TOPLINE

First-line enfortumab vedotin plus pembrolizumab (EV/P) was associated with significantly longer overall survival, delayed need for subsequent therapy, fewer early hospitalizations, and a distinct but manageable toxicity profile compared with gemcitabine plus cisplatin (G/C) in patients with metastatic urothelial carcinoma.

METHODOLOGY

• Metastatic urothelial carcinoma is an aggressive cancer associated with poor survival, and platinum chemotherapy has historically offered limited benefits. Although EV/P became a new standard after the EV-302 trial, evidence of its real-world effectiveness remains limited.
• To evaluate whether EV/P offers benefits in patients with a higher comorbidity burden who received treatment in routine practice, researchers conducted a retrospective cohort study using data from TriNetX, including 4433 adults with metastatic urothelial carcinoma who received first-line EV/P (n = 1841) or first-line G/C (n = 2592) between September 2007 and September 2025.
• Cohorts were matched in a 1:1 ratio to balance for demographic characteristics, comorbidities, kidney function, and location of metastatic disease, resulting in 1395 patients in each cohort.
• The primary outcome was overall survival; secondary outcomes included time to next treatment, hospitalization within 90 days, and adverse events. The median follow-up duration was 249 days for the EV/P cohort and 293 days for the G/C cohort.

TAKEAWAY

• First-line EV/P was associated with a lower risk for all-cause mortality than first-line G/C (hazard ratio [HR], 0.70), with a longer median overall survival (20 vs 11 months). Age-related physical debility (adjusted HR, 2.00), wheelchair dependence (adjusted HR, 1.80), liver metastases (adjusted HR, 1.52), bone metastases (adjusted HR, 1.36), and heart failure (adjusted HR, 1.33) were associated with higher risk for all-cause mortality. The overall survival probability was significantly higher in the EV/P vs G/C cohort at the end of follow-up (25.71% vs 13.92%; P < .001).
• EV/P significantly prolonged treatment durability. Median time to next treatment was 35 months with EV/P compared with 10 months with G/C (HR, 0.49), indicating a 51% lower likelihood of requiring subsequent systemic therapy. The probability of remaining on initial therapy was 33.03% in the EV/P cohort compared with 25.31% in the G/C group (P < .001) at the end of follow-up.
• EV/P was associated with a lower risk for hospitalization within 90 days of treatment initiation than G/C (HR, 0.73). At day 90, the probability of remaining free from inpatient admission was 67.1% with EV/P compared with 57.93% with G/C (P < .001).
• Compared with G/C, EV/P was associated with higher risks for skin rash (HR, 2.77), diarrhea (HR, 1.42), hyperglycemia (HR, 1.62), and hypothyroidism (HR, 1.78) but with lower risks for fatigue (HR, 0.76), nausea (HR, 0.63), anemia (HR, 0.87), and thrombocytopenia (HR, 0.50).
• The survival benefit with EV/P remained consistent across subgroups based on age, sex, race, primary tumor site, the presence of liver metastases, the distribution of metastatic sites, and kidney function categories.

IN PRACTICE

“This retrospective study found that EV/P was associated with meaningful clinical advantages over G/C as first-line therapy for [metastatic urothelial carcinoma],” the authors wrote. “These results reinforce the effectiveness of EV/P in routine clinical practice, even among clinically heterogeneous populations.”

SOURCE

The study, led by Eusebio Luna Velasquez, MD, Houston Methodist Hospital, Houston, was published online on July 1 in JAMA Network Open.

LIMITATIONS

The study was limited by its retrospective study design, possible changes in practice over time, misclassification bias, and missing data.

DISCLOSURES

The authors did not disclose any funding information. Several authors reported personal fees, grants, speaking fees, or other relationships with multiple pharmaceutical companies, including Merck, Pfizer, AstraZeneca, Seagen, Astellas, and others. Full disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.