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

Purpose

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.

Methods

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.

Results

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).

Conclusion

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.