Pembrolizumab + Enfortumab Vedotin + Surgery for Bladder Cancer

Recruiting at 249 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Nonurothelial malignancy, Metastatic disease, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 18

595 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a study of perioperative pembrolizumab or enfortumab vedotin in combination with pembrolizumab in participants who are cisplatin-ineligible or decline cisplatin with muscle-invasive bladder cancer (MIBC). The primary hypothesis is that perioperative pembrolizumab plus radical cystectomy (RC) plus pelvic lymph node dissection (PLND) and perioperative enfortumab vedotin in combination with pembrolizumab plus RC+PLND will achieve superior event-free survival (EFS) compared with RC+PLND alone. With Amendment 5, outcome measures for programmed cell death ligand 1 (PD-L1) combined positive score (CPS) were removed. With Amendment 8, the primary outcome measure of pathologic complete response (pCR) rates was changed to a secondary outcome measure.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on chronic systemic steroid therapy or any other form of immunosuppressive therapy, you may need to stop these at least 7 days before starting the study drug.

What data supports the effectiveness of the drug combination of enfortumab vedotin and pembrolizumab for bladder cancer?

Enfortumab vedotin and pembrolizumab have shown effectiveness in treating advanced urothelial cancer, which often occurs in the bladder. Enfortumab vedotin was approved by the FDA for patients who had previously received other treatments, with a 44% response rate in a study, and both drugs have shown survival benefits compared to chemotherapy. ^{1 2 3 4 5}

What safety data exists for the treatment combination of Pembrolizumab and Enfortumab Vedotin?

Enfortumab Vedotin has been approved for treating advanced bladder cancer, but it can cause serious side effects in some patients. These include high blood sugar, nerve damage, eye problems, skin reactions, and risks to unborn babies. In studies, 73% of patients experienced severe side effects. ^{1 2 3 4 6}

What makes the drug combination of enfortumab vedotin and pembrolizumab unique for bladder cancer treatment?

This drug combination is unique because it offers a new first-line treatment option for patients with advanced bladder cancer who cannot receive the standard cisplatin-based chemotherapy, providing a potential survival benefit without the severe side effects associated with cisplatin. ^{1 2 3 5 6}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

This trial is for adults with muscle-invasive bladder cancer who can't take cisplatin or choose not to. They must be able to undergo surgery, have good organ function, and an ECOG status of 0-2. Women must use effective contraception or abstain from sex if they're of childbearing potential; men also have similar requirements if receiving enfortumab vedotin.

Inclusion Criteria

A WOCBP must have a negative highly sensitive pregnancy test within 24 hours before the first dose of study intervention

My bladder cancer has not spread, as confirmed by scans.

My organs are working well.

Exclusion Criteria

My diabetes is not under control.

I have had radiation therapy to my bladder before.

I have received a transplant from another person.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preoperative Treatment

Participants receive 3 preoperative cycles of pembrolizumab or enfortumab vedotin + pembrolizumab

9 weeks

3 visits (in-person)

Surgery

Participants undergo radical cystectomy (RC) and pelvic lymph node dissection (PLND)

1 week

1 visit (in-person)

Postoperative Treatment

Participants receive 14 cycles of postoperative pembrolizumab or 6 cycles of enfortumab vedotin + pembrolizumab followed by 8 cycles of pembrolizumab alone

42 weeks

14 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 7.6 years

Treatment Details

Interventions

• Enfortumab Vedotin
• Pembrolizumab
• Radical Cystectomy (RC) plus Pelvic Lymph Node Dissection [PLND]

Trial Overview The study tests perioperative pembrolizumab (a drug) alone or combined with enfortumab vedotin (another drug), plus bladder removal surgery against surgery alone. The goal is to see which approach leads to better survival without the disease progressing.

Participant Groups

Group I: Arm C: Enfortumab Vedotin + Pembrolizumab + Surgery Experimental Treatment 1 Intervention

Participants receive 3 preoperative cycles of enfortumab vedotin + pembrolizumab, followed by standard of care surgery, followed by 6 cycles of postoperative enfortumab vedotin + pembrolizumab, followed by 8 cycles of pembrolizumab alone. Each cycle is 21 days.

Group II: Arm A: Pembrolizumab + Surgery Experimental Treatment 2 Interventions

Participants receive 3 preoperative cycles of pembrolizumab, followed by standard of care surgery, followed by 14 cycles of postoperative pembrolizumab. Each cycle is 21 days.

Group III: Arm B: Surgery alone Active Control 1 Intervention

Participants receive standard of care surgery alone.

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?

Merck Sharp & Dohme Corp.

Lead Sponsor

Trials

2,287

Recruited

4,582,000+

Chirfi Guindo

Merck Sharp & Dohme Corp.

Chief Medical Officer

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

Robert M. Davis

Merck Sharp & Dohme Corp.

Chief Executive Officer since 2021

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

Merck Sharp & Dohme LLC

Lead 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

Astellas Pharma Global Development, Inc.

Industry Sponsor

Trials

204

Recruited

123,000+

Tadaaki Taniguchi

Astellas Pharma Global Development, Inc.

Chief Medical Officer

M.D., Ph.D.

Naoki Okamura

Astellas Pharma Global Development, Inc.

Chief Executive Officer

Not available

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]

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 (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]

In a study of 45 cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer, the combination of enfortumab vedotin and pembrolizumab resulted in a high confirmed objective response rate of 73.3%, indicating significant tumor shrinkage.

The treatment demonstrated a manageable safety profile, with most adverse events being manageable, and showed promising median durations of response and overall survival of 25.6 months and 26.1 months, respectively, suggesting its potential as an effective first-line therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. Hoimes, CJ., Flaig, TW., Milowsky, MI., 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]

References

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

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

2. 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]

3. 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]

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

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

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

Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. [2023]

6. 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]