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Peer-reviewedCC BY 4.0International Journal of Clinical Oncology

Efficacy and biomarker analysis for nivolumab in cancer of unknown primary: results from an investigator-initiated expanded access program

  • Junko Tanizaki1
  • Kan Yonemori2
  • Yuichi Takiguchi3
  • Kohei Akiyoshi4
  • Keigo Komine5
  • Yusuke Onozawa6
  • Mariko Sato7
  • Kenro Hirata8
  • Takuma Onoe9
  • Ryotaro Ohkuma10
  • Yosuke Horita11
  • Hironobu Minami12
10 more authors
  • Kazunori Honda13
  • Koichi Suyama14
  • Akihiko Ito15
  • Yasutaka Chiba16
  • Hiroko Watanabe17
  • Yosuke Togashi17
  • Kazuko Sakai18
  • Kazuto Nishio18
  • Kazuhiko Nakagawa19
  • Hidetoshi Hayashi1
19 affiliations
  1. 1Department of Medical Oncology, Kindai University Faculty of Medicine, 1-14-1 Mihara-dai, Minami-ku, Sakai, Osaka 590-0197 Japan
  2. 2Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
  3. 3Medical Oncology Department, Chiba University, Chiba, Japan
  4. 4Department of Medical Oncology, Osaka City General Hospital, Osaka, Japan
  5. 5Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan
  6. 6Division of Clinical Oncology, Shizuoka Cancer Center, Shizuoka, Japan
  7. 7Department of Medical Oncology, NHO Nagoya Medical Center, Nagoya, Japan
  8. 8Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
  9. 9Department of Medical Oncology, Hyogo Cancer Center, Akashi, Japan
  10. 10Department of Medicine, Division of Medical Oncology, Graduate School of Medicine, Showa Medical University, Tokyo, Japan
  11. 11Department of Medical Oncology, Saitama Medical University International Medical Center, Saitama, Japan
  12. 12Department of Medical Oncology/Hematology, Kobe University Graduate School of Medicine and Hospital, Kobe, Japan
  13. 13Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
  14. 14Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan
  15. 15Department of Pathology, Kindai University Faculty of Medicine, Osaka, Japan
  16. 16Clinical Research Center, Kindai University Hospital, Osaka, Japan
  17. 17Department of Tumor Microenvironment, Faculty of Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
  18. 18Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan
  19. 19Kindai University Hospital Cancer Center, Osaka, Japan
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Abstract

Background: Cancer of unknown primary (CUP) remains a challenging malignancy with a poor prognosis. Although immune checkpoint inhibitors have shown activity in CUP, available data remains limited. We describe clinical outcomes and a comprehensive biomarker analysis from an expanded access trial of nivolumab in CUP.

Methods: Patients with CUP were enrolled regardless of treatment history and received intravenous nivolumab (240 mg every 2 weeks or 480 mg every 4 weeks) until disease progression, unacceptable toxicity, or withdrawal. Enrollment concluded after regulatory approval of nivolumab for CUP in Japan. The primary objective was safety; secondary endpoints addressed efficacy, and exploratory biomarker analyses were performed.

Results: A total of 53 patients (31 previously treated, 22 untreated) received nivolumab. Adverse events (AEs) occurred in 77.4% of patients, including 24.5% grade 3–4 and 15.1% serious AEs; no treatment-related deaths occurred. The objective response rate was 17.0% (95% confidence interval [CI] 8.1–29.8%) overall and 20.5% (95% CI 9.8–35.3%) in the response-evaluable subset. Median progression-free survival was 4.5 months (95% CI 2.9–7.9) and median overall survival was 17.5 months (95% CI 11.9–25.1). Higher PD-L1 expression was associated with better efficacy, whereas no meaningful differences were observed across estimated tissue-of-origin subgroups.

Conclusions: This study provides additional prospective evidence consistent with the preceding NivoCUP trial, supporting the reproducibility of the efficacy and safety of nivolumab for patients with CUP. These findings support PD-1-targeted therapy as a feasible treatment option for this rare malignancy.

Trial registration: Japan Registry of Clinical Trials (jRCT) identifier, jRCT2051200146.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s10147-026-03187-9.

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Cite

BibTeXRIS
BibTeX
@article{tanizaki2026efficacy,
  title = {{Efficacy and biomarker analysis for nivolumab in cancer of unknown primary: results from an investigator-initiated expanded access program}},
  author = {Junko Tanizaki and Kan Yonemori and Yuichi Takiguchi and Kohei Akiyoshi and Keigo Komine and Yusuke Onozawa and Mariko Sato and Kenro Hirata and Takuma Onoe and Ryotaro Ohkuma and Yosuke Horita and Hironobu Minami and Kazunori Honda and Koichi Suyama and Akihiko Ito and Yasutaka Chiba and Hiroko Watanabe and Yosuke Togashi and Kazuko Sakai and Kazuto Nishio and Kazuhiko Nakagawa and Hidetoshi Hayashi},
  journal = {International Journal of Clinical Oncology},
  year = {2026},
  month = sep,
  doi = {10.1007/s10147-026-03187-9},
  url = {https://doi.org/10.1007/s10147-026-03187-9},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Efficacy and biomarker analysis for nivolumab in cancer of unknown primary: results from an investigator-initiated expanded access program
AU  - Junko Tanizaki
AU  - Kan Yonemori
AU  - Yuichi Takiguchi
AU  - Kohei Akiyoshi
AU  - Keigo Komine
AU  - Yusuke Onozawa
AU  - Mariko Sato
AU  - Kenro Hirata
AU  - Takuma Onoe
AU  - Ryotaro Ohkuma
AU  - Yosuke Horita
AU  - Hironobu Minami
AU  - Kazunori Honda
AU  - Koichi Suyama
AU  - Akihiko Ito
AU  - Yasutaka Chiba
AU  - Hiroko Watanabe
AU  - Yosuke Togashi
AU  - Kazuko Sakai
AU  - Kazuto Nishio
AU  - Kazuhiko Nakagawa
AU  - Hidetoshi Hayashi
PY  - 2026
DA  - 2026/09/24
JO  - International Journal of Clinical Oncology
DO  - 10.1007/s10147-026-03187-9
UR  - https://doi.org/10.1007/s10147-026-03187-9
AB  - Background: Cancer of unknown primary (CUP) remains a challenging malignancy with a poor prognosis. Although immune checkpoint inhibitors have shown activity in CUP, available data remains limited. We describe clinical outcomes and a comprehensive biomarker analysis from an expanded access trial of nivolumab in CUP.  Methods: Patients with CUP were enrolled regardless of treatment history and received intravenous nivolumab (240 mg every 2 weeks or 480 mg every 4 weeks) until disease progression, unacceptable toxicity, or withdrawal. Enrollment concluded after regulatory approval of nivolumab for CUP in Japan. The primary objective was safety; secondary endpoints addressed efficacy, and exploratory biomarker analyses were performed.  Results: A total of 53 patients (31 previously treated, 22 untreated) received nivolumab. Adverse events (AEs) occurred in 77.4% of patients, including 24.5% grade 3–4 and 15.1% serious AEs; no treatment-related deaths occurred. The objective response rate was 17.0% (95% confidence interval [CI] 8.1–29.8%) overall and 20.5% (95% CI 9.8–35.3%) in the response-evaluable subset. Median progression-free survival was 4.5 months (95% CI 2.9–7.9) and median overall survival was 17.5 months (95% CI 11.9–25.1). Higher PD-L1 expression was associated with better efficacy, whereas no meaningful differences were observed across estimated tissue-of-origin subgroups.  Conclusions: This study provides additional prospective evidence consistent with the preceding NivoCUP trial, supporting the reproducibility of the efficacy and safety of nivolumab for patients with CUP. These findings support PD-1-targeted therapy as a feasible treatment option for this rare malignancy.  Trial registration: Japan Registry of Clinical Trials (jRCT) identifier, jRCT2051200146.  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s10147-026-03187-9.
SN  - 1341-9625
SN  - 1437-7772
ER  -