Enfortumab Vedotin + Pembrolizumab for Bladder Cancer

Overseen By Clinical Trials Referral Office

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Mayo Clinic

Must not be taking: Immunosuppressants, Corticosteroids, TNF blockers, others

Disqualifiers: Active malignancies, Cardiovascular disease, Autoimmune disease, 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: 16

Duration: 12 weeks

75 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the effectiveness of combining two drugs, enfortumab vedotin and pembrolizumab, for treating bladder and upper urinary tract cancers that have spread. Enfortumab vedotin directly targets cancer cells, while pembrolizumab enhances the immune system's ability to fight the tumor. After drug treatment, some patients may undergo surgery to remove part of the bladder or urinary tract. Ideal candidates have been diagnosed with advanced bladder or upper urinary tract cancer within the last 90 days and are open to potential surgery. As a Phase 4 trial, this research aims to understand how the already FDA-approved and effective treatment benefits more patients.

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 immunosuppressive medications or have had certain treatments recently, you may need to discuss this with the trial team.

What is the safety track record for enfortumab vedotin and pembrolizumab?

Research has shown that the combination of enfortumab vedotin and pembrolizumab is generally well-tolerated by patients. In studies, most participants managed the treatment without major problems. Specifically, about 73.3% of patients experienced a positive response to the treatment.

However, some side effects did occur. Common issues included fatigue, skin problems like itching, and nerve issues. More serious side effects occurred in about 55.9% of patients, but medical care addressed these.

Overall, the treatment appears safe for many, but like any medical treatment, there are risks. Consulting a doctor is important to understand what this could mean for individual patients. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about Enfortumab Vedotin and Pembrolizumab for bladder cancer because these treatments offer a novel approach compared to standard chemotherapy options. Most treatments for bladder cancer target the cancer cells broadly, but Enfortumab Vedotin is an antibody-drug conjugate that specifically targets Nectin-4, a protein commonly found on bladder cancer cells, delivering a potent toxin directly to them. Pembrolizumab, on the other hand, is an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells more effectively. Together, they offer a targeted and potentially more effective attack on cancer cells while minimizing damage to healthy tissues.

What is the effectiveness track record for enfortumab vedotin and pembrolizumab in treating bladder cancer?

In this trial, participants will receive a combination of enfortumab vedotin and pembrolizumab. Research has shown that this combination can greatly improve outcomes for patients with advanced bladder cancer. In one study, patients who received this combination lived for a median of 33.8 months, compared to 15.9 months for those who only had chemotherapy. Another study found that 46.6% of patients experienced tumor shrinkage, and 28.3% had no detectable cancer. These findings suggest the combination is effective in treating advanced bladder cancer. Additionally, it generally causes fewer side effects compared to standard treatments. ^{1 6 7 8 9}

Who Is on the Research Team?

Jacob J. Orme, MD, PhD

Principal Investigator

Mayo Clinic in Rochester

Paras H. Shah, MD

Principal Investigator

Mayo Clinic in Rochester

Are You a Good Fit for This Trial?

This trial is for patients with locally advanced or metastatic bladder and upper urothelial tract cancer. Participants should be eligible for standard care involving enfortumab vedotin and pembrolizumab, followed by surgical removal of the bladder or ureter if needed.

Inclusion Criteria

Ability to complete questionnaire(s) by themselves or with assistance

Hemoglobin ≥ 8.0 g/dL

Absolute neutrophil count (ANC) ≥ 1500/mm^3

Exclusion Criteria

Active autoimmune disease requiring systemic treatment

I have not had uncontrolled heart problems in the last 6 months.

I have active tuberculosis.

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 intravenously. Cycles repeat every 3 weeks for at least 4 cycles in the absence of disease progression or unacceptable toxicity.

12 weeks

4 visits (in-person)

Surgery

Patients who are surgical candidates may undergo cytoreductive cystectomy and/or ureterectomy.

1-2 weeks

Maintenance Treatment

After surgery, patients may continue to receive maintenance enfortumab vedotin and pembrolizumab.

Variable

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up occurs every 12 weeks for up to 5 years.

5 years

Every 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cystectomy
• Enfortumab Vedotin
• Pembrolizumab
• Ureterectomy

Trial Overview The CAST-AI Trial is examining the effectiveness of combining enfortumab vedotin (a drug that targets tumor cells) with pembrolizumab (an immunotherapy), followed by surgery to remove affected organs in treating advanced forms of urinary tract cancers.

How Is the Trial Designed?

Group I: Treatment (enfortumab vedotin, pembrolizumab) Experimental Treatment 10 Interventions

Patients receive standard of care enfortumab vedotin IV over 30 minutes on day 1 and day 8 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for at least 4 cycles (12 weeks) in the absence of disease progression or unacceptable toxicity. Patients who are surgical candidates may then undergo cytoreductive cystectomy and/or ureterectomy. Patients may also undergo MDT at any time per standard of care. After surgery, patients may then continue to receive maintenance enfortumab vedotin and pembrolizumab. Additionally, patients undergo urine and blood sample collection, CT, PET/CT or MRI throughout the study.

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

Published Research Related to This Trial

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 showed a 44% overall response rate in a phase II trial involving 125 patients with locally advanced or metastatic urothelial carcinoma who had previously undergone platinum-based chemotherapy and PD-1 or PD-L1 checkpoint inhibitor treatment.

While nearly all patients experienced treatment-related adverse events, most of these side effects were mild to moderate, indicating a manageable safety profile for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab Vedotin Checks Urothelial Cancer. [2020]

Enfortumab vedotin, a treatment for advanced bladder cancer, can cause severe skin reactions, with a case report highlighting a patient who developed toxic epidermal necrolysis shortly after starting the drug.

The case emphasizes the need for careful monitoring of skin reactions and suggests that if such reactions occur, treatment may need to be reduced or stopped to prevent serious complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxic epidermal necrolysis after the administration of enfortumab vedotin for urinary bladder urothelial carcinoma. Mimura, Y., Kobayashi, A., Utazu, H., et al.[2023]

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]

Enfortumab vedotin, an antibody drug conjugate for advanced urothelial carcinoma, can cause extravasation leading to serious skin reactions like bullae and cellulitis, as seen in two reported cases.

Both patients successfully managed their cellulitis conservatively and resumed treatment without further complications, suggesting that with proper management, the risks associated with extravasation can be mitigated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug extravasation with Enfortumab vedotin. Grant, CR., de Kouchkovsky, D., Kalebasty, AR., 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]

In a study of 34 patients with metastatic urothelial carcinoma treated with enfortumab vedotin, 56% showed a partial response or stable disease, with a median overall survival of 16 months and progression-free survival of 9 months, indicating its efficacy in a real-world setting.

The treatment was associated with a high incidence of adverse events, with 76% of patients experiencing some level of toxicity, primarily skin-related, but the safety profile was consistent with findings from clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab vedotin following platinum-based chemotherapy and immune checkpoint inhibitors for advanced urothelial carcinoma: response, survival and safety analysis from a multicentre real-world Japanese cohort. Miyake, M., Nishimura, N., Oda, 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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.745

Clinical efficacy of enfortumab vedotin-pembrolizumab (EV ... The median follow-up time was 7.1 months (IQR: 4.93-9.26). In terms of BOR, 56 patients (46.6%) experienced PR, 34 (28.3%) CR, 12 (10%) PD, 7 ( ...

2. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2831221

Enfortumab Vedotin With or Without Pembrolizumab in ... The findings suggest that enfortumab vedotin, especially combined with pembrolizumab, offers promising beneficial outcomes in metastatic urothelial carcinoma ...

3. annalsofoncology.org annalsofoncology.org/article/S0923-7534(25)00762-8/fulltext

2.5-year median follow-up of the phase III EV-302 ... The median OS was 33.8 months (95% CI 26.1-39.3 months) for the EV+P arm and 15.9 months (95% CI 13.6-18.3 months) for the chemotherapy arm (HR ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S1098301525019667

Cost-Effectiveness of Enfortumab Vedotin and ... The trial reported a median survival of 16.1 months for standard of care and 31.5 months for the new combination therapy, with an improved toxicity profile ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12451449/

Case report series: Pembrolizumab and enfortumab vedotin in ... The survival rate to chemotherapy in urothelial carcinoma is historically very low with a 5-year survival rate <5%, and many patients are ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10476837/

Enfortumab Vedotin Plus Pembrolizumab in Previously ... Enfortumab vedotin plus pembrolizumab showed a tolerable and manageable safety profile and a confirmed objective response rate of 73.3%. With the median ...

7. urotoday.com urotoday.com/conference-highlights/asco-gu-2024/asco-gu-2024-bladder-cancer/149388-asco-gu-2024-safety-and-efficacy-of-enfortumab-vedotin-in-patients-with-metastatic-locally-advanced-urothelial-cancer-real-world-evidence-from-a-european-database.html

ASCO GU 2024: Safety and Efficacy of Enfortumab Vedotin ... The most common and relevant adverse events with EV are neurotoxicity, dermatologic toxicity/pruritis, and fatigue. Adverse events of special interest include ...

8. nejm.org nejm.org/doi/abs/10.1056/NEJMoa2312117

Enfortumab Vedotin and Pembrolizumab in Untreated ... Treatment-related adverse events of grade 3 or higher occurred in 55.9% of the patients in the enfortumab vedotin–pembrolizumab group and in ...

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1470204525001585

Articles Enfortumab vedotin plus pembrolizumab versus ... Enfortumab vedotin plus pembrolizumab significantly improved survival outcomes versus platinum-based chemotherapy without detriment to GHS/QOL, pain, or ...