Enfortumab Vedotin + Pembrolizumab for Testicular and Urinary Tract Cancer

Overseen By Andrea B Apolo, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: Neuropathy, CNS metastases, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 7

Duration: Up to 5 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for rare cancers of the testicles and urinary tract. Researchers are testing two medications, enfortumab vedotin (an antibody-drug conjugate) and pembrolizumab (an immunotherapy drug), to determine their effectiveness in treating these specific cancers. Some participants will receive both drugs, while others will receive only one. This trial suits adults with advanced or treatment-resistant testicular or urinary tract cancers. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important advancements in cancer treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, if you are on systemic intravenous or oral corticosteroids or other immunosuppressive agents, these must be discontinued at least 1 week prior to treatment initiation for recent short-term use or at least 4 weeks prior for long-term use. Hormonal therapies for other cancers may be continued if stopping them could increase the risk of disease progression.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that enfortumab vedotin, a drug in this study, has been tested in patients with advanced urinary cancers. Patients generally tolerate it well, though some may experience side effects like skin reactions, high blood sugar, and nerve problems. These serious side effects can be managed with medical care.

When combined with pembrolizumab, another drug in this study, the safety profile remains similar. Studies have shown that this combination is already approved for treating certain urinary cancers and offers an alternative to traditional chemotherapy. This approval indicates that the combination is considered safe for patients with these conditions.

The current trial is in an early phase, focusing on closely examining the safety of these treatments for people with less common types of testicle and urinary cancers. While previous studies provide some reassurance, participating in this trial will help gather more data on safety for these specific conditions. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they introduce a novel approach to tackling testicular and urinary tract cancers. Unlike traditional chemotherapy or radiation, Enfortumab Vedotin is an antibody-drug conjugate that specifically targets cancer cells by delivering a potent anti-cancer agent directly to them, minimizing damage to healthy cells. Pembrolizumab, on the other hand, is an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells more effectively. Together, these drugs offer a dual mechanism: precise targeting of cancer cells and enhanced immune response, which could improve outcomes for patients compared to existing therapies.

What evidence suggests that this trial's treatments could be effective for testicular and urinary tract cancer?

Research has shown that combining enfortumab vedotin with pembrolizumab effectively treats certain urinary cancers. Studies found that this combination reduced the risk of death by 49% compared to standard chemotherapy. This finding is encouraging, as it suggests patients might have a better chance of living longer. In this trial, participants in Arm 2 will receive this combination treatment. Meanwhile, Arm 1 will focus on enfortumab vedotin alone, which has also demonstrated effectiveness, with lasting effects over several years. Both treatments target specific cancer markers, making them potentially good options for rare testicular and urinary tract cancers. ^{6 7 8 9 10}

Who Is on the Research Team?

Andrea B Apolo, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Adults with rare testicular or urinary tract cancers, including advanced adenocarcinoma and squamous cell carcinoma of the urinary tract, or refractory testicular germ cell tumors. Must have measurable disease and be in good physical condition (ECOG <=1). Some must have had prior anti-PD-1/PD-L1 therapy; others should not have received immune checkpoint inhibitors before. Women must agree to contraception use and discontinue breastfeeding.

Inclusion Criteria

Pre-study treatment tissue availability (sufficient tissue for 25 unstained slides) is mandatory for enrollment

My organs and bone marrow are functioning well.

Participants must be able to understand and willing to sign a written informed consent document

Exclusion Criteria

You have had serious allergic reactions to drugs similar to EV or pembrolizumab.

I have brain metastases that are causing symptoms or have not been treated.

Pregnant women as evaluated by a positive serum or urine beta-human chorionic gonadotropin (Beta-hCG) test at screening

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive enfortumab vedotin with or without pembrolizumab in 21-day or 28-day cycles

Up to 5 years

3 visits per 28-day cycle or 2 visits per 21-day cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Every 3 to 4 weeks until disease progression, then every 3 months by phone

Open-label extension (optional)

Participants may continue to receive enfortumab vedotin for up to 5 years if they have completed 35 cycles of pembrolizumab

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Enfortumab Vedotin
• Pembrolizumab

Trial Overview The trial is testing Enfortumab Vedotin (EV), alone or combined with Pembrolizumab, for treating certain rare genitourinary cancers. Participants will receive treatments through an IV at varying intervals over cycles lasting several weeks, potentially continuing up to five years, accompanied by regular scans and tests.

How Is the Trial Designed?

Group I: Arm 2 Experimental Treatment 2 Interventions

Treatment with enfortumab vedotin and pembrolizumab

Group II: Arm 1 Experimental Treatment 1 Intervention

Treatment with enfortumab vedotin

Enfortumab Vedotin is already approved in United States, European Union for the following indications:

Approved in United States as Padcev for:

• Locally advanced or metastatic urothelial cancer

Approved in European Union as Padcev for:

• Locally advanced or metastatic urothelial cancer

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Enfortumab vedotin (Padcev) is the first FDA-approved treatment specifically for adults with locally advanced or metastatic urothelial cancer who have already undergone treatment with PD-1/PD-L1 inhibitors and platinum-based chemotherapy.

This approval marks a significant advancement in cancer therapy, providing a new option for patients who have limited treatment choices after previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approves First Agent to Treat Locally Advanced, Metastatic Urothelial Cancer. Kahl, KL.[2023]

Enfortumab vedotin (PADCEV) received accelerated FDA approval for treating locally advanced or metastatic urothelial cancer in patients who have already undergone specific prior therapies, based on substantial evidence from a study involving 125 patients.

The treatment showed a confirmed objective response rate of 44%, with a median response duration of 7.6 months, although 73% of patients experienced grade 3-4 adverse reactions, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Carcinoma. Chang, E., Weinstock, C., Zhang, L., et al.[2022]

In a study of 45 patients with locally advanced or metastatic urothelial cancer, the combination of enfortumab vedotin and pembrolizumab resulted in tumor shrinkage in 73% of patients within 2 months, with effects lasting over 2 years.

While 16% of patients experienced serious side effects, most were manageable, although 24% had to stop treatment due to these side effects, indicating a need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A plain language summary exploring a new treatment combination for untreated locally advanced or metastatic urothelial cancer: enfortumab vedotin plus pembrolizumab. Hoimes, CJ., Flaig, TW., Milowsky, MI., et al.[2023]

Enfortumab vedotin-ejfv (EV) is an effective treatment for locally advanced or metastatic urothelial carcinoma (UC), showing a 44% overall response rate and a median overall survival of 11.7 months in heavily pretreated patients.

While EV demonstrates significant antitumor activity, it also presents unique toxicity concerns that require careful monitoring, highlighting the need for further studies to optimize its use in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab Vedotin-ejfv: A First-in-Class Anti-Nectin-4 Antibody-Drug Conjugate for the Management of Urothelial Carcinoma. Halford, Z., Anderson, MK., Clark, MD.[2021]

The combination of enfortumab vedotin (EV) and pembrolizumab (Pembro) demonstrated a high confirmed objective response rate (cORR) of 64.5% in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer, indicating its efficacy as a first-line treatment option.

Patients receiving the combination therapy also experienced durable responses, with 65.4% maintaining their response at 12 months, while the safety profile showed manageable adverse events, with no new safety signals identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer. O'Donnell, PH., Milowsky, MI., Petrylak, DP., et al.[2023]

In a subgroup analysis of 86 Japanese patients with locally advanced or metastatic urothelial carcinoma, enfortumab vedotin (EV) demonstrated a median overall survival of 15.18 months, significantly longer than the 10.55 months observed with standard chemotherapy.

EV also showed a higher confirmed overall response rate (34.4%) compared to standard chemotherapy (21.3%), while having a lower incidence of treatment-related adverse events, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Japanese subgroup analysis of EV-301: An open-label, randomized phase 3 study to evaluate enfortumab vedotin versus chemotherapy in subjects with previously treated locally advanced or metastatic urothelial carcinoma. Matsubara, N., Yonese, J., Kojima, T., et al.[2023]

Enfortumab vedotin (EV) and platinum rechallenge both demonstrated comparable oncological outcomes in patients with advanced urothelial carcinoma after prior treatments, with progression-free survival (PFS) and overall survival (OS) rates being similar between the two groups.

In a study of 64 patients, both treatments showed effective results, suggesting that EV can be a viable alternative to platinum rechallenge for patients who have already undergone platinum-based chemotherapy and pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab vedotin versus platinum rechallenge in post-platinum, post-pembrolizumab advanced urothelial carcinoma: A multicenter propensity score-matched study. Taguchi, S., Kawai, T., Ambe, Y., et al.[2023]

Citations

1. urotoday.com urotoday.com/conference-highlights/esmo-2025/esmo-2025-bladder-cancer/164052-esmo-2025-ev-103-cohort-k-efficacy-and-safety-of-enfortumab-vedotin-with-or-without-pembrolizumab-in-cisplatin-ineligible-patients-with-previously-untreated-locally-advanced-or-metastatic-urothelial-cancer-with-a-median-follow-up-of-3-5-years.html

ESMO 2025: EV-103 Cohort K: Efficacy and Safety ... After 5 years of follow-up in the Dose Escalation/Cohort A, EV+P continued to show durable responses and a meaningful survival, with a median OS ...

2. urotoday.com urotoday.com/conference-highlights/asco-gu-2025/asco-gu-2025-press-releases/158093-pfizer-and-astellas-padcev-enfortumab-vedotin-ejfv-plus-keytruda-pembrolizumab-shows-long-term-efficacy-in-first-line-treatment-of-locally-advanced-or-metastatic-urothelial-cancer-la-muc.html

Pfizer and Astellas' PADCEV® (enfortumab vedotin-ejfv) ... Results showed enfortumab vedotin plus pembrolizumab reduced the risk of death by 49% versus chemotherapy (hazard ratio [HR] = 0.51, 95% ...

3. tandfonline.com tandfonline.com/doi/full/10.1080/14796694.2025.2497719?src=

E-VIRTUE: a study of enfortumab vedotin with or without ... The immunotherapy drug, pembrolizumab, has been shown to lengthen life in multiple cancer types including melanoma skin cancer, lung cancer, bladder cancer and ...

4. padcev.com padcev.com/trial-results

Clinical Study Results | PADCEV® (enfortumab vedotin-ejfv) See clinical study data for PADCEV® in adults with advanced bladder cancer or cancers of the urinary tract. See full PI, including Serious Side Effects.

5. cancernetwork.com cancernetwork.com/view/exploring-the-use-of-enfortumab-vedotin-in-rare-genitourinary-cancers

Exploring The Use of Enfortumab Vedotin in Rare ... Based on prior reports, common toxicities associated with enfortumab vedotin may include rash, neuropathy, and blood glucose increases.

6. ema.europa.eu ema.europa.eu/en/documents/product-information/padcev-epar-product-information_en.pdf

Padcev, INN-enfortumab vedotin - EMA At the recommended dose of 1.25 mg/kg, enfortumab vedotin did not prolong the mean QTc interval to any clinically relevant extent based on ECG data from a study ...

7. urotoday.com urotoday.com/recent-abstracts/urologic-oncology/bladder-cancer/163593-treatment-related-adverse-events-and-associated-outcomes-in-patients-with-advanced-urothelial-carcinoma-treated-with-enfortumab-vedotin-analysis-of-the-unite-study.html

Analysis of the UNITE Study. Enfortumab vedotin-ejfv (EV), an antibody-drug conjugate approved for advanced urothelial carcinoma (aUC), has limited real-world safety data ...

8. padcev.com padcev.com/side-effects

Possible Side Effects | PADCEV® (enfortumab vedotin-ejfv) PADCEV may cause serious side effects, including: Skin reactions, High blood sugar (hyperglycemia), Lung problems, Nerve problems, Eye problems.

9. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2023/761137s018.pdf

Padcev - accessdata.fda.gov Nonclinical data suggest that the anticancer activity of enfortumab vedotin-ejfv is due to the binding of the ADC to Nectin-4-expressing cells, followed by ...

10. pfizer.com pfizer.com/news/press-release/press-release-detail/pfizer-and-astellas-padcevr-enfortumab-vedotin-ejfv-plus-0

Pfizer and Astellas' PADCEV® (enfortumab vedotin-ejfv) ... Enfortumab vedotin plus pembrolizumab also reduced the risk of disease progression or death by 52% versus chemotherapy (HR = 0.48, 95% CI, 0.41- ...