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

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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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Correspondence to Thomas Powles.

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*At the time the trial was conducted.

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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).

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