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In the phase\u20093 KEYNOTE-361 study, pembrolizumab with and without chemotherapy was compared with chemotherapy alone in patients with metastatic urothelial cancer. The study did not meet prespecified efficacy thresholds for statistical significance. To identify potential biomarkers of response, we retrospectively evaluated the association of pre- and posttreatment ctDNA with clinical outcomes in a subset of patients who received pembrolizumab (<jats:italic>n<\/jats:italic>\u2009=\u2009130) or chemotherapy (<jats:italic>n<\/jats:italic>\u2009=\u2009130) in KEYNOTE-361. Baseline ctDNA was associated with best overall response (BOR; <jats:italic>P<\/jats:italic>\u2009=\u20090.009), progression-free survival (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001) and overall survival (OS; <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001) for pembrolizumab but not for chemotherapy (all; <jats:italic>P<\/jats:italic>\u2009&gt;\u20090.05). Chemotherapy induced larger ctDNA decreases from baseline to treatment cycle\u20092 than pembrolizumab; however, change with pembrolizumab (<jats:italic>n<\/jats:italic>\u2009=\u200987) was more associated with BOR (<jats:italic>P<\/jats:italic>\u2009=\u20094.39\u2009\u00d7\u200910<jats:sup>\u22125<\/jats:sup>) and OS (<jats:italic>P<\/jats:italic>\u2009=\u20097.07\u2009\u00d7\u200910<jats:sup>\u22125<\/jats:sup>) than chemotherapy (<jats:italic>n<\/jats:italic>\u2009=\u2009102; BOR: <jats:italic>P<\/jats:italic>\u2009=\u20091.01\u2009\u00d7\u200910<jats:sup>\u22124<\/jats:sup>; OS: <jats:italic>P<\/jats:italic>\u2009=\u20090.018). Tumor tissue-informed versions of ctDNA change metrics were most associated with clinical outcomes but did not show a statistically significant independent value for explaining OS beyond radiographic change by RECIST v.1.1 when jointly modeled (pembrolizumab <jats:italic>P<\/jats:italic>\u2009=\u20090.364; chemotherapy <jats:italic>P<\/jats:italic>\u2009=\u20090.823). These results suggest distinct patterns in early ctDNA changes with immunotherapy and chemotherapy and differences in their association with long-term outcomes, which provide preliminary insights into the utility of liquid biopsies for treatment monitoring in metastatic urothelial cancer. Clinical trial registration: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT02853305\">NCT02853305<\/jats:ext-link>.<\/jats:p>","DOI":"10.1038\/s41591-024-03091-7","type":"journal-article","created":{"date-parts":[[2024,6,1]],"date-time":"2024-06-01T14:01:42Z","timestamp":1717250502000},"page":"2508-2516","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Pembrolizumab for advanced urothelial carcinoma: exploratory ctDNA biomarker analyses of the KEYNOTE-361 phase 3 trial"],"prefix":"10.1038","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7760-4724","authenticated-orcid":false,"given":"Thomas","family":"Powles","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen-Hwa","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiaki","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Munoz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe","family":"Reyes-Cosmelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avivit","family":"Peer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan Y.","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Lorch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhishek","family":"Bavle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca","family":"Homet Moreno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Markensohn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mackenzie","family":"Edmondson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cai","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9978-0339","authenticated-orcid":false,"given":"Razvan","family":"Cristescu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Pe\u00f1a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jared","family":"Lunceford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyda","family":"Gunduz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,1]]},"reference":[{"key":"3091_CR1","doi-asserted-by":"publisher","first-page":"351","DOI":"10.4143\/crt.2022.1026","volume":"55","author":"H Kim","year":"2023","unstructured":"Kim, H. & Park, K. 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J. Munoz reports receiving honoraria for presentations from LEO pharma and GlaxoSmithKline and support for attending meetings and\/or travel from LEP Pharma, GlaxoSmithKline and AstraZeneca. A.P. reports receiving consulting fees from Astellas Pharma, Janssen-Cilag, Bayer, Novartis, Merck Serono, Bristol-Myers Squibb, Eisai, MSD Oncology, Takeda, AstraZeneca and Pfizer; support for attending meetings and\/or travel from Pfizer, Astellas Pharma, Bristol-Myers Squibb and MSD; and honoraria from Astellas Pharma, Janssen Oncology, Bayer, Merck Serono, Bristol-Myers Squibb, Exelixis, MSD, Medison, Roche and AstraZeneca. E.Y.Y. reports consulting for Jansen, Merck, AAA Novartis, Bayer, Aadi Bioscience, Oncternal, Bristol-Myers Squibb, Loxo, and Lantheus, and receiving research grants to his institution from Dendreon, Merck, SeaGen, Blue Earth, Bayer \u2013 DAROL and citDNA, Lantheus, Tyra, Oncternal, Daiichi-Sankyo, Taiho and Surface. A.L. reports receiving consulting fees from Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Esai, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer and Roche; honoraria from Astellas, Novartis and Healthbook Company Switzerland; support for attending meetings and\/or travel from Ipsen, Janssen and Bayer; and holds a leadership or fiduciary role for European Association of Urology (EAU) guidelines bladder cancer, European Society Medical Oncology (ESMO) faculty nonprostate, German Society of Hematology and Medical Oncology (DGHO) guideline bladder and testis cancer, the Swiss Group for Clinical Cancer Research (SAKK) scientific board committee and the National Center for Tumors (NCT) scientific board committee. A.B. is an employee of MSD, a subsidiary of Merck & Co., Inc., and holds stock in Merck & Co., Inc. B.H.M. is an employee of MSD, a subsidiary of Merck & Co., Inc., and holds stock in Merck & Co., Inc. J. Markensohn is an employee of MSD, a subsidiary of Merck & Co., Inc., and holds stock in Merck & Co., Inc. M.E. is an employee of MSD, a subsidiary of Merck & Co., Inc. C.C. is an employee of MSD, a subsidiary of Merck & Co., Inc., and holds stock in Merck & Co., Inc. R.C. is an employee of MSD, a subsidiary of Merck & Co., Inc., and holds stock in Merck & Co., Inc. C.P. is an employee of MSD, a subsidiary of Merck & Co., Inc., and holds stock in Merck & Co., Inc. J.L. Is an employee of MSD, a subsidiary of Merck & Co., Inc., and holds stock in Merck & Co., Inc. Y.-H.C., Y.Y., F.R-C., G.P. and S.G. have no conflicts of interest to disclose.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}