Enfortumab Vedotin + Pembrolizumab for Bladder Cancer

Recruiting at 2 trial locations

Overseen By Debbie Schwartz, RN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must not be taking: PD-1 inhibitors, CTLA-4 inhibitors

Disqualifiers: Uncontrolled diabetes, Active infections, Autoimmune disease, others

Stay on Your Current Meds You can continue your current medications while participating

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: 35

Duration: 24 months

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, enfortumab vedotin (an antibody-drug conjugate) and pembrolizumab (an immunotherapy), to treat high-grade upper tract urothelial cancer, a type of bladder cancer. Researchers aim to determine if this combination can help patients who prefer to avoid surgery live as long without cancer returning as those who choose surgery. This trial targets individuals diagnosed with high-grade upper tract urothelial cancer who have opted against surgery and have not received previous treatment for advanced cancer. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are on high doses of steroids or other immunosuppressive medications, you may not be eligible to participate. It's best to discuss your specific medications with the study team.

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

Research shows that combining enfortumab vedotin and pembrolizumab is generally safe. In earlier studies, patients with bladder cancer tolerated this treatment well. Common side effects included fatigue, hair loss, and skin issues, typical for cancer treatments. Serious side effects occurred less frequently.

The FDA has approved this combination for treating advanced bladder cancer, indicating trust in its safety. However, since each person's experience can vary, discussing potential risks with a doctor is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Enfortumab vedotin combined with Pembrolizumab for bladder cancer because these treatments use a unique approach to target cancer cells. Enfortumab vedotin is an antibody-drug conjugate that specifically delivers a cancer-killing agent directly to bladder cancer cells, which minimizes damage to healthy tissues. Pembrolizumab, on the other hand, is an immunotherapy that boosts the body's own immune response to fight cancer. This combination aims to provide a more effective treatment by directly attacking the cancer cells while also enhancing the immune system's ability to combat the disease, offering hope beyond traditional chemotherapy and surgery options.

What evidence suggests that the combination of enfortumab vedotin and pembrolizumab could be effective for high grade UTUC?

Research has shown that the combination of enfortumab vedotin and pembrolizumab, under study in this trial, may effectively treat certain types of bladder cancer. Studies have found that this combination can significantly extend the time patients live without cancer progression and improve overall survival. Specifically, patients receiving these drugs lived a median of 31.5 months, compared to 16.1 months for those on standard chemotherapy. These treatments target cancer cells more effectively, leading to better outcomes than traditional methods. The FDA has granted accelerated approval for this combination to treat advanced bladder cancer, underscoring its potential effectiveness. ^{1 2 3 4 6}

Who Is on the Research Team?

Jean Hoffman-Censits, MD

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

This trial is for adults with high grade upper tract urothelial cancer who haven't had systemic therapy for advanced cancer, are opting out of or can't have surgery, and don’t have metastatic disease. Participants must be in good health otherwise, able to consent, and meet specific conditions if they can have children.

Inclusion Criteria

I cannot or choose not to have major surgery to remove my kidney and ureter.

I have not had any treatment for advanced bladder cancer.

I am 18 or older with a confirmed diagnosis of high-grade upper tract urothelial cancer.

Exclusion Criteria

I had a stroke or similar brain event in the last 6 months.

I have not had radiotherapy in the last 2 weeks.

I have another cancer besides non-melanoma skin cancer or prostate cancer that is not actively growing.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive enfortumab vedotin and pembrolizumab every 3 weeks for up to 35 cycles (approximately 2 years) until disease progression or intolerance

24 months

35 cycles (in-person)

Follow-up

Participants are monitored for overall survival and progression-free survival

48 months

What Are the Treatments Tested in This Trial?

Interventions

• Enfortumab vedotin
• Pembrolizumab

Trial Overview The study tests combining pembrolizumab and enfortumab vedotin as a treatment option instead of standard surgery. It aims to see if this drug combo can lead to survival rates similar to those achieved by the usual surgical procedure without spreading the cancer.

How Is the Trial Designed?

Group I: Enfortumab vedotin with Pembrolizumab Experimental Treatment 2 Interventions

The study population will include male and female patients over the age of 18 with high grade UTUC (cN0/xM0) and is ineligible for or refuses definitive radical nephroureterectomy (RNU). Enfortumab vedotin will be administered on Days 1 and 8 at 1.25mg/kg of every 3-week cycle by intravenous (IV) infusion given over approximately 30 minutes. Pembrolizumab will be administered on Day 1 at 200mg of every 3-week cycle by IV infusion over approximately 30 minutes. Enfortumab vedotin and Pembrolizumab may be administered for up to total of 35 cycles (approximately 2 years).

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:

• Unresectable or metastatic urothelial carcinoma in adults who are eligible for platinum-containing chemotherapy

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Astellas Pharma Inc

Industry Sponsor

Trials

700

Recruited

236,000+

Headquarters

Tokyo, Japan

Top Products

- Xtandi (enzalutamide) for prostate cancer, - Xospata (gilteritinib) for AML, - Padcev (enfortumab vedotin) for bladder cancer, - Prograf (tacrolimus) for organ rejection prevention

Tadaaki Taniguchi

Astellas Pharma Inc

Chief Medical Officer since 2023

MD, PhD

Naoki Okamura

Astellas Pharma Inc

Chief Executive Officer since 2023

University of Tokyo, Faculty of Pharmacy

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Seagen Inc.

Industry Sponsor

Trials

212

Recruited

73,800+

Founded

1997

Headquarters

Bothell, USA

Known For

Antibody-Drug Conjugates

Top Products

Adcetris (brentuximab vedotin), Tukysa (tucatinib), Padcev (enfortumab vedotin-ejfv), Tivdak (tisotumab vedotin-tftv)

Dr. Roger Dansey

Seagen Inc.

Chief Medical Officer since 2018

MD from University of Witwatersrand

David R. Epstein

Seagen Inc.

Chief Executive Officer since 2022

BSc in Pharmacy from Rutgers University, MBA from Columbia University

Published Research Related to This Trial

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 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 (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 (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]

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]

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]

Citations

1. merck.com merck.com/news/keytruda-pembrolizumab-plus-padcev-enfortumab-vedotin-ejfv-significantly-improved-event-free-and-overall-survival-and-pathologic-complete-response-rate-for-certain-patients-with-muscle/

KEYTRUDA® (pembrolizumab) plus Padcev® (enfortumab ... KEYTRUDA® (pembrolizumab) plus Padcev® (enfortumab vedotin-ejfv) Significantly Improved Event-Free and Overall Survival and Pathologic Complete ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06764095

NCT06764095 | Enfortumab Vedotin and Pembrolizumab ... This phase IV trial tests the impact of standard of care enfortumab vedotin and pembrolizumab followed by removal of all or part of the bladder ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38446675/

Enfortumab Vedotin and Pembrolizumab in Untreated ... Treatment with enfortumab vedotin and pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or ...

4. padcevhcp.com padcevhcp.com/padcev-pembrolizumab-efficacy

1L PADCEV + Pembrolizumab Efficacy - Enfortumab vedotin Graph showing 31.5 months median overall survival with PADCEV + pembrolizumab and 16.1 months median overall. The median survival follow-up time was 17.2 months ...

5. 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 ... FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma.

6. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer

FDA approves enfortumab vedotin-ejfv with ... The major efficacy outcome measures were overall survival (OS) and progression-free survival (PFS) as assessed by blinded independent central ...