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Phase 3 Study of Enfortumab Vedotin plus Pembrolizumab in Adults with Muscle‑Invasive Bladder Cancer Ineligible for Cystectomy

Verified siteRegistered drugNo placebo
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What is this trial about?

A plain-language summary of the goals, design and what participants do

The study focuses on Muscle-Invasive Bladder Cancer, a type of bladder cancer that has grown into the muscle layer of the bladder wall. This condition often requires aggressive treatment because the cancer cells have spread beyond the inner lining.

The purpose of the study is to determine whether adding the medication enfortumab vedotin together with pembrolizumab can improve survival compared with the standard chemoradiation approach. Participants receive the drugs by intravenous infusion, which means the medicines are delivered slowly through a vein. The trial is described as phase 3, open‑label, and randomized: “phase 3” indicates a large study aimed at confirming effectiveness, “open‑label” means both doctors and participants know which treatment is being given, and “randomized” means participants are assigned to treatment groups by chance.

During the study, participants attend regular clinic visits where the infusion is given, followed by periodic health checks to monitor how the disease is responding and to watch for any side effects. The overall period includes several months of treatment and additional follow‑up visits after the infusions are finished to track long‑term outcomes.

The research process

The trial runs in 7 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Enrollment Confirmation

    After you decide to join the study, you will sign the consent form that explains the purpose of the research and your rights as a participant.

    The study staff will verify that you meet the eligibility criteria for muscle‑invasive bladder cancer.

  2. Step 2

    Baseline Assessments

    You will undergo a physical examination, blood tests, and imaging studies to document the current status of your cancer.

    These results create a reference point for later comparisons during the trial.

  3. Step 3

    First Treatment Session

    You will receive enfortumab vedotin at a dose of 1.25 mg per kilogram of body weight by intravenous infusion.

    Immediately after, you will receive pembrolizumab at a fixed dose of 400 mg, also by intravenous infusion.

    Both infusions are administered in a clinical setting under medical supervision.

  4. Step 4

    Ongoing Treatment Cycles

    You will continue to receive the same two infusions (enfortumab vedotin 1.25 mg/kg and pembrolizumab 400 mg) according to the study schedule.

    Each cycle repeats the infusion process and follows the timing defined in the trial protocol.

  5. Step 5

    Safety and Efficacy Monitoring

    At regular intervals, you will return to the clinic for blood tests, imaging, and physical examinations.

    These visits allow the study team to track side effects, assess tumor response, and ensure your safety.

  6. Step 6

    End of Treatment

    Treatment will stop after the predetermined number of cycles or earlier if the study protocol requires discontinuation because of disease progression or unacceptable side effects.

    You will be informed of the reason for ending the treatment.

  7. Step 7

    Follow‑Up Period

    After treatment ends, you will continue to have scheduled visits to monitor overall survival and any long‑term effects of the therapy.

    These follow‑up appointments may include physical exams, laboratory tests, and imaging studies.

Who can join the trial?

7 criteria

  • You are at least 18 years old (or meet the minimum age required by local laws) and can give consent to join the study.
  • You have a confirmed diagnosis of Muscle‑Invasive Bladder Cancer that is stage T2‑T4a N0M0, with at least half of the tumor made of urothelial carcinoma. You have not received chemotherapy or radiation for bladder cancer before. You must have had a complete transurethral resection of bladder tumor (TURBT) within about 60 days before randomisation, and the tissue sample must include the detrusor muscle (the muscle layer of the bladder). You also need a recent imaging scan (radiological staging) done within four weeks, and you should not have swelling of the kidneys (hydronephrosis) unless your kidney function is normal.
  • You must be able to receive and agree to a treatment that combines chemotherapy and radiation, called chemoradiotherapy, together with a special chemotherapy that makes the radiation work better (radiosensitizing chemotherapy).
  • Any side effects from earlier treatments must have improved to mild levels (grade ≤ 1 on the NCI CTCAE scale), meaning they are little or no trouble for you.
  • You should be healthy enough, in the doctor’s opinion, to tolerate whole‑body (systemic) treatment and you must choose to keep your bladder instead of having it surgically removed (cystectomy). This includes people who cannot have surgery or who decide not to have it.
  • Your overall ability to carry out daily activities must be rated as 0‑2 on the ECOG performance status scale, where 0 means fully active and 2 means up and about more than 50 % of waking hours.
  • You must sign a written document agreeing to take part in the study (informed consent).

Who cannot join the trial?

21 criteria

  • Having cancer that has spread beyond the bladder (called advanced or metastatic disease), having many separate early‑stage lesions in the bladder (four or more), or having bladder‑type cancer in other parts of the body within the past two years (except certain cases after complete removal of the kidney and ureter).
  • Having a history of HIV infection with a low count of CD4+ T‑cells (less than 350 cells/µL) or recent AIDS‑related infections, active hepatitis B that needs treatment but hasn’t started, uncontrolled hepatitis C infection, active tuberculosis, or currently taking medicines for a serious infection (except routine preventive antibiotics).
  • Having a past or current lung condition such as interstitial lung disease, idiopathic pulmonary fibrosis, organizing pneumonia, drug‑induced pneumonitis, or any sign of active lung inflammation on a chest scan.
  • Having a known genetic disorder that makes the body very sensitive to radiation (examples include ataxia‑telangiectasia, Nijmegen breakage syndrome, and Fanconi syndrome).
  • Having an autoimmune disease that required strong medicines (like disease‑modifying drugs, corticosteroids, or other immune‑suppressing drugs) in the two years before the study. Simple hormone replacements (such as thyroid or insulin) are not counted as systemic treatment.
  • Having had major surgery within the four weeks before enrollment and not fully recovered. Minor procedures need at least one week of recovery.
  • Having taken any experimental drug or vaccine for any reason within 30 days (or five drug half‑lives, whichever is longer) before the first study dose, or having participated in another clinical study with the same treatment within four weeks.
  • Having received any prior systemic chemotherapy, chemoradiation, or radiation therapy for muscle‑invasive or non‑muscle‑invasive bladder cancer. (Prior bladder‑instillation therapy such as BCG is allowed.)
  • Having previously received any of the following: the study drug EV or similar antibody‑drug conjugates, any PD‑1 or PD‑L1 immune checkpoint inhibitor (e.g., pembrolizumab, atezolizumab), other experimental immune‑cell‑targeting agents, an allogeneic stem‑cell or solid‑organ transplant, or pelvic radiation for any reason.
  • Using any prohibited medication within 30 days before the first study dose, or being unwilling or unable to take required study medications.
  • Having a baseline heart test (12‑lead ECG) that shows serious abnormalities, such as a corrected QT interval (QTc) longer than 470 ms, a wide QRS complex (>120 ms), certain types of heart block, or dangerous fast or slow heart rhythms.
  • Having inadequate bladder function, defined by frequent small urine volumes (less than 30 mL), urinary incontinence, or the need for a self‑catheter or a permanent catheter.
  • Having experienced any major heart or blood‑vessel problems in the six months before enrollment, such as heart attack, long QT syndrome, dangerous arrhythmias, severe heart failure (NYHA class III or IV), stroke, transient ischemic attack, serious blood clot, or other significant cardiac events.
  • Being a member of the study staff, a family member of study staff, or an employee of the sponsor who is directly involved in conducting the trial.
  • Having any other active cancer within the past three years, except for adequately treated basal‑cell or squamous‑cell skin cancer, carcinoma in situ of the upper urinary tract, or low‑grade prostate cancer that is being watched without treatment.
  • Having a known severe allergy (hypersensitivity) to the study drugs (EV or pembrolizumab) or any of their ingredients, including platinum‑based drugs, fluorouracil, or gemcitabine.
  • Having any of the following current medical problems: uncontrolled diabetes (HbA1c ≥ 8% or 7‑8% with symptoms), moderate or worse nerve damage (sensory or motor neuropathy grade 2+), active eye infection such as keratitis or corneal ulcer, serious psychiatric illness or recent suicidal thoughts or behavior, or any laboratory abnormality that the doctor believes makes participation unsafe.
  • Having an immune‑deficiency disorder or taking high‑dose systemic steroids (more than 10 mg of prednisone‑equivalent daily) or other immune‑suppressing medicines within seven days before the first dose. Inhaled or topical steroids are allowed.
  • Having reduced kidney function, measured as a creatinine clearance (CrCl) less than 30 mL/min (or an equivalent eGFR).
  • Having significant liver problems, such as total bilirubin more than 1.5 times the upper limit of normal, or liver enzymes (AST or ALT) more than 2.5 times the upper limit.
  • Having abnormal blood counts, including low neutrophils (ANC < 1500/µL), low platelets (< 100,000/µL), or low hemoglobin (< 9.0 g/dL), unless these values are due to recent transfusion or growth‑factor use.
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Investigated drugs

Enfortumab Vedotin is an antibody‑drug conjugate that seeks out a protein found on bladder cancer cells. Once it binds to the cancer cell, it delivers a chemotherapy agent directly to the tumor, helping to kill the cancer while causing less damage to normal cells. In this study the medicine is given through an IV infusion as part of the experimental treatment.

Pembrolizumab is an immunotherapy drug that helps the immune system see and attack cancer cells. It works by blocking a protein called PD‑1, which normally turns off immune cells. By keeping the immune cells active, the drug allows the body to fight the tumor more effectively. In the trial it is also administered by IV infusion together with Enfortumab Vedotin.

The comparator therapy is concurrent chemoradiotherapy (cCRT). This treatment combines chemotherapy drugs with radiation therapy given at the same time. The goal is to shrink or destroy the bladder tumor before surgery, and it serves as the control arm in this trial.

What is already known about the treatment

  • Enfortumab vedotin

    It is supplied as a powder that is mixed with liquid to create a solution for intravenous infusion. The drug is approved and widely studied for the treatment of advanced bladder cancer. It works by attaching to a protein called Nectin‑4 on cancer cells and delivering a toxin that kills those cells. Enfortumab vedotin belongs to the class of antibody‑drug conjugates.

  • Pembrolizumab

    It is provided as a concentrate that is diluted and given by intravenous infusion. Pembrolizumab is an approved therapy for several cancers, including bladder cancer, and is supported by extensive medical literature. The medication blocks the PD‑1 pathway, allowing the body’s immune system to recognize and attack cancer cells. It is classified as a monoclonal antibody and an immune checkpoint inhibitor.

Investigated diseases

Muscle‑Invasive Bladder Cancer – This cancer starts in the lining of the bladder and has grown into the muscular wall that helps the bladder empty. As the tumor expands, it can reach nearby organs, spread to lymph nodes, and eventually travel to other parts of the body. The disease typically progresses from a localized stage to more widespread involvement if not controlled.
Trial detailsLast updated 17 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2026-525612-34-00Protocol codeC5701009Estimated enrolment390 patientsSponsorPfizer Inc.

sourced from the EU Clinical Trials Register and site verification

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