FDA Expands Pembrolizumab and Enfortumab Vedotin Around Bladder Surgery

What changed on 10 July 2026

FDA approved pembrolizumab, or pembrolizumab with berahyaluronidase alfa-pmph. Each is combined with enfortumab vedotin-ejfv. The regimen is given before surgery and continued after it, for adults with muscle invasive bladder cancer.

The word that matters is "extends." The combination was already approved here for people who could not have cisplatin. This widens it to everyone with muscle invasive bladder cancer who can have surgery.

Cystectomy means surgery to remove the bladder. Muscle invasive means the tumor has grown into the bladder's muscle wall, not just its lining.

The two drugs, and what each does

Enfortumab vedotin, sold as Padcev, is an antibody-drug conjugate. Its antibody targets Nectin-4, a protein on the surface of cells. Attached to it is MMAE, a drug that breaks up microtubules. A linker joins them, and enzymes can cut it.

Microtubules are the scaffolding a cell uses to divide. The label sets out the sequence. The conjugate binds Nectin-4. The cell pulls it inside. The linker is cut, MMAE is freed, and the scaffolding collapses. Our page on what does antibody-drug conjugate mean explains the design.

Pembrolizumab works differently. It blocks PD-1 on T cells, taking the brakes off an immune attack. The Padcev label notes that pairing the two raised immune activity and anti-tumor effect in mouse models.

The trial behind the decision

Efficacy came from KEYNOTE-B15/EV-304, registered as NCT04700124. It was an open-label, randomized, multicenter trial in 808 people. None had been treated before. All were candidates for radical cystectomy with pelvic lymph node dissection, and all could have cisplatin.

Half got pembrolizumab with enfortumab vedotin, then surgery, then the same pair again. Half got gemcitabine and cisplatin, then surgery.

The main measure was event-free survival, judged by blinded independent review. Overall survival was also measured.

What it found

Median event-free survival was not reached in the combination arm. In the chemotherapy arm it was 48.5 months. The hazard ratio was 0.53, with a 95 percent confidence interval of 0.41 to 0.70.

Median overall survival was not reached in either arm. The hazard ratio for death was 0.65, with a confidence interval of 0.48 to 0.89 and p equal to 0.0029.

"Not reached" means fewer than half the group had an event by the analysis. It is a good sign, and an incomplete one.

Both results were statistically significant. Overall survival is the harder endpoint, and many approvals do not have one. Our page on immunotherapy vs chemotherapy covers why the two approaches differ in benefit and harm.

The schedule, which is long

For cisplatin-eligible patients, pembrolizumab is given every 3 weeks, or on a longer schedule of every 6 weeks. Enfortumab vedotin is given on Days 1 and 8 of each 21-day cycle, at an amount the team works out from body weight. That runs 4 cycles, about 12 weeks, before surgery.

After surgery, enfortumab vedotin runs 5 more cycles alongside pembrolizumab, a 15-week stretch. Pembrolizumab then continues alone. Adjuvant treatment lasts 39 weeks in total.

The safety profile is not gentle

Padcev carries a boxed warning for serious skin reactions. The label names Stevens-Johnson syndrome and toxic epidermal necrolysis, in which the skin blisters and peels away. It states these can be fatal. They occurred mostly during the first cycle, but can come later. A confirmed case means stopping the drug for good.

High blood sugar is the second. Hyperglycemia and diabetic ketoacidosis have occurred in people with and without diabetes, including fatal events. Across single-agent trials, 17 percent of 720 patients had hyperglycemia of any grade, and 7 percent had grade 3 or 4. Risk rose with higher body mass index and higher baseline A1C. The label directs holding the drug when blood glucose passes 250 mg/dL.

Also listed are lung inflammation, nerve damage in the hands and feet, eye disorders, and tissue damage if the infusion leaks out of the vein. Pembrolizumab adds immune-mediated reactions in any organ, infusion reactions, and problems in people who have had a donor stem cell transplant.

When to call the team during treatment

These triggers come from the labels, not from general advice:

• Any new rash, above all one that blisters, peels, or hits the mouth or eyes. This is same-day urgent.
• Thirst, frequent urination, blurred vision, or confusion, which can mean blood sugar is climbing
• Numbness, tingling, or weakness in hands or feet
• New or worsening cough or breathlessness
• Pain, swelling, or redness at the infusion site

Where this fits in bladder cancer overall

American Cancer Society projections put new bladder cancers in the United States at 84,530 for 2026, with 17,870 deaths. Five-year relative survival across all stages was 79.1 percent for cases from 2016 to 2022.

Most bladder cancer is caught early. Half are in situ, confined to the layer of cells where they began, with 98.0 percent five-year survival. Thirty-four percent are localized, at 73.0 percent. Seven percent are regional, at 41.8 percent, and 6 percent distant, at 9.6 percent.

The most common symptom is blood in the urine, called hematuria, often rusty to bright red. NCI notes it can appear once and then not return for a while. Other signs are frequent urination, pain or burning when urinating, a need to go when the bladder is not full, and urinating often at night. Infections and stones cause these far more often than cancer does. That is exactly why blood in the urine needs a look rather than a guess. Our page on bladder cancer symptoms goes through them.

What this approval does not mean

An approval sets who is eligible in general terms. This one covers adults with muscle invasive disease who are candidates for cystectomy. It does not cover non-muscle-invasive bladder cancer. It does not cover people who cannot have surgery.

The trial enrolled people eligible for cisplatin. It compared the combination against gemcitabine and cisplatin. That is the comparison the numbers describe. Overall survival medians were not reached in either arm, so the long-run size of the gain is not settled.

And the toxicity is real. A boxed warning for fatal skin reactions is not a footnote, nor is the risk of diabetic ketoacidosis. Whether the regimen fits one person depends on kidney function, diabetes, nerve damage, skin history, and that person's own goals.

Sources

• FDA, FDA approves pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph each with enfortumab vedotin-ejfv for muscle invasive bladder cancer — https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-or-pembrolizumab-and-berahyaluronidase-alfa-pmph-each-enfortumab-vedotin
• DailyMed, PADCEV (enfortumab vedotin-ejfv) prescribing information — https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b5631d3e-4604-4363-8f20-11dfc5a4a8ed
• DailyMed, KEYTRUDA (pembrolizumab) prescribing information — https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287
• NCI, Bladder Cancer Symptoms — https://www.cancer.gov/types/bladder/symptoms
• SEER Cancer Stat Facts, Bladder Cancer — https://seer.cancer.gov/statfacts/html/urinb.html

How this article was prepared

An AI-assisted editorial system helped prepare this page. No named medical reviewer has reviewed it unless one is listed.

The National Cancer Information Foundation publishes Cancer Explained. This page is for learning. It is not medical advice and does not suggest a test or treatment.

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