Enfortumab Vedotin Plus Pembrolizumab Improves Survival Outcomes While Preserving Surgical Feasibility

Perioperative enfortumab vedotin-ejfv (Padcev; Astellas Pharma US, Inc) plus pembrolizumab (Keytruda; Merck Sharp & Dohme LLC) led to superior survival and response outcomes compared with neoadjuvant gemcitabine and cisplatin in patients with muscle-invasive bladder cancer (MIBC). Data from the phase 3 KEYNOTE-B15 study (NCT04700124)¹ were highlighted at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California.²

Treating MIBC and the Rise of Enfortumab Vedotin

Bladder cancer is the sixth most common cancer in the US, with an estimated 84,000 new cases diagnosed annually.³ MIBC is a subtype of bladder cancer found in the detrusor muscle of the bladder and has a high risk of metastasizing to other parts of the body.⁴ According to the Urology Care Foundation, MIBC accounts for nearly 30% of all bladder cancer cases and is the third most common cancer in men in the US.⁴

Treatments for MIBC include bladder removal, cystotomy with or without chemotherapy, chemotherapy in combination with radiation, and transurethral resection of bladder tumor.²

“Radical cystectomy is standard treatment for patients with [MIBC],” explained Matthew D. Galsky, MD, FASCO, professor of medicine, director of genitourinary medical oncology, codirector of the Center of Excellence for Bladder Cancer, and deputy director of the Mount Sinai Tisch Cancer Center at Icahn School of Medicine at Mount Sinai in New York, New York.² “However, with radical cystectomy alone, a substantial subset of patients develop metastatic recurrence, providing the rationale for integrating systemic therapy."

Enfortumab vedotin (EV) is the first-line standard of care for locally advanced or metastatic urothelial carcinoma, representing a novel neoadjuvant and adjuvant treatment strategy for patients. It is an antibody-drug conjugate targeting Nectin-4—a highly expressed protein on the surface of MBIC cells that plays a critical role in cellular adhesion, cell differentiation, and cell proliferation. Through intracellular delivery of monomethyl auristatin E, EV induces cell cycle arrest and apoptosis.^2,4,5

In November 2025, EV received FDA approval in combination with pembrolizumab as neoadjuvant treatment and then as adjuvant treatment after cystectomy (surgery) for adult patients with MIBC who are ineligible for cisplatin-containing chemotherapy.⁶ Data from the phase 3 EV-303 trial (NCT03924895)⁷ supported the decision, with perioperative treatment with EV-pembrolizumab demonstrating a 60% reduction in the risk of recurrence, progression, or death compared with surgery alone.⁶

Study Design of KEYNOTE-B15

KEYNOTE-B15 is a phase 3, randomized, open-label study investigating whether adding EV and pembrolizumab in both neoadjuvant and adjuvant settings improves outcomes compared with standard neoadjuvant gemcitabine plus cisplatin in patients with clinically localized MIBC eligible for cisplatin-based chemotherapy and radical cystectomy.⁸

The patients were randomly assigned 1:1—stratified by PD-L1 status, clinical stage, and geographic region—to 2 arms: EV plus pembrolizumab (n = 405) or gemcitabine plus cisplatin (n = 403). Patients in the EV arm were treated with 4 cycles of neoadjuvant EV (1.25 mg/kg intravenously on days 1 and 8) plus pembrolizumab (200 mg intravenously on day 1 every 3 weeks) prior to radical cystectomy, followed by 13 cycles of adjuvant pembrolizumab. The first 5 cycles of adjuvant treatment were combined with EV.⁸

In the second arm, patients received neoadjuvant gemcitabine (1000 mg/m² on days 1 and 8) plus cisplatin (70 mg/m² on day 1 every 3 weeks), followed by radical cystectomy and postoperative observation. When indicated and available, adjuvant nivolumab (Opdivo; Bristol Myers Squibb) was permitted.⁸

The primary end point was event-free survival (EFS), with key secondary end points of pathological complete response (pCR) rate, overall survival (OS), and safety.⁸

KEYNOTE-B15 Supports EV, Pembrolizumab as Perioperative Treatment

Treatment with EV plus pembrolizumab led to a statistically significant improvement in EFS compared with cisplatin-based chemotherapy. Median EFS was not reached in the EV-pembrolizumab arm compared with 48.5 months in the gemcitabine-cisplatin arm. At 24 months, the EFS rate was 79.4% with EV plus pembrolizumab. The HR for EFS was 0.53, indicating a substantially lower risk of EFS events with the combination regimen (95% Cl, 0.41-0.70; 1-sided P < .0001).^2,8

OS was also significantly prolonged with EV plus pembrolizumab. The survival curves began to separate at approximately 6 months and remained consistently separated over time. Although median OS was not reached in either treatment arm, at 24 months, the OS rate was 86.9% in the EV-pembrolizumab group compared with 81.3% in the cisplatin and gemcitabine arm (HR, 0.65; 95% Cl, 0.48-0.89; 1-sided P = .0029).^2,8

The pCR was centrally assessed, and patients who did not undergo cystectomy were counted as nonresponders under an intent-to-treat approach. The pCR rate was 55.8% in the EV-pembrolizumab arm vs 32.5% in the gemcitabine-cisplatin arm. Among patients who underwent cystectomy, the pCR rate with EV plus pembrolizumab was 64.4%.^2,8

EV Plus Pembrolizumab Safety

The incidence of grade 3 or higher treatment-emergent adverse events was higher in the EV-pembrolizumab arm compared with the gemcitabine-cisplatin arm (75.7% vs 67.2%). Treatment-related deaths were uncommon, occurring in 2 patients receiving EV plus pembrolizumab and in 1 patient treated with gemcitabine plus cisplatin.^2,8

“The safety profile of EV and pembrolizumab and [of] gemcitabine and cisplatin was consistent with prior observations,” explained Galsky.² “Patients on the EV and pembrolizumab arm experienced more pruritus, diarrhea, alopecia, and rash. Patients on the gemcitabine and cisplatin arm experienced more neutropenia, thrombocytopenia, anemia, and nausea.”

Adverse events of special interest were consistent with the individual components of the combination regimen. EV-associated events included skin reactions, peripheral neuropathy, and ocular disorders, whereas pembrolizumab-associated events included immune-mediated toxicities such as skin reactions, hypothyroidism, and pneumonitis.^2,8

Importantly, the proportion of patients who underwent cystectomy was comparable between treatment arms (87% in the EV-pembrolizumab arm and 90% in the gemcitabine-cisplatin arm), suggesting that perioperative feasibility was maintained with the combination regimen.^2,8

Advancing Care for Patients With MIBC

Neoadjuvant and adjuvant EV plus pembrolizumab significantly improved EFS, OS, and pCR rate compared with neoadjuvant gemcitabine and cisplatin in patients with MIBC who were eligible for cisplatin-based chemotherapy.⁸ With a favorable and consistent safety profile,⁸ this treatment strategy represents another approach for the treatment of MIBC.

“I'll state perhaps the obvious, but this is a pivotal moment,” Galsky said.² “For the first time since cisplatin-based neoadjuvant therapy was shown to improve outcomes in patients with [MIBC] almost 25 years ago, a non–platinum-based regimen has surpassed it."

REFERENCES

1. Perioperative enfortumab vedotin (EV) plus pembrolizumab (MK-3475) versus neoadjuvant chemotherapy for cisplatin-eligible muscle invasive bladder cancer (MIBC) (MK-3475-B15/​ KEYNOTE-B15 /​ EV-304) (KEYNOTE-B15). ClinicalTrials.gov. Updated February 5, 2026. Accessed February 27, 2026. https://clinicaltrials.gov/study/NCT04700124

2. Karam J, Galsky M, Powles T, et al. Oral abstract session B: Urothelial carcinoma. Presented at: 2026 ASCO GU Cancers Symposium; February 26-28, 2026; San Francisco, CA.

3. Golijanin DJ. Bladder cancer: small state, big problem. Brown University Health. April 18, 2025. Accessed February 27, 2026. https://www.brownhealth.org/be-well/bladder-cancer-small-state-big-problem#:~:text=The%20disease%20is%20the%20sixth,of%20any%20form%20of%20cancer

4. Muscle-invasive bladder cancer. Urology Care Foundation. Updated August 2024. Accessed December 18, 2025. https://www.urologyhealth.org/urology-a-z/m/muscle-invasive-bladder-cancer

5. Chang BY, Khou T, Contreras A, McQuiston FL, Shin PJ. A review of antibody-drug conjugates for the treatment of urothelial carcinoma: the rise of enfortumab vedotin. Pharmacy Times. November 6, 2025. Accessed February 27, 2026. https://www.pharmacytimes.com/view/a-review-of-antibody-drug-conjugates-for-the-treatment-of-urothelial-carcinoma-the-rise-of-enfortumab-vedotin

6. US FDA approves Padcev plus Keytruda for certain patients with bladder cancer. News release. Pfizer Inc. November 21, 2025. Accessed November 21, 2025. https://www.businesswire.com/news/home/20251117031627/en/U.S.-FDA-Approves-PADCEV-plus-Keytruda-for-Certain-Patients-with-Bladder-Cancer

7. Perioperative pembrolizumab (MK-3475) plus cystectomy or perioperative pembrolizumab plus enfortumab vedotin plus cystectomy versus cystectomy alone in participants who are cisplatin-ineligible or decline cisplatin with muscle-invasive bladder cancer (MK-3475-905/​KEYNOTE-905/​EV-303). ClinicalTrials.gov. Updated August 28, 2025. Accessed February 27, 2026. https://clinicaltrials.gov/study/NCT03924895

8. Galsky M, 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-815 study. Presented at: 2026 ASCO GU Cancers Symposium; February 26-28, 2026; San Francisco, CA. Abstract LBA630.