{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T05:05:19Z","timestamp":1789967119083,"version":"4.0.1"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>KEYNOTE-966, a double-blinded randomized controlled phase III trial comparing pembrolizumab\/placebo + gemcitabine + cisplatin (GC) for biliary tract cancer [BTC], demonstrated the efficacy and safety of addition of pembrolizumab to GC. The effect of steroid and antibiotics use on immune check-point inhibitors is still of interest.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This was a\n                      <jats:italic>post-hoc<\/jats:italic>\n                      , exploratory institutional subgroup analysis of KEYNOTE-966. Dexamethasone was minimized for antiemetic prophylaxis, and antibiotics were administered selectively for cholangitis according to the institutional practice. Thirty-eight patients registered at our institution were randomly assigned to each treatment group. After the key was opened following completion of the protocol treatment in these patients, we compared the efficacy and safety in patients of Pembrolizumab+GC and those of Placebo+GC. We performed multivariable analysis using the Cox regression hazard model and inverse-probability weighting propensity score (IPW) analysis to adjust for between-group background differences.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>It was found that there were 22 and 16 patients in the Pembrolizumab+GC and Placebo+GC groups, respectively. The hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) for the Pembrolizumab+GC group were 0.622 (95% confidence interval [CI], 0.318\u20131.217) and 0.360 (95% CI, 0.178\u20130.728), respectively; the objective response rates were 31.8% and 6.3%, respectively. The HR for OS and PFS in the multivariable and IPW analyses were numerically similar to those in the original analysis, which was better than that observed in the entire KEYNOTE-966 cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our experience of Pembrolizumab + GC over Placebo +GC generates a clinical question whether the efficacy of Pembrolizumab may be enhanced when antibiotics and antiemetic DEX are avoided.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1806667","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T04:29:18Z","timestamp":1789964958000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical outcomes of pembrolizumab plus gemcitabine and cisplatin in a Japanese institutional subgroup of KEYNOTE-966: a dexamethasone-minimizing supportive-care approach"],"prefix":"10.3389","volume":"16","author":[{"given":"Satoshi","family":"Kobayashi","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Kanagawa Cancer Center","place":["Yokohama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomomi","family":"Hamaguchi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Kanagawa Cancer Center","place":["Yokohama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ritsuko","family":"Oishi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Kanagawa Cancer Center","place":["Yokohama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichiro","family":"Tozuka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Kanagawa Cancer Center","place":["Yokohama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taito","family":"Fukushima","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Kanagawa Cancer Center","place":["Yokohama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kouji","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Yokohama City University School of Medicine","place":["Yokohama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junji","family":"Furuse","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Kanagawa Cancer Center","place":["Yokohama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Ueno","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Kanagawa Cancer Center","place":["Yokohama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"B1","unstructured":"National Comprehensive Cancer Network Guidelines for Biliary Tract Cancer Version 2.2025\n          \n          \n          \n          2025"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0908721","article-title":"Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer","volume":"362","author":"Valle","year":"2010","journal-title":"N Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/EVIDoa2200015","article-title":"Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer","volume":"1","author":"Oh","year":"2022","journal-title":"NEJM Evid"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)00727-4","article-title":"Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial","volume":"401","author":"Kelley","year":"2023","journal-title":"Lancet"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1037945","article-title":"Immune microenvironment of cholangiocarcinoma: biological concepts and treatment strategies","volume":"14","author":"Yu","year":"2023","journal-title":"Front Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan3706","article-title":"Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors","volume":"359","author":"Routy","year":"2018","journal-title":"Science"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.2785","article-title":"Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer","volume":"5","author":"Pinato","year":"2019","journal-title":"JAMA Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1075593","article-title":"A systematic review and meta-analysis evaluating the impact of antibiotic use on the clinical outcomes of cancer patients treated with immune checkpoint inhibitors","volume":"13","author":"Crespin","year":"2023","journal-title":"Front Oncol"},{"key":"B9","unstructured":"National Comprehensive Cancer Network Guidelines, Supportive Care. Version 2.2025\n          \n          \n          \n          2025"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2018.79.0006","article-title":"Impact of baseline steroids on efficacy of programmed cell Death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer","volume":"36","author":"Arbour","year":"2018","journal-title":"J Clin Oncol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1080\/2162402x.2020.1824645","article-title":"Association of baseline systemic corticosteroid use with overall survival and time to next treatment in patients receiving immune checkpoint inhibitor therapy in real-world US oncology practice for advanced non-small cell lung cancer, melanoma, or urothelial carcinoma","volume":"9","author":"Drakaki","year":"2020","journal-title":"Oncoimmunology"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1200\/jco.19.00189","article-title":"Immune checkpoint inhibitor outcomes for patients with non-small-cell lung cancer receiving baseline corticosteroids for palliative versus nonpalliative indications","volume":"37","author":"Ricciuti","year":"2019","journal-title":"J Clin Oncol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2020.12.011","article-title":"Survival outcomes associated with corticosteroid use before chemoimmunotherapy in patients with advanced lung cancer","volume":"145","author":"Sorial","year":"2021","journal-title":"Eur J Cancer"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2023.41.4_suppl.550","article-title":"Outcomes by antibiotic use in participants with advanced biliary tract cancer treated with durvalumab or placebo plus gemcitabine and cisplatin in the phase 3 TOPAZ-1 study","volume":"41","author":"He","year":"2023","journal-title":"J Clin Oncol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1172\/JCI184321","article-title":"The gut microbiome and cancer response to immune checkpoint inhibitors","volume":"135","author":"Gazzaniga","year":"2025","journal-title":"J Clin Invest"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1512683","article-title":"Understanding the role of the gut microbiome in solid tumor responses to immune checkpoint inhibitors for personalized therapeutic strategies: a review","volume":"15","author":"Lim","year":"2024","journal-title":"Front Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc9113","article-title":"Enterococcus peptidoglycan remodeling promotes checkpoint inhibitor cancer immunotherapy","volume":"373","author":"Griffin","year":"2021","journal-title":"Science"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1380","DOI":"10.1016\/j.chom.2024.06.010","article-title":"Fecal microbiota transplantation improves anti-PD-1 inhibitor efficacy in unresectable or metastatic solid cancers refractory to anti-PD-1 inhibitor","volume":"32","author":"Kim","year":"2024","journal-title":"Cell Host Microbe"},{"key":"B19","doi-asserted-by":"publisher","first-page":"2324","DOI":"10.1016\/j.cell.2024.03.021","article-title":"A pan-cancer analysis of the microbiome in metastatic cancer","volume":"187","author":"Battaglia","year":"2024","journal-title":"Cell"},{"key":"B20","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1126\/science.aan4236","article-title":"Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients","volume":"359","author":"Gopalakrishnan","year":"2018","journal-title":"Science"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0247798","article-title":"Characterization of biliary microbiota dysbiosis in extrahepatic cholangiocarcinoma","volume":"16","author":"Saab","year":"2021","journal-title":"PloS One"},{"key":"B22","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1002\/jhbp.518","article-title":"Tokyo Guidelines 2018: antimicrobial therapy for acute cholangitis and cholecystitis","volume":"25","author":"Gomi","year":"2018","journal-title":"J Hepato-bil Pancreat Sci"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.66.1389","article-title":"Safety profile of nivolumab monotherapy: A pooled analysis of patients with advanced melanoma","volume":"35","author":"Weber","year":"2017","journal-title":"J Clin Oncol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.708195","article-title":"Immune-related adverse events associated with outcomes in patients with NSCLC treated with anti-PD-1 inhibitors: a systematic review and meta-analysis","volume":"11","author":"Zhao","year":"2021","journal-title":"Front Oncol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/oncolo\/oyad090","article-title":"Association between immune-related adverse events and survival in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab","volume":"28","author":"Fukushima","year":"2023","journal-title":"Oncologist"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1136\/ard.61.8.718","article-title":"Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology","volume":"61","author":"Buttgereit","year":"2002","journal-title":"Ann Rheum Dis"},{"key":"B27","article-title":"Int\u00e9r\u00eat du dosage de la dexam\u00e9thasone dans le test de freination rapide surr\u00e9nalienne [Value of determining dexamethasone in the rapid adrenal suppression test","volume":"50","author":"Lamiable","year":"1989","journal-title":"Ann Endocrinol (Paris)"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-020-02555-2","article-title":"The glucocorticoids prednisone and dexamethasone differentially modulate T cell function in response to anti-PD-1 and anti-CTLA-4 immune checkpoint blockade","volume":"69","author":"Okoye","year":"2020","journal-title":"Cancer Immunol Immunother"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-021-03157-2","article-title":"Effectiveness of palonosetron versus granisetron in preventing chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis","volume":"77","author":"Hsu","year":"2021","journal-title":"Eur J Clin Pharmacol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/s00520-014-2175-6","article-title":"Efficacy and safety of palonosetron for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV): a systematic review and meta-analysis of randomized controlled trials","volume":"22","author":"Popovic","year":"2014","journal-title":"Support Care Cancer"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2022.101480","article-title":"Aprepitant plus palonosetron versus dexamethasone plus palonosetron in preventing chemotherapy-induced nausea and vomiting in patients with moderate-emetogenic chemotherapy: a randomized, open-label, phase 3 trial","volume":"49","author":"Cheng","year":"2022","journal-title":"EClinicalmedicine"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdv482","article-title":"Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy: results of a randomized, double-blind phase III trial","volume":"27","author":"Weinstein","year":"2016","journal-title":"Ann Oncol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mds541","article-title":"Efficacy and safety of single-dose fosaprepitant in the prevention of chemotherapy-induced nausea and vomiting in patients receiving high-dose cisplatin: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial","volume":"24","author":"Saito","year":"2013","journal-title":"Ann Oncol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.01315","article-title":"Randomized, double-blind, Phase III study of fosnetupitant versus fosaprepitant for prevention of highly emetogenic chemotherapy-induced nausea and vomiting: CONSOLE","volume":"40","author":"Hata","year":"2022","journal-title":"J Clin Oncol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.74.4375","article-title":"Placebo-controlled, double-blinded Phase III study comparing dexamethasone on Day 1 with dexamethasone on Days 1 to 3 with combined Neurokinin-1 receptor antagonist and palonosetron in high-emetogenic chemotherapy","volume":"36","author":"Ito","year":"2018","journal-title":"J Clin Oncol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx100","article-title":"The development of a prediction tool to identify cancer patients at high risk for chemotherapy-induced nausea and vomiting","volume":"28","author":"Dranitsaris","year":"2017","journal-title":"Ann Oncol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1111\/cas.12146","article-title":"Risk factors of chemotherapy-induced nausea and vomiting: index for personalized antiemetic prophylaxis","volume":"104","author":"Sekine","year":"2013","journal-title":"Cancer Sci"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.7142","article-title":"Inconsistency in steroid use as antiemetics in clinical trial protocols involving immune checkpoint inhibitors combined with chemotherapy","volume":"13","author":"Park","year":"2024","journal-title":"Cancer Med"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1806667\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T04:29:22Z","timestamp":1789964962000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1806667\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,21]]},"references-count":38,"alternative-id":["10.3389\/fonc.2026.1806667"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1806667","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,21]]},"article-number":"1806667"}}