Upfront Enfortumab Vedotin Dose Reductions May Affect Outcomes in Urothelial Carcinoma, Disease Histology Confers Distinct Prognosis in ccRCC

Patients with advanced urothelial carcinoma who received up-front dose reductions of enfortumab vedotin-ejfv (Padcev) alongside pembrolizumab (Keytruda) experienced worse outcomes compared with those who did not receive a reduced dose, according to data from a retrospective real-world study.¹ Findings from another retrospective study revealed that patients with metastatic clear cell renal cell carcinoma (ccRCC) treated with an immunotherapy doublet experienced differing outcomes depending on whether their disease had sarcomatoid vs rhabdoid dedifferentiation. ²

During the OncLive National Fellows Forum: Genitourinary Cancer, which was held on February 25, 2026, prior to the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium, oncology fellows with an interest in genitourinary malignancies from across the country gathered to share their research, network with their peers, and receive feedback from expert mentors.

Jeffrey Zhong, MD, and his group presented a study titled “Effect of Upfront Dose Reductions on Efficacy of Enfortumab Vedotin and Pembrolizumab (EVP) in Advanced Urothelial Carcinoma (aUC): A UNITE Analysis.” Akshit Chitkara, MD, and his group presented a study titled “Sarcomatoid Versus Rhabdoid Dedifferentiation and Histologic Grade-Specific Outcomes in Metastatic Clear Cell Renal Cell Carcinoma (mccRCC): A Multi-institutional Analysis of 514 Patients.”

Zhong is a hematology/oncology fellow at Case Western Reserve University Hospitals in Cleveland, Ohio. Chitkara is a hematology-oncology fellow at Sidney Kimmel Comprehensive Cancer Center at Jefferson Health in Philadelphia, Pennsylvania.

What were the effects of up-front dose reductions on the efficacy of enfortumab vedotin in advanced urothelial carcinoma?

To conduct their real-world study, Zhong and his coauthors analyzed data of patients with advanced urothelial carcinoma who received enfortumab vedotin plus pembrolizumab from the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) database.¹ UNITE is a multisite database that includes results from 17 academic centers in the United States.

An up-front dose reduction was defined as a starting dose of 1.00 mg/kg or 0.75 mg/kg of enfortumab vedotin. The study authors used the Fisher exact test to assess the correlation between prognostic factors and dose reduction. Logistic regression was employed to evaluate investigator-assessed observed response rate (ORR). Prognostic risk factors were chosen in accordance with Bellmunt criteria and consisted of age (< 75 years vs ≥ 75 years), ECOG performance status (0-1 vs 2-3), hemoglobin levels (≥ 10 vs < 10), and liver metastases (present vs absent).

“[Enfortumab vedotin plus pembrolizumab] is a preferred first-line therapy regimen for patients with advanced or metastatic urothelial cancer,” Zhong said in an interview with Oncology Fellows. “Sometimes, [oncologists] will [reduce the] up-front dose for patients who are particularly frail to try to enhance tolerability or minimize anticipated treatment-related toxicities. We wanted to investigate the [effect] of these up-front enfortumab vedotin dose reductions on real-world outcomes in patients who were treated with [enfortumab vedotin plus pembrolizumab] for advanced urothelial carcinoma.”

Findings from the study demonstrated that patients who received an up-front dose reduction (n = 94) experienced a median progression-free survival (PFS) of 5.1 months compared with 11.5 months among patients with no up-front dose reduction (n = 352; HR, 1.50; 95% CI, 1.11-2.02; P = .008). The median overall survival (OS) values were 11.7 months and 21.6 months, respectively (HR, 1.56; 95% CI, 1.11-2.20; P = .01). A trend toward decreased PFS and OS outcomes was observed with up-front enfortumab vedotin dose reduction, but this was not statistically significant.

Additional data from a multivariable analysis showed that up-front dose reduction was correlated with a lower ORR compared with no up-front dose reduction, with ORRs of 28% and 60%, respectively; this finding persisted after adjusting for age and prognostic factors.

“Patients who did get this up-front dose reduction were more frequently significantly older, [and] they typically had a worse performance status or [were] more anemic at baseline,” Zhong said. “Since a strong trend still persisted, and given the degree of the inferior PFS and OS, early dose intensity does matter, [and] it warrants further investigation moving forward.”

How did sarcomatoid vs rhabdoid differentiation affect outcomes with first-line nivolumab plus ipilimumab in metastatic ccRCC?

Chitkara and his coauthors conducted a retrospective study that included 514 patients with metastatic ccRCC who received frontline nivolumab (Opdivo) in combination with ipilimumab (Yervoy).² The study included patients with the following tumor classifications: sarcomatoid only, rhabdoid only, both sarcomatoid and rhabdoid, grade 4 nonsarcomatoid/nonrhabdoid, and unknown. Patients with grade 3 or lower disease were also included as the reference group.

“We know from a lot of trials that have been done in the past, especially in the preimmunotherapy era, that patients with grade 4 disease usually have worse outcomes, and they were specifically treated with newer treatment options, such as immunotherapy, in most of the trials,” Chitkara said in an interview with Oncology Fellows. “But there was always a question about how these patients do within various subgroups, whether it’s sarcomatoid vs rhabdoid [dedifferentiation]. [We wanted to see] whether all patients within the grade 4 subgroups are responding equally to treatment or if there are any differences in the outcomes.”

Findings from the study showed that patients with grade 3 or higher disease (n = 197) experienced a median OS of 5.4 months (95% CI, 4.5-7.7), a 5-year OS rate of 53% (95% CI, 43%-61%), a median time to next treatment (TTNT) of 12 months (95% CI, 9-18), and a 1-year TTNT rate of 49% (95% CI, 42%-56%). These respective values among patients with sarcomatoid-only disease (n = 61) were 2.9 months (95% CI, 2.0-3.8), 31% (95% CI, 18%-45%), 11 months (95% CI, 6-18), and 49% (95% CI, 36%-61%). Patients with rhabdoid-only disease (n = 67) experienced a median OS that was not reached (NR; 95% CI, 3.2-NR), a 5-year OS rate of 59% (95% CI, 45%-71%), a median TTNT of 8 months (95% CI, 6-31), and a 1-year TTNT rate of 43% (95% CI, 31%-55%).

“In today’s day and age, across institutes, there’s a lot of variation in how the pathology is reported and how patients are graded,” Chitkara said. “It’s still [evaluated] as grade 4, but sometimes they don’t give us the outcomes [by differentiation], whether it’s rhabdoid or sarcomatoid. It’s important to establish up front what the exact histological subtype is from the pathology so that we have the prognostic and treatment implications set early. We know that patients who are sarcomatoid might respond worse to immunotherapy compared with those who are rhabdoid. It would be helpful if clinical trials prospectively have this subgroup analysis built in [so we can] understand how the patients are responding in different subgroups.”

References

1. Zhong J, Zarka J, Zugman M, et al. Effect of upfront dose reductions on efficacy of enfortumab vedotin and pembrolizumab (EVP) in advanced urothelial carcinoma (aUC): a UNITE analysis. Presented at: OncLive National Fellows Forum: Genitourinary Cancer; February 25, 2026; San Francisco, CA.
2. Khatoun WD, El Hajj R, de Goes VA, et al. Sarcomatoid versus rhabdoid dedifferentiation and histologic grade-specific outcomes in metastatic clear cell renal cell carcinoma (mccRCC): a multi-institutional analysis of 514 patients. Presented at: OncLive National Fellows Forum: Genitourinary Cancer; February 25, 2026; San Francisco, CA.