KEYNOTE-B15: EV/pembro sets new benchmark before cystectomy in MIBC

Perioperative enfortumab vedotin-ejfv (EV, Padcev) plus pembrolizumab (Keytruda) significantly improved event-free survival (EFS), overall survival (OS), and pathologic complete response (pCR) compared with cisplatin-based chemotherapy in cisplatin-eligible muscle-invasive bladder cancer (MIBC), marking the first regimen in nearly 25 years to surpass the long-standing standard.¹

The data, from the phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124), were presented by Matthew D. Galsky, MD, the director of genitourinary medical oncology at the Icahn School of Medicine at Mount Sinai and the associate director for translational research at the Tisch Cancer Institute in New York, New York, during the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California.

“Radical cystectomy [RC] is standard treatment for patients with muscle-invasive bladder cancer. However, with radical cystectomy alone, a substantial subset of patients develop metastatic recurrence, providing the rationale for integrating systemic therapy. Almost 25 years ago, cisplatin-based neoadjuvant chemotherapy was shown to improve outcomes in patients with muscle-invasive bladder cancer and was integrated into standard care. However, there has been a marked paucity of improvements to such treatment since that time. Enfortumab vedotin plus pembrolizumab [pembro] is now standard first-line treatment for patients with metastatic urothelial cancer, and has recently been shown to improve outcomes when given as neoadjuvant and adjuvant treatment in patients with muscle-invasive bladder cancer who are cisplatin ineligible,” Galsky said during his introduction.^2-7

KEYNOTE-B15, Galsky explained, is a randomized, open-label, phase 3 trial that evaluated neoadjuvant and adjuvant EV plus pembrolizumab and RC plus pelvic lymph node dissection (PLND) vs neoadjuvant cisplatin plus gemcitabine chemotherapy and RC plus PLND in patients with MIBC who were cisplatin eligible.

Patients were eligible for KEYNOTE-B15 if they were adults with MIBC that was clinical stage T2-T4aN0M0 or T1-T4aN1M0 by central assessment, had a urothelial histology of at least 50%, were eligible to undergo RC plus PLND, did not meet Galsky criteria for cisplatin ineligibility, and had an ECOG performance status of 0 or 1. Patients were randomly assigned 1:1 to receive EV 1.25 mg/kg on day 1 and day 8 intravenously (IV) every 3 weeks for 4 cycles plus pembrolizumab 200 mg on day 1 IV every 3 weeks for 4 cycles (405 patients) or to cisplatin 70 mg/m² on day 1 IV every 3 weeks for 4 cycles plus gemcitabine 1000 mg/m² on day 1 and day 8 IV every 3 weeks for 4 cycles (403 patients). Each cohort underwent RC plus PLND; following this, the EV/pembrolizumab cohort received EV 1.25 mg/kg on day 1 and day 8 IV every 3 weeks for 5 cycles plus pembrolizumab 200 mg on day 1 IV every 3 weeks for 13 cycles; the gemcitabine/cisplatin cohort underwent observation.

The primary end point was EFS as assessed by blinded independent central review (BICR). Key secondary end points included OS and pCR by central pathologist review. Safety was another secondary end point.

Of the 403 patients in the EV/pembrolizumab cohort who began the neoadjuvant phase, 344 completed it. Of 351 patients who underwent surgery, 346 underwent complete resection. A total of 262 patients started the adjuvant phase, of whom 208 completed treatment. Eighty-nine patients underwent surgery but did not begin the adjuvant phase. Reasons for not undergoing surgery included participant withdrawal (26 patients), adverse event (AE, 13 patients), physician decision (7 patients), and progressive disease (6 patients). Reasons for beginning the adjuvant treatment phase included AE (37 patients), participant withdrawal (30 patients), physician decision (16 patients), recurrence/relapse (3 patients), and surgery incomplete (3 patients).

In the gemcitabine/cisplatin cohort, 396 patients began the neoadjuvant phase, of whom 352 completed treatment. A total of 361 patients underwent surgery, of whom 352 received complete resection. Thirty-seven patients did not undergo surgery; reasons for this included participant withdrawal (37 patients), AE (6 patients), progressive disease (6 patients), and physician decision (2 patients).

Median patient age was 66.0 years in both cohorts. ECOG performance status was 0 in 317 (78.3%) patients and 1 in 88 (21.7%) patients in the EV/pembrolizumab cohort. ECOG performance status was 0 in 310 (76.9%) patients and 1 in 93 (23.1%) patients in the gemcitabine/cisplatin cohort. In the EV/pembrolizumab cohort, tumor stage at baseline was T2N0 in 79 (19.5%) patients, T3/T4aN0 in 293 (72.3%) patients, and T1-4aN1 in 33 (8.1%) patients. In the gemcitabine/cisplatin cohort, tumor stage at baseline was T2N0 in 77 (19.1%) patients, T3/T4aN0 in 293 (72.7%) patients, and T1-4aN1 in 33 (8.2%) patients. In the EV/pembrolizumab cohort, creatinine clearance was at least 90 mL/min in 149 (36.8%) patients, between 60 mL/min and less than 90 mL/min in 252 (62.2%) patients, and between 30 mL/min and less than 60 mL/min in 4 (1.0%) patients. In the gemcitabine/cisplatin cohort, creatinine clearance was at least 90 mL/min in 156 (38.7%) patients, between 60 mL/min and less than 90 mL/min in 245 (60.8%) patients, and between 30 mL/min and less than 60 mL/min in 2 (0.5%) patients.

Galsky reported that the trial met its primary end point of EFS by BICR; median EFS was not reached (NR) (95% CI, NR-NR) in the EV/pembrolizumab cohort compared with 48.5 months (95% CI, 43.3-NR) in the gemcitabine/cisplatin cohort (HR, 0.53; 95% CI, 0.41-0.70; 1-sided P < .0001).

“The 24-month EFS rate on the EV/pembro arm was 79.4%,” Galsky noted. The effect of EV/pembrolizumab on EFS was sustained when stratifying the cohort by age, sex, race, region, PD-L1 combined positive score, and tumor stage as %defined by BICR.

EV/pembrolizumab was also associated with significantly prolonged OS; the median OS was NR (95% CI, NR-NR) in the EV/pembrolizumab cohort vs NR (95% CI, NR-NR) in the gemcitabine/cisplatin [gem/cis] cohort (HR, 0.65; 95% CI, 0.48-0.89; 1-sided P = .0029).

“The 24-month OS rate was 86.9% on the EV/pembro arm,” Galsky said. He added, “Notably, among patients on the EV/pembro arm who experienced an EFS event, approximately 51% of patients received any subsequent systemic treatment at the time of the data lock. Among patients on the gem/cis arm experiencing an EFS event, approximately 59% of patients received any subsequent systemic treatment at the time of the data lock.”

In the EV/pembrolizumab arm, 226 patients achieved a pCR, for a pCR rate of 55.8% (95% CI, 50.8-60.7%), compared with 131 patients in the gemcitabine/cisplatin cohort, for a pCR rate of 32.5% (95% CI, 28.0%-37.3%). The estimated difference in pCR rate between the 2 cohorts was 23.4% (95% CI, 16.7%-29.8%; 1-sided P < .0001).

“Of note, among patients who underwent cystectomy, the path[ologic] CR rate on the EV/pembro arm was 64.4%,” Galsky said.

Turning to treatment exposure and safety, Galsky noted that patients in the EV/pembrolizumab cohort had a longer duration of treatment: a median of 10.2 months (range 0.03-25.5 months) compared with 3.5 months (range 0.03-16.8 months) for patients in the gemcitabine/cisplatin cohort. In the EV/pembrolizumab cohort, during the neoadjuvant phase, the median number of both EV and pembrolizumab treatment cycles was 4.0 (range, 1.0-4.0 cycles for both). Median number of cycles in the adjuvant phase was 5.0 (range, 1.0-5.0 cycles for EV) and 13.0 (range 1.0-13.0) for pembrolizumab.

A total of 395 (98.0%) patients had an any-grade treatment-emergent AE (TEAE) vs 389 (98.2%) patients in the gemcitabine/cisplatin cohort. Grade 3 or higher TEAEs were observed in 305 (75.7%) of patients in the EV/pembrolizumab cohort vs 266 (67.2%) of patients in the gemcitabine/cisplatin cohort. There were 2 (0.5%) treatment-related AEs leading to death in the EV/pembrolizumab and 1 (0.3%) treatment-related AE leading to death in the gemcitabine/cisplatin cohort.

“Neoadjuvant and adjuvant EV/pembro significantly improved event-free survival, overall survival, and path CR rate vs neoadjuvant gem/cis in patients with muscle-invasive bladder cancer who are eligible for cisplatin-based chemotherapy and radical cystectomy. The ability to proceed with surgery was similar on both arms, and the safety profile of EV/pembro was consistent with prior observations,” Galsky said in his concluding remarks.

He added, “This is a pivotal moment. For the first time since cisplatin-based neoadjuvant therapy was shown to improve outcomes in patients with muscle-invasive bladder cancer, almost 25 years ago, a nonplatinum-based regimen has surpassed it. The [phase 3] KEYNOTE-905 study [NCT03924895] recently demonstrated improved outcomes with EV/pembro in patients with muscle-invasive bladder cancer who were cisplatin ineligible. The results of these 2 independent phase 3 studies reinforce both the reproducibility and generalizability of outcomes with this treatment regimen. The results of KEYNOTE-B15, coupled with the results of KEYNOTE-905, support neoadjuvant and adjuvant EV/pembro as a novel treatment option for patients with muscle-invasive bladder cancer, regardless of cisplatin eligibility.”

REFERENCES

1. Galsky MD, Pérez-Valderrama B, Maruzzo M, et al. Neoadjuvant and adjuvant enfortumab vedotin (EV) plus pembrolizumab (pembro) for participants with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin: randomized, open-label, phase 3 KEYNOTE-B15 study. Abstract LBA630. Presented at: 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium; February 26-28, 2026; San Francisco, CA. https://meetings.asco.org/meetings/2026-asco-genitourinary-cancers-symposium/334/16924

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6. NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer, version 1.2025. Accessed February 27, 2026. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1417

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