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Peer-reviewedCC BY 4.0Cancers

Circulating Tumor DNA Clearance Is Associated with Response and Survival in Metastatic Urothelial Carcinoma Treated with First-Line Enfortumab Vedotin Plus Pembrolizumab

  • Adam Khorasanchi1
  • Sayan Mullick Chowdhury1
  • Eric Fei Hong2
  • Mingjia Li1
  • Changchuan Jiang3
  • Lin Mei4
  • Michael A. Liu5
  • Katharine A. Collier1
  • Ce Shang1
  • Lei Xu6
  • Ashish Manne1
  • Peng Wang1
10 more authors
  • Sofia Jaroniec7
  • Michael Gong8
  • Eric A. Singer8
  • Feng Hong1
  • Harrison Kim9
  • Khalid Niazi10
  • Robert Wesolowski1
  • Mark Rubinstein1
  • Yuanquan Yang1
  • Lingbin Meng1
10 affiliations
  1. 1Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
  2. 2Olentangy Liberty High School, Powell, OH 43065, USA
  3. 3Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
  4. 4Abramson Cancer Center, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA
  5. 5Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
  6. 6Center for Tobacco Research, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
  7. 7Kenyon College, Gambier, OH 43022, USA
  8. 8Division of Urologic Oncology, Department of Urology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
  9. 9Department of Radiology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
  10. 10Department of Pathology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
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Abstract

Background/Objectives: Enfortumab vedotin plus pembrolizumab (EV+pembro) is the standard first-line treatment for metastatic urothelial carcinoma (mUC), yet no validated on-treatment biomarker identifies patients deriving a durable benefit. We evaluated whether circulating tumor DNA (ctDNA) clearance is associated with response and survival with this regimen alone. Methods: This single-center retrospective study included 25 patients with mUC receiving first-line EV+pembro. A tumor-informed assay (Signatera) measured ctDNA longitudinally. Responses were assessed by RECIST 1.1. Progression-free survival (PFS) and overall survival (OS) hazard ratios (HRs) were estimated by Cox regression and, to address immortal time bias, with clearance as a time-dependent covariate. Results: Fifteen of 25 patients (60%) achieved ctDNA clearance (ever undetectable). The objective response rate was 76% overall and 100% (15/15) with clearance versus 40% (4/10) without (p = 0.0012). Clearance was associated with longer PFS (HR 0.16, 95% CI 0.05–0.54; p = 0.003) and OS (HR 0.08, 95% CI 0.01–0.68; p = 0.021), with similar Firth penalized HRs (0.17 and 0.11). In the time-dependent analysis, the associations were attenuated (PFS HR 0.35, 95% CI 0.09–1.15, p = 0.085; OS HR 0.14, 95% CI 0.01–0.84, p = 0.029; profile likelihood CIs). A post-nadir ctDNA rise preceded progression or death by a median of 95 days in four patients (death in two). Conclusions: In this first-line EV+pembro cohort, all patients who cleared ctDNA responded, and clearance was associated with longer survival, although this association was attenuated in the time-dependent analysis. These hypothesis-generating findings support the prospective evaluation of ctDNA-guided monitoring.

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Cite

BibTeXRIS
BibTeX
@article{khorasanchi2026circulating,
  title = {{Circulating Tumor DNA Clearance Is Associated with Response and Survival in Metastatic Urothelial Carcinoma Treated with First-Line Enfortumab Vedotin Plus Pembrolizumab}},
  author = {Adam Khorasanchi and Sayan Mullick Chowdhury and Eric Fei Hong and Mingjia Li and Changchuan Jiang and Lin Mei and Michael A. Liu and Katharine A. Collier and Ce Shang and Lei Xu and Ashish Manne and Peng Wang and Sofia Jaroniec and Michael Gong and Eric A. Singer and Feng Hong and Harrison Kim and Khalid Niazi and Robert Wesolowski and Mark Rubinstein and Yuanquan Yang and Lingbin Meng},
  journal = {Cancers},
  year = {2026},
  month = nov,
  doi = {10.3390/cancers18213532},
  url = {https://www.mdpi.com/2072-6694/18/21/3532},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Circulating Tumor DNA Clearance Is Associated with Response and Survival in Metastatic Urothelial Carcinoma Treated with First-Line Enfortumab Vedotin Plus Pembrolizumab
AU  - Adam Khorasanchi
AU  - Sayan Mullick Chowdhury
AU  - Eric Fei Hong
AU  - Mingjia Li
AU  - Changchuan Jiang
AU  - Lin Mei
AU  - Michael A. Liu
AU  - Katharine A. Collier
AU  - Ce Shang
AU  - Lei Xu
AU  - Ashish Manne
AU  - Peng Wang
AU  - Sofia Jaroniec
AU  - Michael Gong
AU  - Eric A. Singer
AU  - Feng Hong
AU  - Harrison Kim
AU  - Khalid Niazi
AU  - Robert Wesolowski
AU  - Mark Rubinstein
AU  - Yuanquan Yang
AU  - Lingbin Meng
PY  - 2026
DA  - 2026/11/03
JO  - Cancers
DO  - 10.3390/cancers18213532
UR  - https://www.mdpi.com/2072-6694/18/21/3532
AB  - Background/Objectives: Enfortumab vedotin plus pembrolizumab (EV+pembro) is the standard first-line treatment for metastatic urothelial carcinoma (mUC), yet no validated on-treatment biomarker identifies patients deriving a durable benefit. We evaluated whether circulating tumor DNA (ctDNA) clearance is associated with response and survival with this regimen alone. Methods: This single-center retrospective study included 25 patients with mUC receiving first-line EV+pembro. A tumor-informed assay (Signatera) measured ctDNA longitudinally. Responses were assessed by RECIST 1.1. Progression-free survival (PFS) and overall survival (OS) hazard ratios (HRs) were estimated by Cox regression and, to address immortal time bias, with clearance as a time-dependent covariate. Results: Fifteen of 25 patients (60%) achieved ctDNA clearance (ever undetectable). The objective response rate was 76% overall and 100% (15/15) with clearance versus 40% (4/10) without (p = 0.0012). Clearance was associated with longer PFS (HR 0.16, 95% CI 0.05–0.54; p = 0.003) and OS (HR 0.08, 95% CI 0.01–0.68; p = 0.021), with similar Firth penalized HRs (0.17 and 0.11). In the time-dependent analysis, the associations were attenuated (PFS HR 0.35, 95% CI 0.09–1.15, p = 0.085; OS HR 0.14, 95% CI 0.01–0.84, p = 0.029; profile likelihood CIs). A post-nadir ctDNA rise preceded progression or death by a median of 95 days in four patients (death in two). Conclusions: In this first-line EV+pembro cohort, all patients who cleared ctDNA responded, and clearance was associated with longer survival, although this association was attenuated in the time-dependent analysis. These hypothesis-generating findings support the prospective evaluation of ctDNA-guided monitoring.
SN  - 2072-6694
ER  -