Efficacy and safety of nivolumab in Japanese patients with first recurrence of glioblastoma: an open-label, non-comparative study

Tomokazu Aoki¹, Naoki Kagawa², Kazuhiko Sugiyama³, Toshihiko Wakabayashi⁴, Yoshiki Arakawa⁵, Shigeru Yamaguchi⁶, Shota Tanaka⁷, Eiichi Ishikawa⁸, Yoshihiro Muragaki⁹, Motoo Nagane¹⁰, Mitsutoshi Nakada¹¹, Satoshi Suehiro¹², Nobuhiro Hata¹³, Junichiro Kuroda¹⁴, Yoshitaka Narita¹⁵, Yukihiko Sonoda¹⁶, Yasuo Iwadate¹⁷, Manabu Natsumeda¹⁸, Yoichi Nakazato¹⁹, Hironobu Minami²⁰, Yuki Hirata²¹, Shunsuke Hagihara²², Ryo Nishikawa²³

Affiliations

¹ Department of Neurosurgery, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihatacho, Fushimi Ward, Kyoto, 612-8555, Japan. totorolangdom@yahoo.co.jp.
² Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan.
³ Department of Clinical Oncology and Neuro-Oncology Program, Hiroshima University Hospital, Hiroshima, Japan.
⁴ Department of Neurosurgery, Nagoya University Hospital, Nagoya, Japan.
⁵ Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁶ Department of Neurosurgery, Hokkaido University Hospital, Hokkaido, Japan.
⁷ Department of Neurosurgery, The University of Tokyo Hospital, Tokyo, Japan.
⁸ Department of Neurosurgery, University of Tsukuba Hospital, Ibaraki, Japan.
⁹ Department of Neurosurgery, Tokyo Women's Medical University Hospital, Tokyo, Japan.
¹⁰ Faculty of Medicine, Department of Neurosurgery, Kyorin University, Tokyo, Japan.
¹¹ Department of Neurosurgery, Kanazawa University Hospital, Kanazawa, Japan.
¹² Department of Neurosurgery, Ehime University Hospital, Ehime, Japan.
¹³ Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹⁴ Department of Neurosurgery, Kumamoto University Hospital, Kumamoto, Japan.
¹⁵ Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan.
¹⁶ Department of Neurosurgery, Yamagata University Hospital, Yamagata, Japan.
¹⁷ Department of Neurological Surgery, Chiba University Hospital, Chiba, Japan.
¹⁸ Department of Neurosurgery, Niigata University Medical and Dental Hospital, Niigata, Japan.
¹⁹ Hidaka Center for Pathologic Diagnosis and Research, Hidaka Hospital, Gunma, Japan.
²⁰ Department Medical Oncology/Hematology, Kobe University, Kobe, Japan.
²¹ Oncology Early Clinical Development Planning, Ono Pharmaceutical Co., Ltd, Osaka, Japan.
²² Department of Statistical Analysis, Ono Pharmaceutical Co., Ltd, Osaka, Japan.
²³ Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, Japan.

PMID: 34586548
PMCID: PMC8580927
DOI: 10.1007/s10147-021-02028-1

Efficacy and safety of nivolumab in Japanese patients with first recurrence of glioblastoma: an open-label, non-comparative study

Tomokazu Aoki et al. Int J Clin Oncol. 2021 Dec.

. 2021 Dec;26(12):2205-2215.

doi: 10.1007/s10147-021-02028-1. Epub 2021 Sep 29.

Authors

Affiliations

¹ Department of Neurosurgery, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihatacho, Fushimi Ward, Kyoto, 612-8555, Japan. totorolangdom@yahoo.co.jp.
² Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan.
³ Department of Clinical Oncology and Neuro-Oncology Program, Hiroshima University Hospital, Hiroshima, Japan.
⁴ Department of Neurosurgery, Nagoya University Hospital, Nagoya, Japan.
⁵ Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁶ Department of Neurosurgery, Hokkaido University Hospital, Hokkaido, Japan.
⁷ Department of Neurosurgery, The University of Tokyo Hospital, Tokyo, Japan.
⁸ Department of Neurosurgery, University of Tsukuba Hospital, Ibaraki, Japan.
⁹ Department of Neurosurgery, Tokyo Women's Medical University Hospital, Tokyo, Japan.
¹⁰ Faculty of Medicine, Department of Neurosurgery, Kyorin University, Tokyo, Japan.
¹¹ Department of Neurosurgery, Kanazawa University Hospital, Kanazawa, Japan.
¹² Department of Neurosurgery, Ehime University Hospital, Ehime, Japan.
¹³ Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹⁴ Department of Neurosurgery, Kumamoto University Hospital, Kumamoto, Japan.
¹⁵ Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan.
¹⁶ Department of Neurosurgery, Yamagata University Hospital, Yamagata, Japan.
¹⁷ Department of Neurological Surgery, Chiba University Hospital, Chiba, Japan.
¹⁸ Department of Neurosurgery, Niigata University Medical and Dental Hospital, Niigata, Japan.
¹⁹ Hidaka Center for Pathologic Diagnosis and Research, Hidaka Hospital, Gunma, Japan.
²⁰ Department Medical Oncology/Hematology, Kobe University, Kobe, Japan.
²¹ Oncology Early Clinical Development Planning, Ono Pharmaceutical Co., Ltd, Osaka, Japan.
²² Department of Statistical Analysis, Ono Pharmaceutical Co., Ltd, Osaka, Japan.
²³ Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, Japan.

PMID: 34586548
PMCID: PMC8580927
DOI: 10.1007/s10147-021-02028-1

Abstract

Background: An open-label, non-comparative study assessed the efficacy and safety of nivolumab in Japanese patients with first recurrence glioblastoma.

Methods: Patients with first recurrence of histologically confirmed World Health Organization Grade IV glioma, after treatment with temozolomide and radiotherapy, received nivolumab 3 mg/kg every 2 weeks until confirmed disease progression (Response Assessment in Neuro-Oncology criteria) or toxicity. Primary endpoint was 1-year overall survival rate assessed by Bayesian approach. The prespecified efficacy criterion was that the Bayesian posterior probability threshold for exceeding the 1-year overall survival of bevacizumab (34.5%) from the Japanese phase 2 study (JO22506) would be 93%.

Results: Of the 50 enrolled patients, 44 (88.0%) had recurrent malignant glioma (glioblastoma, gliosarcoma), and of these, 26 (59.1%) had at least one measurable lesion at baseline. The Bayesian posterior mean 1-year overall survival (90% Bayesian credible intervals) with nivolumab was 54.4% (42.27-66.21), and the Bayesian posterior probability of exceeding the threshold of the 1-year overall survival rate of bevacizumab (34.5%) was 99.7%. Median (90% confidence interval) overall and progression-free survival was 13.1 (10.4-17.7) and 1.5 (1.4-1.5) months, respectively. One partial response was observed (objective response rate 1/26 evaluable patients [3.8%]). Treatment-related adverse event rates were 14.0% for Grade 3-4 and 2.0% for Grade 5; most adverse events resolved and were manageable.

Conclusions: The 1-year overall survival with nivolumab monotherapy in Japanese patients with glioblastoma met the prespecified efficacy criterion. The safety profile of nivolumab was consistent with that observed in other tumor types.

Clinical trial registration: JapicCTI-152967.

Keywords: Bayesian approach; Bevacizumab; Clinical Trial; Glioblastoma; Nivolumab; Phase II; Programmed cell death.

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Conflict of interest statement

T. Aoki, N. Kagawa, T. Wakabayashi, S. Yamaguchi, E. Ishikawa, S. Suehiro, J. Kuroda, Y. Iwadate, M. Natsumeda, Y. Nakazato, and S. Hagihara have no conflicts of interest to declare. K. Sugiyama has received research funding from Ono Pharmaceutical Co., Ltd., Daiichi-Sankyo Co., Ltd., and Sumitomo Dainippon Pharma Co. Ltd. Y. Arakawa has received research funding from Ono Pharmaceutical Co., Ltd., Siemens, Philips, Chugai Pharmaceutical Co., Ltd., Daiichi-Sankyo Co., Ltd., and Taiho Pharmaceutical Co., Ltd.; and honoraria from Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., and Daiichi-Sankyo Co., Ltd. S. Tanaka has received research funding from Eisai Co., Ltd., Ono Pharmaceutical Co., Ltd., and Sumitomo Dainippon Pharma Co. Ltd. Y. Muragaki has received lecture fees, honoraria, or other fees from Eisai Co., Ltd. and Novocure Limited. M. Nagane has received lecture fees, honoraria, or other fees from MSD and Ono Pharmaceutical Co., Ltd.; has received research funding from Toray Industries, Inc., AbbVie Inc., and Ono Pharmaceutical Co., Ltd.; and has received scholarship (incentive) endowments or research grants from Eisai Co., Ltd., Pfizer, Nippon Kayaku Co., Ltd., and Chugai Pharmaceutical Co., Ltd. M. Nakada has received research funding from Ono Pharmaceutical Co., Ltd.; and has received scholarship (incentive) endowments or research grants from Otsuka Pharmaceutical Co., Ltd., Stryker Corporation, Eisai Co., Ltd., MSD, and Chugai Pharmaceutical Co., Ltd. N. Hata has received research funding from Daiichi-Sankyo Co., Ltd. Y. Narita has received research funding from Eisai Co., Ltd., Ono Pharmaceutical Co., Ltd., AbbVie Inc., Bayer AG, Sumitomo Dainippon Pharma Co. Ltd., Taiho Pharmaceutical Co., Ltd., and Daiichi-Sankyo Co., Ltd. Y. Sonoda has received scholarship (incentive) endowments or research grants from Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and Fujifilm. H. Minami has received lecture fees, honoraria, or other fees from Daiichi-Sankyo Co., Ltd. and Ono Pharmaceutical Co., Ltd.; has received research funding from Amgen Astellas BioPharma K.K., Bayer AG, Bristol-Myers Squibb, Daiichi-Sankyo Co., Ltd., Novartis, Pfizer, and Ono Pharmaceutical Co., Ltd.; and has received scholarship (incentive) endowments or research grants from Astellas, Bayer AG, Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., Daiichi-Sankyo Co., Ltd., Kyowa Kirin, Eli Lilly, Ono Pharmaceutical Co., Ltd., Pfizer, Taiho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Company Limited. Y. Hirata is an employee and shareholder at Ono Pharmaceutical Co., Ltd. R. Nishikawa has received manuscript fees from Eisai Co., Ltd.; has received research funding from AbbVie Inc., Daiichi-Sankyo Co., Ltd., Ono Pharmaceutical Co., Ltd., Toray Industries, Inc., and Medi-Physics, Inc.; and has received scholarship (incentive) endowments or research grants from Chugai Pharmaceutical Co., Ltd. and MSD.

Figures

**Fig. 1**
a Overall survival and b progression-free survival by central assessment. Vertical dashes represent censored observations. CI confidence interval, *mOS* modified overall survival, *mPFS* modified progression-free survival, *PFS* progression-free survival

**Fig. 2**
a Percentage change and b maximum percentage change from baseline in SPD of measurable lesions by investigator assessment. Panel a includes measurements from baseline to follow-up (including measurements after PD documentation). N = 31 patients; 13 patients who had a best overall response of NE^a were excluded. Panel b includes measurements from baseline up to PD documentation. N = 29; 13 patients who had a best overall response of NE^a and two patients with no MRI prior to a diagnosis of PD based on clinical deterioration were excluded. ^aWhere NE was owing to no measurable lesion available by investigator review or no evaluable MRI scans available after dosing. *MRI* magnetic resonance imaging, NE not estimable, PD progressive disease, *SPD* sum of the products of maximal perpendicular diameter

See this image and copyright information in PMC

References

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Efficacy and safety of nivolumab in Japanese patients with first recurrence of glioblastoma: an open-label, non-comparative study

Affiliations

Efficacy and safety of nivolumab in Japanese patients with first recurrence of glioblastoma: an open-label, non-comparative study

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

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LinkOut - more resources

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Miscellaneous