- Article
- Published:
- Thomas Powles1,
- Yen-Hwa Chang2,
- Yoshiaki Yamamoto3,
- Jose Munoz4,
- Felipe Reyes-Cosmelli5,
- Avivit Peer6,
- Graham Cohen7,
- Evan Y. Yu8,
- Anja Lorch9,10,
- Abhishek Bavle11,
- Blanca Homet Moreno11,
- Julia Markensohn11,
- Mackenzie Edmondson11,
- Cai Chen11,
- Razvan Cristescu ORCID: orcid.org/0000-0002-9978-033911,
- Carol Pena11,
- Jared Lunceford11 &
- …
- Seyda Gunduz12
Nature Medicine (2024)Cite this article
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Subjects
- Bladder cancer
- Prognostic markers
Abstract
Circulating 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 association of pre- and post-treatment ctDNA with clinical outcomes in a subset of patients who received pembrolizumab (n = 130) or chemotherapy (n = 130) in KEYNOTE-361. Baseline ctDNA were associated with best overall response (BOR;P = 0.009), progression-free survival (PFS;P < 0.001), and overall survival (OS;P < 0.001) for pembrolizumab, but not chemotherapy (all, P > 0.05). Chemotherapy induced larger ctDNA decreases from baseline to treatment cycle 2 than pembrolizumab; however, change with pembrolizumab (n = 87) were more associated with BOR (P = 4.39 × 10−5) and OS (P = 7.07 × 10−5) versus chemotherapy (n = 102; BOR: P = 1.01 × 10−4; OS: P = 0.018). Tumor tissue-informed versions of ctDNA change metrics were most associated with clinical outcomes but did not show statistically significant independent value for explaining OS beyond radiographic change by RECIST v1.1 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 on the utility of liquid biopsies for treatment monitoring in metastatic urothelial cancer. Clinical trial registration: NCT02853305.
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Authors and Affiliations
Barts Cancer Institute, Queen Mary University of London, London, UK
Thomas Powles
Taipei Veterans General Hospital, Taipei, Taiwan
Yen-Hwa Chang
Yamaguchi University Hospital, Yamaguchi, Japan
Yoshiaki Yamamoto
Hospital Universitari i Politècnic La Fe, Valencia, Spain
Jose Munoz
Fundación Arturo López Pérez, Santiago, Chile
Felipe Reyes-Cosmelli
Rambam Health Care Campus, Haifa, Israel
Avivit Peer
Mary Potter Oncology Centre, Gauteng, South Africa
Graham Cohen
Fred Hutchinson Cancer Center and University of Washington, Seattle, WA, USA
Evan Y. Yu
Universitätsspital Zürich, Zürich, Switzerland
Anja Lorch
University Hospital Düsseldorf, Düsseldorf, Germany
Anja Lorch
Merck & Co., Inc., Rahway, NJ, USA
Abhishek Bavle,Blanca Homet Moreno,Julia Markensohn,Mackenzie Edmondson,Cai Chen,Razvan Cristescu,Carol Pena&Jared Lunceford
Istinye University Liv Hospital, Istanbul, Turkey
Seyda Gunduz
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- Razvan Cristescu
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- Carol Pena
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- Jared Lunceford
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- Seyda Gunduz
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Correspondence to Thomas Powles.
Additional information
*At the time the trial was conducted.
Supplementary information
Supplementary Information
Supplementary Figure 1–5 and supplementary table 1.
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Powles, T., Chang, YH., Yamamoto, Y. et al. Pembrolizumab for advanced urothelial carcinoma: exploratory ctDNA biomarker analyses of the KEYNOTE-361 phase 3 trial. Nat Med (2024). https://doi.org/10.1038/s41591-024-03091-7
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DOI: https://doi.org/10.1038/s41591-024-03091-7