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

Trial Summary

What is the purpose of this trial?

This trial is a multi-site, single-arm, phase 2 trial of neoadjuvant combination of enfortumab vedotin and pembrolizumab in cisplatin-eligible patients with high-grade localized/locally advanced cT1-4 N0-1 M0 upper tract urothelial cancer who are deemed eligible for curative-intent surgery (radical nephroureterectomy or distal ureterectomy) followed by adjuvant pembrolizumab.

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.

What data supports the effectiveness of the drug combination Enfortumab Vedotin and Pembrolizumab for bladder cancer?

Enfortumab Vedotin has been approved by the FDA for treating advanced bladder cancer, showing a 44% response rate in patients who had prior treatments. Additionally, both Enfortumab Vedotin and Pembrolizumab have individually shown benefits in treating advanced bladder cancer, suggesting their combination could be effective. ^{1 2 3 4 5}

Is the combination of Enfortumab Vedotin and Pembrolizumab safe for humans?

Enfortumab Vedotin has been associated with serious side effects like high blood sugar, nerve damage, eye problems, skin reactions, and risks to unborn babies. In a study, 73% of patients experienced severe side effects. Pembrolizumab, used in combination, also has its own set of potential side effects. ^{1 2 3 4 6}

How is the drug combination of enfortumab vedotin and pembrolizumab unique for bladder cancer?

The combination of enfortumab vedotin and pembrolizumab is unique because it targets bladder cancer by combining an antibody-drug conjugate (enfortumab vedotin) that specifically attacks cancer cells with an immune checkpoint inhibitor (pembrolizumab) that helps the immune system fight cancer. This approach is different from traditional chemotherapy and offers a new option for patients with advanced bladder cancer who have limited treatment choices. ^{1 2 3 4 6}

Research Team

Irene Tsung

Principal Investigator

University of Michigan

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

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

2. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Carcinoma. [2022]

3. England 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. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Enfortumab Vedotin-ejfv: A First-in-Class Anti-Nectin-4 Antibody-Drug Conjugate for the Management of Urothelial Carcinoma. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer. [2023]

6. Australia pubmed.ncbi.nlm.nih.gov

Enfortumab vedotin versus platinum rechallenge in post-platinum, post-pembrolizumab advanced urothelial carcinoma: A multicenter propensity score-matched study. [2023]