Pembrolizumab for advanced urothelial carcinoma: exploratory ctDNA biomarker analyses of the KEYNOTE-361 phase 3 trial

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dc.authorscopusidŞeyda Gündüz / 53879546000
dc.authorwosidŞeyda Gündüz / FCD-5483-2022
dc.contributor.authorPowles, Thomas
dc.contributor.authorChang, Yen-Hwa
dc.contributor.authorYamamoto, Yoshiaki
dc.contributor.authorMunoz, Jose
dc.contributor.authorReyes-Cosmelli, Felipe
dc.contributor.authorPeer, Avivit
dc.contributor.authorCohen, Graham
dc.contributor.authorYu, Evan Y.
dc.contributor.authorLorch, Anja
dc.contributor.authorBavle, Abhishek
dc.contributor.authorMoreno, Blanca Homet
dc.contributor.authorMarkensohn, Julia
dc.contributor.authorEdmondson, Mackenzie
dc.contributor.authorChen, Cai
dc.contributor.authorCristescu, Razvan
dc.contributor.authorPena, Carol
dc.contributor.authorLunceford, Jared
dc.contributor.authorGündüz, Şeyda
dc.date.accessioned2025-04-18T10:13:58Z
dc.date.available2025-04-18T10:13:58Z
dc.date.issued2024
dc.departmentİstinye Üniversitesi, Tıp Fakültesi, Cerrahi Tıp Bilimleri Bölümü
dc.description.abstractCirculating tumor DNA (ctDNA) is emerging as a potential biomarker in early-stage urothelial cancer, but its utility in metastatic disease remains unknown. In the phase 3 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 (n = 130) or chemotherapy (n = 130) in KEYNOTE-361. Baseline ctDNA was associated with best overall response (BOR; P = 0.009), progression-free survival (P < 0.001) and overall survival (OS; P < 0.001) for pembrolizumab but not for chemotherapy (all; P > 0.05). Chemotherapy induced larger ctDNA decreases from baseline to treatment cycle 2 than pembrolizumab; however, change with pembrolizumab (n = 87) was more associated with BOR (P = 4.39 x 10(-5)) and OS (P = 7.07 x 10(-5)) than chemotherapy (n = 102; BOR: P = 1.01 x 10(-4); OS: P = 0.018). 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 P = 0.364; chemotherapy P = 0.823). 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: NCT02853305.
dc.description.sponsorshipMerck (Merck Co., Inc.) Merck Sharp & Dohme LLC, a subsidiary of Merck Co., Inc. Biomedical Research Centre at Barts Health
dc.identifier.citationPowles, T., Chang, Y. H., Yamamoto, Y., Munoz, J., Reyes-Cosmelli, F., Peer, A., ... & Gunduz, S. (2024). Pembrolizumab for advanced urothelial carcinoma: exploratory ctDNA biomarker analyses of the KEYNOTE-361 phase 3 trial. Nature Medicine, 30(9), 2508-2516.
dc.identifier.doi10.1038/s41591-024-03091-7
dc.identifier.issn1078-8956
dc.identifier.issn1546-170X
dc.identifier.pmid38823511
dc.identifier.scopus2-s2.0-85200154048
dc.identifier.scopusqualityQ1
dc.identifier.urihttp://dx.doi.org/10.1038/s41591-024-03091-7
dc.identifier.urihttps://hdl.handle.net/20.500.12713/6999
dc.identifier.wosWOS:001282861600001
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorGündüz, Şeyda
dc.language.isoen
dc.publisherNature portfolio
dc.relation.ispartofNature medicine
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.titlePembrolizumab for advanced urothelial carcinoma: exploratory ctDNA biomarker analyses of the KEYNOTE-361 phase 3 trial
dc.typeArticle

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