{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T17:39:42Z","timestamp":1793036382861,"version":"4.5.0"},"reference-count":21,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100013170","name":"Ono Pharmaceutical","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013170","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Int J Clin Oncol"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Patients with CUP were enrolled regardless of treatment history and received intravenous nivolumab (240\u00a0mg every 2\u00a0weeks or 480\u00a0mg every 4\u00a0weeks) 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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\u20134 and 15.1% serious AEs; no treatment-related deaths occurred. The objective response rate was 17.0% (95% confidence interval [CI] 8.1\u201329.8%) overall and 20.5% (95% CI 9.8\u201335.3%) in the response-evaluable subset. Median progression-free survival was 4.5\u00a0months (95% CI 2.9\u20137.9) and median overall survival was 17.5\u00a0months (95% CI 11.9\u201325.1). Higher PD-L1 expression was associated with better efficacy, whereas no meaningful differences were observed across estimated tissue-of-origin subgroups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>Japan Registry of Clinical Trials (jRCT) identifier, jRCT2051200146.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s10147-026-03187-9","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:45:47Z","timestamp":1790257547000},"page":"2740-2750","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Efficacy and biomarker analysis for nivolumab in cancer of unknown primary: results from an investigator-initiated expanded access program"],"prefix":"10.1007","volume":"31","author":[{"given":"Junko","family":"Tanizaki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kan","family":"Yonemori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Takiguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Akiyoshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keigo","family":"Komine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Onozawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariko","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenro","family":"Hirata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuma","family":"Onoe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryotaro","family":"Ohkuma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Horita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironobu","family":"Minami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazunori","family":"Honda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Suyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiko","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasutaka","family":"Chiba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroko","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Togashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuko","family":"Sakai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuto","family":"Nishio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiko","family":"Nakagawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8787-5587","authenticated-orcid":false,"given":"Hidetoshi","family":"Hayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"issue":"9824","key":"3187_CR1","doi-asserted-by":"publisher","first-page":"1428","DOI":"10.1016\/S0140-6736(11)61178-1","volume":"379","author":"N Pavlidis","year":"2012","unstructured":"Pavlidis N, Pentheroudakis G (2012) Cancer of unknown primary site. 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J.T. also reports personal fees for participation on a Data Safety Monitoring Board or Advisory Board from AstraZeneca, Janssen Pharmaceutical, and Pfizer Japan. K.Y. reports grants or contracts (paid to institution) from MSD, Daiichi Sankyo, Merck Biopharma, AstraZeneca, Taiho Pharmaceutical, Pfizer, Novartis, Takeda Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Sanofi, Seattle Genetics, Eisai, Eli Lilly, Genmab, Boehringer Ingelheim, Kyowa Hakko Kirin, Nippon Kayaku, and Haihe. K.Y. reports personal fees from Pfizer, Eisai, AstraZeneca, Eli Lilly, Takeda Pharmaceutical, Chugai Pharmaceutical, Fujifilm Pharma, PDR Pharma, MSD, Boehringer Ingelheim, Ono Pharmaceutical, Daiichi Sankyo, Bayer, Janssen, Astellas, Bristol Myers Squibb, Novartis, Sanofi, Merck Biopharma, Genmab, and Gilead. K.Y. also reports personal fees for participation on a Data Safety Monitoring Board or Advisory Board from Eisai, AstraZeneca, Sanofi, Genmab, Gilead, Takeda Pharmaceutical, Novartis, MSD, Henlius, Eli Lilly, Daiichi Sankyo, GSK, Haihe, EP Biopharma, and Swanier. Y.Tak. reports personal fees from Oncolys BioPharma. Y.Tak. reports personal fees (honoraria for lectures) from AstraZeneca, Janssen Pharma, and Taiho Pharmaceutical. Y.Tak. also reports personal fees for participation on a Data Safety Monitoring Board or Advisory Board (as Data Monitoring Committee member) from Taiho Pharmaceutical. Ke.H. reports grants or contracts (paid to institution) from Taiho Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, EA Pharma, Pfizer, and Amgen. Ke.H. reports personal fees from Eli Lilly Japan, Taiho Pharmaceutical, Ono Pharmaceutical, Takeda Pharmaceutical, Daiichi Sankyo, Bristol Myers Squibb, Merck Biopharma, MSD, Chugai Pharmaceutical, Astellas Pharma, Zeria Pharmaceutical, Novartis, BeiGene, and Guardant Health. Ke.H. also reports personal fees for participation on a Data Safety Monitoring Board or Advisory Board from Daiichi Sankyo. K.K. reports personal fees from Chugai Pharmaceutical, MSD, Guardant Health, Bristol Myers Squibb, and Daiichi Sankyo. H.M. reports grants or contracts (paid to institution) from Chugai Pharmaceutical, Nippon Kayaku, Teijin Pharma, and Sumitomo Pharma. H.M. reports personal fees from Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Kyowa Kirin, Eli Lilly, Novartis, Otsuka Pharmaceutical, Pfizer, Taiho Pharmaceutical, Takeda Pharmaceutical, Shionogi, GenMab, Miyarisan Pharmaceutical, Rakuten Medical, Guardant Health, Bristol Myers Squibb, BeOne Medicines, Nippon Shinyaku, and Ono Pharmaceutical. Ka.H. reports personal fees from Kyowa Kirin, Eisai, Chugai Pharmaceutical, AstraZeneca, and Celltrion Healthcare Japan. Y.To. reports grants or contracts from Daiichi Sankyo, Takeda Pharmaceutical, Taiho Pharmaceutical, KORTUC, Janssen, AstraZeneca, and Boehringer Ingelheim. Y.To. reports personal fees from Ono Pharmaceutical, Bristol Myers Squibb, MSD, Chugai Pharmaceutical, Eisai, and AstraZeneca. Ka.S. reports personal fees from Takeda Pharmaceutical, Nippon Kayaku, Qiagen, and Life Technologies Japan. Kazuto.N. reports grants or contracts (paid to institution) from West Japan Oncology Group, Hitachi Osakaminami Hospital, Thoracic Oncology Research Group, Eli Lilly Japan, Okayama University, Japan Breast Cancer Research Group, Nippon Boehringer Ingelheim, Otsuka Pharmaceutical, and Kyushu Study Group of Clinical Cancer. Kazuto.N. reports personal fees from SymBio Pharmaceuticals, Eli Lilly Japan, Otsuka Pharmaceutical, Chugai Pharmaceutical, MSD, Guardant Health, Janssen Pharmaceutical, AstraZeneca, Nichirei, Maruho, Daiichi Sankyo, Nittobo Medical, and Nihon Servier. Kazuhiko.N. reports grants or contracts (paid to institution) from A2 Healthcare, AbbVie, Amgen, Ascent Development Services, Astellas Pharma, AstraZeneca, Bayer Yakuhin, Bristol Myers Squibb, Chugai Pharmaceutical, CMIC, Eisai, EP-CRSU, EPS Corporation, GlaxoSmithKline, ICON Clinical Research, IQVIA, Janssen Pharmaceutical, Japan Clinical Cancer Research Organization, Kobayashi Pharmaceutical, Labcorp Development Japan, MSD, Nippon Boehringer Ingelheim, Nippon Kayaku, Otsuka Pharmaceutical, Pfizer Japan, Pfizer R&D Japan, PRA Health Sciences, Sanofi, Shionogi, SRL Medisearch, SYNEOS HEALTH CLINICAL, Taiho Pharmaceutical, Takeda Pharmaceutical, and Thoracic Oncology Research Group. Kazuhiko.N. reports personal fees from Ono Pharmaceutical, Eli Lilly Japan, 3H Medi Solution, AstraZeneca, Bayer Yakuhin, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Global Health Consulting Japan, Hisamitsu Pharmaceutical, Incyte Biosciences Japan, Janssen Pharmaceutical, M3, Medical Mobile Communications, MedPartners, Merck Biopharma, MSD, Nippon Boehringer Ingelheim, Novartis, Otsuka Pharmaceutical Factory, Patientricity, Pfizer Japan, Taiho Pharmaceutical, The Yomiuri Shimbun, and YODOSHA. H.H. reports grants or contracts (paid to institution) from A2 Healthcare, AbbVie, Aichi Cancer Network, Amgen, Ascent Development Services, Astellas Pharma, AstraZeneca, Bayer Yakuhin, Boehringer Ingelheim International, Bristol Myers Squibb, Chugai Pharmaceutical, CMIC, Comprehensive Support Project for Oncological Research of Breast Cancer, Daiichi Sankyo, Eisai, Eli Lilly Japan, EPS Corporation, Fortrea Japan, GlaxoSmithKline, ICON Clinical Research, Intellim, IQVIA, Janssen Pharmaceutical, Japan Breast Cancer Research Group, Japanese Gastric Cancer Association, Kobayashi Pharmaceutical, Kyowa Kirin, Kyushu Study Group of Clinical Cancer, Labcorp Development Japan, Mebix, Mediscience Planning, Medpace Japan, Merck Biopharma, Mochida Pharmaceutical, MSD, National Cancer Center, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis, Novocure, Ono Pharmaceutical, Osaka Gyoumeikan Hospital, PAREXEL International, Pfizer Japan, Pfizer R&D Japan, PPD-SNBL, PRA Health Sciences, Public Health Research Foundation, Sanofi, SYNEOS HEALTH CLINICAL, Sysmex, Taiho Pharmaceutical, Thoracic Oncology Research Group, and West Japan Oncology Group. H.H. reports personal fees from AbbVie, Amgen, AstraZeneca, BeOne Medicines, Bristol Myers Squibb, Care Net, Chugai Pharmaceutical, CMIC Inizio, Daiichi Sankyo, Eisai, Eli Lilly Japan, Exact Sciences, Gilead Sciences, Hisamitsu Pharmaceutical, Ishiyaku Publishers, Janssen Pharmaceutical, Kyowa Kirin, Medical Review, Merck Biopharma, MSD, Nikkei Visual Images, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis, Novocure, Ono Pharmaceutical, Pfizer Japan, Regeneron Japan, Reno. Medical, Taiho Pharmaceutical, and Takeda Pharmaceutical. H.H. also reports personal fees for participation on a Data Safety Monitoring Board or Advisory Board from AbbVie, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Henlius, Innovent Biologics, Janssen Pharmaceutical, Junshi Pharmaceuticals, Nippon Boehringer Ingelheim, Nippon Kayaku, and Novocure. The remaining authors declare no competing interests.","order":1,"name":"Ethics","label":"Conflict of interests","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and national research committees and with the 1964 Helsinki Declaration and its later amendments, as well as with the International Conference for Harmonisation Good Clinical Practice Guideline. The study protocol was approved by the institutional review board at each participating site.","order":2,"name":"Ethics","label":"Ethics approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Written informed consent was obtained from all individual participants included in the study before enrollment.","order":3,"name":"Ethics","label":"Consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable. The manuscript does not contain identifying information for any individual participant.","order":4,"name":"Ethics","label":"Consent to publish","group":{"name":"EthicsHeading","label":"Declarations"}}]}}