Enfortumab Vedotin Plus Pembrolizumab Expands Bladder Preservation in MIBC

Radical cystectomy retains a role in the management of muscle-invasive bladder cancer (MIBC), but with highly active perioperative systemic therapy and circulating tumor DNA (ctDNA)–guided staging now available, it is one option among several rather than the default for most patients, according to a presentation from the LUGPA 2026 Annual Meeting.¹

"The big change that occurred in 2026 is really thinking about MIBC as a systemic problem," Joshua J. Meeks, MD, PhD, said during the presentation at the meeting.

Meeks, chief of the Division of Urologic Oncology, associate professor of Urology and Biochemistry, and the Edward M. Schaeffer Professor of Urology at Northwestern University Feinberg School of Medicine in Chicago, Illinois, framed his talk around why lethal MIBC behaves as a systemic disease, how enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) has doubled pathologic complete response (pCR) rates, and how he now selects patients for cystectomy, trimodal therapy (TMT), or observation.

Why is MIBC viewed as a systemic disease?

Meeks drew a parallel to breast cancer, in which the more extensive surgery yields a greater chance of cure gave way to the recognition that metastatic risk is systemic; in that setting, 40% of patients with clinically node-negative disease had pathologically positive nodes.²

He argued the same pattern holds in MIBC, and looked to a series of 1054 patients who underwent radical cystectomy between 1971 and 1997, only 5% received perioperative chemotherapy.³

"These are the best surgeons in the world doing radical cystectomy," Meeks said. Nevertheless, 5- and 10-year overall survival (OS) rates were 66% and 43%, respectively, and 30% of patients experienced recurrence, 75% of which were distant.^1,3 Ten-year recurrence-free survival rates were 82% for organ-confined disease, 47% for extravesical disease, and 31% for lymph node–positive disease.

"We have better staging today. That's a huge improvement," Meeks said, pointing to ctDNA. In an analysis presented at the 2026 ASCO Genitourinary Cancers Symposium, patients with ctDNA-positive disease at baseline had worse metastasis-free survival than those who were ctDNA negative (HR, 12.62; 95% CI, 3.74-42.57; P < .0001).⁴

Moreover, in a ctDNA analysis of the phase 3 NIAGARA trial (NCT03732677), 22% of patients across both arms (n = 89) were ctDNA positive before cystectomy, and only 3% of those patients achieved pCR.⁵

How has enfortumab vedotin plus pembrolizumab improved outcomes?

In the SWOG-8710 trial, median survival was not reached among patients who received neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) followed by cystectomy and achieved pT0 status, compared with 3.8 years for those with residual disease after MVAC and 2.4 years for those with residual disease after cystectomy alone.⁶ Early retrospective evidence also suggests that patients who achieved a clinical CR to neoadjuvant chemotherapy and declined cystectomy could do well, with the 5-year disease-free survival rate for these patients being 60% and the 5-year cancer-specific survival rate was 90%.⁷

Additionally, the phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124) of cisplatin-eligible patients (n = 808), the regimen produced a pCR rate of 55.8% (95% CI, 50.8%-60.7%) vs 32.5% (95% CI, 28.0%-37.3%) with cisplatin plus gemcitabine, for an estimated difference of 23.4% (95% CI, 16.7%-29.8%; 1-sided P < .0001).⁸ The HRs for event-free survival (EFS) and OS were 0.53 and 0.65, respectively, and the 24-month EFS rates were 79.4% vs 66.2%.

In the phase 3 KEYNOTE-905/EV-303 (NCT03924895) trial of cisplatin-ineligible patients (n = 344), the pCR rate with enfortumab vedotin plus pembrolizumab was 57.1% vs 8.6% with surgery alone, with HRs of 0.40 for EFS and 0.50 for OS, respectively; 24-month EFS rates were also 74.7% and 39.4%.⁹

"If we give [a patient] chemotherapy, 1 in 3 patients will have a CR. Now we can tell them 3 out of 5 or 2 out of 3 people will have a CR," Meeks said. "The drugs are better. Our chances of getting rid of the cancer are better." With a 2-fold increase in pathologic CRs according to KEYNOTE-B15/EV-304, he added, bladder preservation becomes a realistic consideration.

Where does trimodal therapy fit?

Historically, bladder-sparing approaches were reserved for patients with poor functional status, those who refused cystectomy or could not tolerate neoadjuvant chemotherapy, and those with advanced disease. Meeks described a patient who worked as a chef and was unwilling to undergo urinary diversion. "I have a chef who showed up and said, listen, if I have a stoma, I can't work, if. I can't have an appliance around all the food. I said, let's think about bladder preservation for you" he recalled.

He credited the phase 3 SWOG/NRG S1806 (INTACT) trial (NCT03775265) with shifting that paradigm. The study randomly assigned 475 patients with cT2-T4N0M0 disease to concurrent chemoradiation with or without 9 cycles of atezolizumab (Tecentriq), with bladder-intact EFS as the primary end point.¹⁰ According to Meeks, the trial standardized how bladder preservation is delivered and helped build buy-in for TMT among community urologists.

How should MIBC be managed today?

Meeks outlined his current suggested workflow. Patients with cT2-T4bN0-N+ disease are referred to medical oncology for 3 to 4 cycles of enfortumab vedotin plus pembrolizumab, with PET-CT and ctDNA used as staging biomarkers. "Don't worry about your bladder. That's not the most important part. You need to get you to a medical oncologist and see if you're okay," he tells patients at the.

Restaging with blue light cystoscopy, transurethral resection of bladder tumor, and mapping biopsies then directs next steps: patients with residual cT2 or greater, ctDNA-positive disease are counseled toward radical cystectomy followed by ctDNA monitoring. Those with cT1, ctDNA-negative disease may proceed to TMT followed by pembrolizumab. Finally, those with cT0, ctDNA-negative disease may be observed while continuing enfortumab vedotin plus pembrolizumab as tolerated. Meeks acknowledged that prospective data supporting observation remain limited and that these patients require close surveillance.

For patients with persistent ctDNA-positive muscle-invasive disease, Meeks explained his rationale for surgery: "The way I look at it is that it's maximal therapy for a tumor that was resistant to treatment."

He identified the best candidates for cystectomy as patients who want a definitive pathologic response, wish to avoid repeated resections and cystoscopy, want to stop systemic therapy, or cannot receive radiation or further systemic therapy, as well as those with sarcomatoid or other variant histology, prostatic urethral involvement, node-positive disease that has converted to node-negative bladder-only disease, or a nonfunctional bladder.

What unmet needs remain?

Meeks concluded that systemic therapy is critical for all patients with MIBC and that, given the efficacy of enfortumab vedotin plus pembrolizumab in the cisplatin-ineligible population, cisplatin eligibility should no longer determine whether patients receive systemic treatment.

He called for biomarkers that reduce the risk of inaccurate staging to be incorporated into routine practice and emphasized that shared decision-making is central when choosing among preservation strategies. "Every patient is different, and we can work with them," Meeks said, adding that ongoing trials will be needed to refine patient selection for bladder preservation.

References

1. Meeks J. Redefining organ preservation in MIBC: modern bladder preservation strategies. Presented at: Large Urology Group Practice Association 2026 Annual Meeting; November 5-7, 2026; Chicago, IL.
2. Fisher B, Jeong JH, Anderson S, et al. Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. N Engl J Med. 2002;347(8):567-575. doi:10.1056/NEJMoa020128
3. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol. 2001;19(3):666-675. doi:10.1200/JCO.2001.19.3.666
4. Ghatalia P, Ross AE, Zibelman MR, et al. Circulating tumor DNA (ctDNA) to guide response-adapted bladder preservation in muscle-invasive bladder cancer (MIBC): combined analysis of the RETAIN studies. J Clin Oncol. 2026;44(suppl 7):LBA632. doi:10.1200/JCO.2026.44.7_suppl.LBA632
5. Powles T, Van Der Heijden MS, Wang Y, et al. Circulating tumor DNA (ctDNA) in patients with muscle-invasive bladder cancer (MIBC) who received perioperative durvalumab (D) in NIAGARA. J Clin Oncol. 2025;43(suppl 16). doi:10.1200/JCO.2025.43.16_suppl.4503
6. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859-866. doi:10.1056/NEJMoa022148
7. Robins D, Matulay J, Lipsky M, et al. Outcomes following clinical complete response to neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma of the bladder in patients refusing radical cystectomy. Urology. 2018;111:116-121. doi:10.1016/j.urology.2017.09.003
8. Galsky M, Valderrama B, Powles T, et al. Enfortumab vedotin and pembrolizumab in cisplatin-eligible bladder cancer. N Engl J Med. 2026;395(4):338-348. doi:10.1056/NEJMoa2601486
9. Vulsteke C, Adra N, Danchaivijitr P, et al. Perioperative enfortumab vedotin and pembrolizumab in bladder cancer. N Engl J Med. 2026;394(13):1257-1269. doi:10.1056/NEJMoa2511674
10. Chemoradiotherapy with or without atezolizumab in treating patients with localized muscle invasive bladder cancer. ClinicalTrials.gov. Updated August 28, 2026. Accessed November 6, 2026. https://clinicaltrials.gov/study/NCT03775265