Real-World Tumor-Informed Circulating Tumor DNA Dynamics and Survival Associations in Advanced Urothelial Cancer Treated With First-Line Enfortumab Vedotin and Pembrolizumab.

Authors

Vivek Nimgaonkar, Alyssa Arbuiso, Evangelia Vlachou, Burles Avner Johnson, Armine Smith, Max Kates, Sunil Patel, Nirmish Singla, Stephanie Russell, Kelli Rourke, Roy Elias, Andres Matoso, Ezra G Baraban, Noah M Hahn, Jean Hoffman-Censits

Published in

JCO precision oncology. Volume 10. Issue 10. Pages e2600691. Epub Oct 13, 2026.

Abstract

Enfortumab vedotin and pembrolizumab (EVP) is the standard first-line treatment for locally advanced and metastatic urothelial cancer (la/mUC) although response biomarkers remain an unmet need. Tumor-informed circulating tumor DNA (ctDNA) has proven to be useful as a marker of response in a variety of cancers. We sought to explore whether ctDNA dynamics is associated with survival outcomes.
This retrospective study included patients with la/mUC receiving first-line EVP, who had plasma ctDNA collected using the Signatera assay within 3 months after treatment initiation. Associations between ctDNA clearance and overall survival (OS) and progression-free survival (PFS) were assessed using multivariable time-dependent Cox proportional hazard (CPH) models and landmark analyses at 1, 2, and 3 months after EVP initiation. Longitudinal ctDNA trends were examined in a subpopulation with baseline ctDNA values collected.
Fifty-eight patients were included. In multivariable time-dependent CPH models, ctDNA clearance was associated with both OS (hazard ratio [HR], 0.04 [95% CI, 0.01 to 0.24], P < .001) and PFS (HR, 0.09 [95% CI, 0.02 to 0.32], P < .001). In landmark analyses, ctDNA clearance was associated with longer OS and PFS at 2 months (log-rank test P = .003, P < .001, respectively). Among patients with baseline ctDNA (n = 42), 69% achieved ctDNA clearance after EVP initiation, whereas just 14% (n = 6) never had a decrease in ctDNA. The median time to clearance of ctDNA was 1.41 months (IQR, 0.85-1.94).
While primarily hypothesis-generating, this study suggests that patients with la/mUC treated with first-line EVP frequently and rapidly clear ctDNA. Clearance of ctDNA in this population is associated with longer survival and merits further study.

PMID:
42868336
Bibliographic data and abstract were imported from PubMed on 14 Oct 2026.

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