{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T15:39:53Z","timestamp":1788881993614,"version":"build-2803163510"},"reference-count":22,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"BeOne Medicines, Ltd."}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Esophagus"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>In the global phase 3 RATIONALE-306 study (NCT03783442), first-line tislelizumab plus chemotherapy showed significant overall survival (OS) benefit versus chemotherapy alone for unresectable locally advanced\/metastatic esophageal squamous cell carcinoma (ESCC). We report post hoc results for the Japanese subgroup.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Eligible Japanese patients were randomized (1:1) to tislelizumab 200\u00a0mg or placebo every 3\u00a0weeks plus chemotherapy (cisplatin plus fluoropyrimidine) and included in the Japanese analysis set. Endpoints included OS, progression-free survival (PFS), objective response rate (ORR), OS in patients with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score\u2009\u2265\u200910%, and safety.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Overall, 66\/649 (10.2%) patients were randomized in Japan (n\u2009=\u200933 per arm). After a minimum follow-up of 37.9\u00a0months (data cutoff November 24, 2023), tislelizumab plus chemotherapy showed improvements in median OS versus placebo plus chemotherapy (24.5 vs. 15.1\u00a0months; hazard ratio [HR]: 0.75; 95% CI 0.43\u20131.30). An improvement in OS was also seen in patients with PD-L1 TAP score\u2009\u2265\u200910% (HR: 0.79; 95% CI 0.26\u20132.36). There was improvement in median PFS (HR: 0.77; 95% CI 0.45\u20131.32) and a higher ORR (63.6% vs. 45.5%) in the tislelizumab plus chemotherapy versus placebo plus chemotherapy arm, respectively. Treatment-related adverse events (TRAEs) with tislelizumab plus chemotherapy versus placebo plus chemotherapy occurred in, respectively, 45.5% versus 36.4% (any-grade) and 27.3% versus 6.1% (grade\u2009\u2265\u20093) of patients. No TRAE-related deaths occurred.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>After 3\u00a0years, first-line tislelizumab plus chemotherapy demonstrated sustained efficacy and a tolerable safety profile in Japanese patients with unresectable locally advanced\/metastatic ESCC, consistent with the global RATIONALE-306 population.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s10388-026-01199-y","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T03:04:02Z","timestamp":1775012642000},"page":"501-511","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["First-line tislelizumab plus chemotherapy versus placebo plus chemotherapy in adults with advanced or metastatic esophageal squamous cell carcinoma: a Japanese subgroup analysis of RATIONALE-306 with\u2009\u2265\u20093\u00a0years of follow-up"],"prefix":"10.1007","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6453-6408","authenticated-orcid":false,"given":"Takashi","family":"Ogata","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7721-1031","authenticated-orcid":false,"given":"Takashi","family":"Kojima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8796-718X","authenticated-orcid":false,"given":"Ryu","family":"Ishihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3881-9815","authenticated-orcid":false,"given":"Hiroki","family":"Hara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4919-6780","authenticated-orcid":false,"given":"Sheng","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1733-5072","authenticated-orcid":false,"given":"Ken","family":"Kato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"key":"1199_CR1","unstructured":"Foundation for Promotion of Cancer Research. Cancer statistics in Japan 2024. 2024. https:\/\/ganjoho.jp\/public\/qa_links\/report\/statistics\/2024_en.html. Accessed February 11, 2025."},{"key":"1199_CR2","doi-asserted-by":"publisher","first-page":"233","DOI":"10.2188\/jea.JE20120162","volume":"23","author":"Y Lin","year":"2013","unstructured":"Lin Y, Totsuka Y, He Y, et al. Epidemiology of esophageal cancer in Japan and China. J Epidemiol. 2013;23:233\u201342.","journal-title":"J Epidemiol"},{"key":"1199_CR3","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1016\/S0140-6736(21)01234-4","volume":"398","author":"JM Sun","year":"2021","unstructured":"Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021;398:759\u201371.","journal-title":"Lancet"},{"key":"1199_CR4","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1056\/NEJMoa2111380","volume":"386","author":"Y Doki","year":"2022","unstructured":"Doki Y, Ajani JA, Kato K, et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med. 2022;386:449\u201362.","journal-title":"N Engl J Med"},{"key":"1199_CR5","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/S1470-2045(23)00108-0","volume":"24","author":"J Xu","year":"2023","unstructured":"Xu J, Kato K, Raymond E, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023;24:483\u201395.","journal-title":"Lancet Oncol"},{"key":"1199_CR6","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1002\/2211-5463.13102","volume":"11","author":"Y Hong","year":"2021","unstructured":"Hong Y, Feng Y, Sun H, et al. Tislelizumab uniquely binds to the CC\u2019 loop of PD-1 with slow-dissociated rate and complete PD-L1 blockage. FEBS Open Bio. 2021;11:782\u201392.","journal-title":"FEBS Open Bio"},{"key":"1199_CR7","unstructured":"Department of Health and Aged Care Therapeutic Goods Administration. TEVIMBRA BeiGene Aus Pty Ltd. https:\/\/www.tga.gov.au\/resources\/auspmd\/tevimbra-tislelizumab. Accessed September 11, 2024."},{"key":"1199_CR8","unstructured":"US Food and Drug Administration. TEVIMBRA\u2122 (tislelizumab-jsgr) injection, for intravenous use. Prescribing information. 2024. https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2024\/761232Orig1s000lbl.pdf. Accessed June 20, 2024."},{"key":"1199_CR9","unstructured":"BeOne Medicines. BeiGene receives positive CHMP opinions for TEVIMBRA\u00ae as a first-line treatment for advanced\/metastatic gastric or gastroesophageal junction cancer and esophageal squamous cell carcinoma. 2024. https:\/\/ir.beonemedicines.com\/news\/beigene-receives-positive-chmp-opinions-for-tevimbrar-as-a-first-line-treatment-for-advancedmetastatic-gastric-or\/ed86eb4d-f10f-4a73-8744-2f212a91d349. Accessed July 2, 2025."},{"key":"1199_CR10","unstructured":"European Medicines Agency. Tevimbra 100 mg concentrate for solution for infusion. Summary of product characteristics. 2023. https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/tevimbra-epar-product-information_en.pdf. Accessed June 20, 2024."},{"key":"1199_CR11","doi-asserted-by":"publisher","first-page":"4032","DOI":"10.1200\/JCO.2024.42.16_suppl.4032","volume":"42","author":"HH Yoon","year":"2024","unstructured":"Yoon HH, Kato K, Raymond E, et al. Global, randomized, phase III study of tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced\/metastatic esophageal squamous cell carcinoma (RATIONALE-306 update): minimum 3-year survival follow-up. J Clin Oncol. 2024;42:4032.","journal-title":"J Clin Oncol"},{"key":"1199_CR12","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1007\/s10388-022-00920-x","volume":"19","author":"T Kojima","year":"2022","unstructured":"Kojima T, Hara H, Tsuji A, et al. First-line pembrolizumab + chemotherapy in Japanese patients with advanced\/metastatic esophageal cancer from KEYNOTE-590. Esophagus. 2022;19:683\u201392.","journal-title":"Esophagus"},{"key":"1199_CR13","doi-asserted-by":"crossref","unstructured":"Raymond E, Xu J, Kato K, et al. Tislelizumab (TIS) + chemotherapy (CT) vs placebo (PBO) + CT in locally advanced unresectable or metastatic esophageal squamous cell carcinoma. PD-L1 biomarker analysis from RATIONALE-306. Presented at: European Society for Medical Oncology World Congress on Gastrointestinal Cancer; June 26\u201329, 2024, Munich, Germany.","DOI":"10.1016\/j.annonc.2024.05.310"},{"key":"1199_CR14","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2025.43.4_suppl.420","author":"T Kojima","year":"2025","unstructured":"Kojima T, Ogata T, Ishihara R, et al. First-line (1L) tislelizumab (TIS) plus chemotherapy (CT) vs placebo (PBO) plus CT in advanced\/metastatic esophageal squamous cell carcinoma (ESCC): RATIONALE-306 Japanese subgroup analysis with longer follow-up. J Clin Oncol. 2025. https:\/\/doi.org\/10.1200\/JCO.2025.43.4_suppl.420.","journal-title":"J Clin Oncol"},{"key":"1199_CR15","doi-asserted-by":"publisher","DOI":"10.1016\/j.modpat.2025.100793","volume":"38","author":"M Moehler","year":"2025","unstructured":"Moehler M, Yoon HH, Wagner DC, et al. Concordance between the PD-L1 tumor area positivity score and combined positive score for gastric or esophageal cancers treated with tislelizumab. Mod Pathol. 2025;38:100793.","journal-title":"Mod Pathol"},{"key":"1199_CR16","unstructured":"US Food and Drug Administration. KEYTRUDA\u00ae (pembrolizumab) injection, for intravenous use. Prescribing information. 2014. https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2024\/125514s157lbl.pdf. Accessed February 11, 2025."},{"key":"1199_CR17","unstructured":"European Medicines Agency. OPDIVO 10 mg\/mL concentrate for solution for infusion. 2015. https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/opdivo-epar-product-information_en.pdf. Accessed September 16, 2024."},{"key":"1199_CR18","unstructured":"US Food and Drug Administration. OPDIVO\u00ae (nivolumab) injection, for intravenous use. Prescribing information. 2014. https:\/\/packageinserts.bms.com\/pi\/pi_opdivo.pdf. 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Ann Oncol. 2022;33:992\u20131004.","journal-title":"Ann Oncol"}],"container-title":["Esophagus"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10388-026-01199-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10388-026-01199-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10388-026-01199-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T07:45:09Z","timestamp":1782805509000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10388-026-01199-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,1]]},"references-count":22,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["1199"],"URL":"https:\/\/doi.org\/10.1007\/s10388-026-01199-y","relation":{},"ISSN":["1612-9059","1612-9067"],"issn-type":[{"value":"1612-9059","type":"print"},{"value":"1612-9067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,1]]},"assertion":[{"value":"17 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 April 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"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 later versions. Informed consent or substitute for it was obtained from all patients for being included in the study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical statement"}},{"value":"Takashi Ogata has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Bristol Myers Squibb, MSD, and Ono Pharmaceutical. Takashi Kojima has received grants or contracts from Amgen, BeOne Medicines, Bristol Myers Squibb, Chungai Pharmaceutical, EPS Corporation, Merck Biopharma Co., Ltd., Merck Sharp & Dohme K.K., Ono Pharmaceutical, Parexel International, Shionogi & Co., Ltd., Taiho Pharmaceutical Co., Ltd.; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Coviden Japan Inc., Ono Pharmaceutical, Merck Sharp & Dohme K.K., Taiho Pharmaceutical Co., Ltd.,\u00a0and Oncolys Biopharma Inc.; and participation on a data safety monitoring board or advisory board for Astellas Pharma Inc., Bristol Myers Squibb, Merck Biopharma Co., Ltd., Merck Sharp & Dohme K.K., and\u00a0Oncolys BioPharma Inc. Ryu Ishihara has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from AI Medical Service, AstraZeneca, Daiichi Sankyo, Fujifilm Medical, Miyarisian Pharmaceutical, Merck Sharp & Dohme, Olympus, and Ono Pharmaceutical; and has participated on a data safety monitoring board or advisory board for Astellas Pharma Inc., Bristol Myers Squibb, Merck Biopharma Co., Ltd., Merck Sharp & Dohme K.K., and Oncolys BioPharma Inc. Hiroki Hara declares that they have no conflicts of interest. Ken Kato has received consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, BeOne Medicines, Janssen, Merck Bio, Merck & Co., Ono Pharmaceutical, and Roche; has received payment for expert testimony from Bristol Myers Squibb and Ono Pharmaceutical; and has participated on a data safety monitoring board or advisory board for Bristol Myers Squibb, Chungai, Merck & Co., and Ono Pharmaceutical. Sebastian Yan and Sheng Xu are employees of BeOne Medicines.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interests"}},{"value":"Data were presented in part at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, San Francisco, CA, USA, January 23\u201325, 2025.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Meeting presentation"}}]}}