Validation, Investigation, Writing – review & editing. N Nakamura: Resources, Investigation, Writing – review & editing. M Kojima: Resources, Investigation, Writing – review & editing. H Kawachi: Validation, Investigation, Writing – review & editing. R Kirsch: Validation, Investigation, Writing – review & editing. T Yoshida: Validation, Investigation, Writing – review & editing. A Sato: Data curation, Formal analysis, Project administration, Writing – review & editing. H Nishikawa: Investigation, Supervision, Writing – review & editing. M Ito: Conceptualization, Investigation, Supervision, Writing – review & editing. T Yoshino: Conceptualization, Supervision, Funding acquisition, Writing – review & editing.

Corresponding author

Correspondence to Yuichiro Tsukada.

Ethics declarations

Competing interests

HB has received research funding from AstraZeneca and Sysmex, and honoraria from Taiho Pharmaceutical and Eli Lilly Japan. MW has received honoraria from Nihon Medi-Physics Co., Ltd. YT has received honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, AstraZeneca, and MSD; and research grants from Ono Pharmaceutical, Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, AstraZeneca, KOTAI Biotechnologies Inc, and KORTUC outside this study. SK has received research funding from Otsuka Pharmaceutical and Chugai Pharmaceutical. DK has received honoraria from Takeda, Chugai, Lilly, MSD, Ono, Taiho, Bristol-Myers Squibb, Daiichi-Sankyo, Pfizer, Novartis, Eisai, Seagen, Merck Biopharma, and Sysmex; research funding from Ono, MSD, Novartis, Servier, Janssen, IQVIA, Syneoshealth, Cimic, and Cimicshiftzero. SY has received honoraria from Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Bayer Yakuhin Ltd., Bristol-Myers Squibb K.K., Takeda Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., MSD K.K., Ono Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., and Daiichi Sankyo Co., Ltd. AT has received research grants from Taiho Pharmaceutical, Astellas Pharma, Takeda Pharmaceutical, Bayer Yakuhin, and Ono Pharmaceutical. AS has received research funding from Taiho Pharmaceutical, Boehringer Ingelheim, Bayer, Chugai Pharma, Eisai, Ono Pharmaceutical, Takeda, Aspyerian Therapeutics, Pentax Medical Devices, and Daiichi Sankyo/UCB Japan. HN has received research funding and honoraria from Ono Pharmaceutical, Chugai Pharmaceutical, MSD, and Bristol-Myers Squibb, and research funding from Daiichi-Sankyo, Kyowa Kirin, Zenyaku Kogyo, Taiho Pharmaceutical, Oncolys BioPharma, Debiopharm, Asahi-Kasei, Sysmex, Fujifilm, SRL, Astellas Pharmaceutical, Sumitomo Dainippon Pharma, and BD Japan outside this study. HN also serves as a board member and founder of Sustainable Cell Therapeutics and CELLIAN-BiCLO outside this study. TY has received research grants from Amgen, Chugai, Daiichi Sankyo, Eisai, FALCO Biosystems, Genomedia Inc., Molecular Health, MSD, Nippon Boehringer Ingelheim, Ono, Pfizer, Roche Diagnostics, Sanofi, Sysmex, and Taiho, honoraria from Chugai Pharma, Takeda Pharma, Merck, Bayer Yakuhin, Ono Pharmaceutical, and MSD K.K., and consulting fee from Sumitomo Corp.

Ethics approval and consent to participate

Written informed consent was obtained from all patients. The trial protocol was approved by the institutional review board of each participating site before the initiation of the study. The study was conducted in accordance with the tenets of the Declaration of Helsinki and Good Clinical Practice Guidelines after approval by the ethics board of each institution.

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Written informed consent for publication was obtained from the participants.

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Tsukada, Y., Bando, H., Inamori, K. et al. Three-year outcomes of preoperative chemoradiotherapy plus nivolumab in microsatellite stable and microsatellite instability-high locally advanced rectal cancer. Br J Cancer 131, 283–289 (2024). https://doi.org/10.1038/s41416-024-02730-7

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