Enfortumab Vedotin Plus Pembrolizumab Yields Benefit in Key Subgroups With Advanced Urothelial Cancer

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The combination of the nectin-4–directed antibody-drug conjugate enfortumab vedotin-ejfv plus the PD-1 inhibitor pembrolizumab achieved favorable rates of progression-free survival, overall survival, and objective responses compared with chemotherapy among key subgroups of patients with previously untreated, locally advanced or metastatic urothelial carcinoma—those with visceral metastases, lymph node–alone metastases, and cisplatin-eligible or cisplatin-ineligible patients—-according to findings of prespecified subgroup analyses of the phase III EV-302/KEYNOTE-A39 trial.1 These findings further support the role of this combination as standard of care for metastatic urothelial carcinoma.

Primary results of the trial were first presented at the European Society for Medical Oncology (ESMO) Congress 2023.2 Enfortu-mab vedotin plus pembrolizumab was approved for the treatment of patients with locally advanced or metastatic urothelial cancer in 2023, based on these primary results.

Among subgroups, progression-free survival in patients with visceral metastases was improved by 55% with enfortumab vedotin plus pembrolizumab and by 60% in those with lymph node–alone metastasis. These findings were consistent with those of the overall population (a risk reduction of 55%, P < .00001).1,2

The overall survival benefit in subgroups was similar to that of the overall population, with a 53% improvement vs chemotherapy (P < .00001) in patients with visceral metastases. Median overall survival with the combination in the patients with visceral metastases was 25.6 months vs 13.6 months with chemotherapy. In the lymph node–alone cohort, median overall survival was not reached with the combination vs 27.5 months with chemotherapy.

Michiel S. Van Der Heijden, MD, PhD

Michiel S. Van Der Heijden, MD, PhD

“The benefit of enfortumab vedotin plus pembrolizumab in all prespecified subgroups, including cisplatin-eligible/ineligible patients and those with visceral metastases, was consistent with that in the overall patient population. These results further support enfortumab vedotin plus pembrolizumab as a new standard of care in locally advanced or metastatic urothelial carcinoma,” said lead author Michiel S. Van Der Heijden, MD, PhD, leader of the Michiel Van Der Heijden Research Group at the Netherlands Cancer Institute.

Study Details

The EV-302 trial enrolled patients with treatment-naive, locally advanced or metastatic urothelial cancer with no contraindications to platinum, enfortumab vedotin, or pembrolizumab. Entry criteria called for a glomerular filtration rate of at least 30 mL/min, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and no prior exposure to a checkpoint inhibitor.

Patients were randomly assigned 1:1 to receive the combination of enfortumab vedotin plus pembrolizumab (n = 443) or up to six cycles of chemotherapy with gemcitabine plus either cisplatin or carboplatin (n = 483). Treatment in the investigational arm was continued until disease progression, unacceptable toxicity, or completion of 35 cycles of pembrolizumab. Maintenance therapy was allowed following the completion and/or discontinuation of platinum-containing therapy at the investigator’s discretion.

Patients were stratified by cisplatin eligibility, PD-L1 expression (low [combined positive score (CPS) < 10] vs high [CPS ≥ 10]), liver metastases (present vs absent), age (< 65 vs ≥ 65 years), region (North America vs Europe vs the rest of the world), sex (female vs male), race (White vs other), ECOG performance status at baseline (0 vs 1 to 2), metastases (visceral vs lymph node alone), primary disease site of origin (upper tract vs lower tract), and renal function (normal vs mild vs moderate vs severe). In the primary analysis, the combination had an overall survival advantage vs chemotherapy in cisplatin-eligible and -ineligible patients, as well as PD-L1–high and PD-L1–low subgroups.

Among patients who received enfortumab vedotin plus pembrolizumab, there was a similar 47% improvement in overall survival among those with liver metastases (43 of 100 patients) and those without liver metastases (90 of 342 patients), Patients who received enfortumab vedotin who had liver metastases had an overall survival of 19.1 months vs 10.1 months for those patients with liver metastases who received chemotherapy (67 of 99 patients). Patients who received enfortumab vedotin plus pembrolizumab who did not have liver metastases had an overall survival that was not reached vs 17.9 months in patients without liver metastases who received chemotherapy.

The current analysis showed that objective response rates in additional key subgroups were consistent with those in the primary analysis. Objective response rate was 67.7% with the combination vs 44.4% with chemotherapy.


For more on the EV-302 trial of enfortumab vedotin plus pembrolizumab vs chemotherapy in metastatic urothelial carcinoma, see an interview with Michiel S. Van Der Heijden, MD, PhD, on The ASCO Post Newsreels at

In cisplatin-eligible patients, objective response rate was 70.8% with the combination vs 53.0% with chemotherapy. In cisplatin-ineligible patients, objective response rate was 63.9% vs 34.9%, respectively. In the PD-L1–low subgroup, this rate was 63.3% vs 41.0%, respectively. Among the PD-L1–high subgroup, objective response rate was 71.1% vs 46.6%, respectively. In patients with liver metastases, objective response rate was 60.0% vs 41.4%. The rate in patients without liver metastases was 70.0% vs 45.3%.

Patients with visceral metastases had an objective response rate of 64.1% vs 39.6%. In patients with lymph node–alone disease, objective response rate was 77.5% vs 53.4%, respectively.


Toxicity was reported to be generally manageable with enfortu-mab vedotin plus pembrolizumab. No new safety signals were observed. Grade 3 or higher events were reported in 56% of patients who received enfortumab vedotin plus pembrolizumab vs 70% of those given chemotherapy.

The most common treatment-related adverse effects reported with the combination were peripheral sensory neuropathy, alopecia, maculopapular rash, fatigue, diarrhea, decreased appetite, nausea, anemia, neutropenia, and thrombocytopenia. In the arm given enfortumab vedotin plus pembrolizumab, four treatment-related adverse events led to death; in the chemotherapy arm, there were also four treatment-related deaths. 

DISCLOSURE: Dr. Van Der Heijden has served as an institutional consultant or advisor to Astellas Pharma, AstraZeneca/MedImmune, Bristol Myers Squibb, Janssen, MSD Oncology, Pfizer, Roche/Genentech, and Seagen; has received institutional research funding from 4SC, AstraZeneca, Bristol Myers Squibb, Roche, and Seagen; and has received reimbursement for travel expenses from Bristol Myers Squibb.


1. Van Der Heijden MS, et al: 2024 ASCO Genitourinary Cancers Symposium. Abstract LBA530. Presented January 26, 2024.

2. Powles TB, et al: Ann Oncol 34(suppl 4):S1557-S1558, 2023.



Invited discussant of the EV-302/KEYNOTE-A39 trial, Parminder Singh, MD, of the Mayo Clinic, Phoenix, commented: “The combination of enfortumab vedotin plus pembrolizumab represents a new standard of care, with a consistent benefit in survival across key subgroups. A future area of study would be de-escalation of therapy in patients with complete response by stopping enfortumab vedotin and continuing pembrolizumab.”

Parminder Singh, MD

Parminder Singh, MD

Dr. Singh continued: “[With enfortumab vedotin plus pembrolizumab], there is a learning curve in managing new patterns of toxicity. About 60% of patients have skin toxicity, peripheral neuropathy, and sensory events, and about 20% have ocular toxicity.” He suggested the following measures to deal with the adverse events: early dose reduction of enfortumab vedotin for neuropathy; growth factor support for cytopenias; topical steroids for skin rash (lotion not ointment); strict diabetes management; and treatment of ocular toxicity.

DISCLOSURE: Dr. Singh has received honoraria from Curio Science and Medpage/ASCO; has served as a consultant or advisor to AVEO, Bayer, EMD Serono, ImmunityBio, Janssen Oncology, Seagen, and Seattle Genetics/Astellas; and has received institutional research funding from EMD Serono.