Enfortumab Vedotin + Pembrolizumab for Bladder Cancer

(NEPTUNE Trial)

Overseen By Cancer AnswerLine

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Michigan Rogel Cancer Center

Must not be taking: Immunosuppressants, Monomethyl auristatin E

Disqualifiers: Autoimmune disorders, Metastasis, Active infection, 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: 21

32 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two treatments: enfortumab vedotin (an antibody-drug conjugate) and pembrolizumab (an immunotherapy drug), to determine their effectiveness for certain bladder cancer patients. The goal is to assess whether these drugs can shrink tumors before surgery and prevent recurrence afterward. The trial seeks participants diagnosed with high-grade urothelial carcinoma, a type of bladder cancer, who are candidates for curative surgery. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on immunosuppressive medication, you must stop it 14 days before starting the trial, unless it's a low-dose steroid or certain other exceptions.

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

Research has shown that using enfortumab vedotin and pembrolizumab together is promising in terms of safety. Studies have found that this combination can greatly improve survival rates for people with bladder cancer. The combination is usually well-tolerated, with a safety profile similar to each drug on its own.

In earlier studies, some patients experienced side effects, mostly mild to moderate ones like tiredness or a rash. Serious side effects were less common, but they can occur. Discussing possible side effects with a doctor is important to understand how they might affect health. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Enfortumab vedotin and Pembrolizumab for bladder cancer because it introduces a unique mechanism of action. Enfortumab vedotin is an antibody-drug conjugate that specifically targets Nectin-4, a protein highly expressed in bladder cancer cells, delivering a potent cytotoxic agent directly to the tumor. Pembrolizumab, on the other hand, is an immune checkpoint inhibitor that unleashes the body's immune system to attack cancer cells. This dual approach not only targets the cancer directly but also boosts the immune response, offering a promising new strategy compared to traditional treatments like chemotherapy.

What evidence suggests that this trial's treatments could be effective for bladder cancer?

Research has shown that using enfortumab vedotin and pembrolizumab together holds promise for treating bladder cancer. In this trial, participants will receive a combination therapy of these two drugs. Studies have found that this combination can significantly improve survival rates for patients with advanced bladder cancer. Specifically, patients receiving these drugs lived a median of 31.5 months, compared to 16.1 months with other treatments. This combination also prolongs the time patients live without disease progression and increases the likelihood of achieving no signs of cancer after treatment. These findings suggest that enfortumab vedotin and pembrolizumab could be effective options for treating certain types of bladder cancer. ^{3 5 6 7 8}

Who Is on the Research Team?

Irene Tsung

Principal Investigator

University of Michigan

Are You a Good Fit for This Trial?

This trial is for adults with high-grade upper tract urothelial cancer that hasn't spread far (localized/locally advanced cT1-4 N0-1 M0). They must be able to receive cisplatin and surgery aimed at curing the cancer. People who can't have cisplatin or are not fit for curative surgery cannot join.

Inclusion Criteria

All patients must be informed of the investigational nature of the study and provide written informed consent

Prior uro-oncologic history is allowed under specific conditions

Patients must not have any other medical condition(s) that make(s) their participation unadvisable

Exclusion Criteria

Enrolled in another interventional clinical trial at the time of registration

Pregnant or lactating patients

I have another cancer that is currently active.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive enfortumab vedotin and pembrolizumab every 21 days for 4 cycles

12 weeks

4 visits (in-person)

Surgery

Participants undergo definitive surgery (radical nephroureterectomy or distal ureterectomy)

1 day

1 visit (in-person)

Adjuvant Treatment

Participants receive pembrolizumab every 21 days for up to 13 cycles post-surgery

up to 39 weeks

13 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 2 years post-surgery

Regular visits every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Enfortumab vedotin
• Pembrolizumab

Trial Overview The study tests a combination of two drugs, Enfortumab Vedotin and Pembrolizumab, given before surgery to patients eligible for cisplatin. After surgery, participants will continue receiving Pembrolizumab as an additional treatment.

How Is the Trial Designed?

Group I: Combination Therapy Experimental Treatment 2 Interventions

Enfortumab vedotin 1.25 mg/kg IV on Days 1 and 8 and Pembrolizumab 200 mg IV on Day 1 (every 21 days for 4 cycles) Definitive surgery (radical nephroureterectomy RNU or distal ureterectomy per treating urologist) Pembrolizumab 200 mg IV on day 1 (every 21 days for up to 13 cycles) after surgery

Who Is Running the Clinical Trial?

University of Michigan Rogel Cancer Center

Lead Sponsor

Trials

303

Recruited

20,700+

Published Research Related to This Trial

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 (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-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]

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]

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]

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 ... The trial is continuing to evaluate the secondary EFS, OS, and pCR rate endpoints for neoadjuvant and adjuvant KEYTRUDA versus surgery alone as ...

2. 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.

3. 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 ... Terence Friedlander presented the results of EV-103 Cohort K that evaluated the efficacy and safety of enfortumab vedotin (EV) +/- pembrolizumab ...

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. onclive.com onclive.com/view/perioperative-enfortumab-vedotin-plus-pembrolizumab-displays-positive-topline-data-in-muscle-invasive-bladder-cancer

Perioperative Enfortumab Vedotin Plus Pembrolizumab ... Enfortumab vedotin plus pembrolizumab significantly improved survival outcomes in patients with muscle-invasive bladder cancer who were ...

6. merck.com merck.com/news/keytruda-pembrolizumab-plus-padcev-enfortumab-vedotin-ejfv-reduced-risk-of-event-free-survival-events-by-60-and-risk-of-death-by-50-for-certain-patients-with-muscle-invasive-bladder-ca/

KEYTRUDA® (pembrolizumab) Plus Padcev ... - Merck.com KEYTRUDA® (pembrolizumab) Plus Padcev® (enfortumab vedotin-ejfv) Reduced Risk of Event-Free Survival Events by 60% and Risk of Death by 50% for Certain Patients ...

7. pfizer.com pfizer.com/news/press-release/press-release-detail/padcevtm-plus-keytrudatm-given-and-after-surgery-cuts-risk

PADCEV™ Plus KEYTRUDA™, Given Before and After ... “The compelling EV-303 results may establish a new efficacy benchmark in muscle-invasive bladder cancer. For the first time, a systemic ...

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

Enfortumab Vedotin and Pembrolizumab in Untreated ... Conclusions: Treatment with enfortumab vedotin and pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with ...