Primary tumor response to enfortumab vedotin with/without pembrolizumab in patients with upper tract urothelial cancer.
Authors: Vlachou Evangelia , Hoffman-Censits Jeannie , Singla Nirmish , Hahn Noah M. , Johnson Burles Avner , Kates Max , Patel Sunil , Russell Stephanie , Smith Armine , Rourke Kelli , Sedaghat Farzad , McMahon Timothy 
Published: February 2025

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Background:
Cisplatin-based chemotherapy remains the standard for invasive urothelial cancer (UC) in the perioperative setting. Patients with upper tract UC (UTUC) are often ineligible for cisplatin due to disease- and surgery-related renal dysfunction. Modern perioperative trials focus on bladder UC, and cap or preclude enrollment for UTUC. Given the unprecedented activity of enfortumab vedotin and pembrolizumab (EV/P) in advanced UC and safety in impaired renal function, the assessment of this combination in earlier disease settings for patients with UTUC is an urgent need. This retrospective series evaluated the primary tumor response to EV and EV/P in aUTUC, a disease which is challenging to stage radiographically.
Methods:
This retrospective study included patients with intact primary UTUC tumors treated with EV and EV/P at Johns Hopkins. Baseline characteristics were collected through chart review. Primary tumor and overall response were assessed by 2 radiologists using RECIST1.1 criteria. Overall and primary tumor Response Rate (RR) [Complete Response (CR) + Partial Response (PR)] and Disease Control Rate (DCR) [CR + PR + Stable Disease (SD)] were calculated. Primary tumor was defined as any lesion in the ureter and/or renal pelvis. Non-measurable and sub-centimeter lesions (long axis <10mm) were deemed non-target per RECIST 1.1.
Results:
From December 2017 until June 2024, 50 patients with UTUC treated with EV or EV/P were identified. 22/50 patients had intact primary tumors and were included in this study. Median age was 72 years, 13 (59.1%) patients were male and 17 (77.3%) were white. Nineteen (86.4%) patients had pure urothelial histology and 18 (81.8%) had visceral metastases at baseline. Thirteen (59.1%) received EV and 9 (40.9%) EV/P. Three (13.6%) patients started EV at a reduced dose. Median number of EV cycles was 4 (range 0.5-14) and median duration of treatment was 3.3 months (range: 0.5-10). ORR was 36.4% and DCR was 72.3% in the entire cohort. Two (9%) patients had only non-target lesions at baseline and 6 (27.3%) had only non-target primary tumor lesions (Table).
Conclusions:
In this small study, EV and EV/P demonstrated promising radiographic response in primary UTUC lesions. Larger prospective studies are needed to assess the efficacy of this promising regimen in the perioperative setting for patients with this rare and aggressive disease.

Radiologist-assessed RECIST response among patients with and without target lesions at baseline.

Overall Response, N (%)
Primary Lesion Response, N (%)

Target lesions at baseline
20/22
16/22

Response Rate
8/20 (40.0)
4/16 (25.0)

CR

0 (0)
0 (0)

PR

8 (40.0)
4 (25.0)

Disease Control Rate
17/20 (85.0)
14/16 (87.5)

SD

9 (45.0)
10 (45.5)

PD
3 (15.0)
2 (12.5)

Only non-target lesions at baseline

2/22

6/22

Non-CR/Non-PD
2 (100)

6 (100)
a

a
Non-target primary lesions decreased in size in 4/6 patients and remained stable in 2/6.