Perioperative Enfortumab Vedotin Plus Pembrolizumab Improves ctDNA Clearance in Cisplatin-Eligible MIBC

Perioperative enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) led to a higher rate of presurgical circulating tumor DNA (ctDNA) clearance compared with neoadjuvant gemcitabine plus cisplatin in patients with cisplatin-eligible muscle-invasive bladder cancer (MIBC), and ctDNA status was strongly prognostic for event-free survival (EFS) in both arms, according to data from an exploratory analysis of the phase 3 KEYNOTE-B15 trial (NCT04700124) presented at the 2026 ESMO Congress.¹

Enfortumab vedotin plus pembrolizumab (EV/pembrolizumab) was also associated with favorable EFS compared with chemotherapy, irrespective of ctDNA status at baseline or after surgery.

Findings showed that among patients with detectable ctDNA at baseline and evaluable ctDNA before surgery, the ctDNA clearance rate was 82.1% with enfortumab vedotin plus pembrolizumab (n = 84) vs 66.7% with gemcitabine plus cisplatin (n = 102). Patients who cleared ctDNA had more favorable EFS than those who did not, and the 24-month EFS rate among patients who converted from ctDNA positive to ctDNA negative was 81.1% in the enfortumab vedotin plus pembrolizumab arm (n = 69) vs 63.2% in the chemotherapy arm (n = 68).

For patients who remained ctDNA positive at both time points, the respective 24-month EFS rates were 33.3% (n = 15) and 35.3% (n = 34); patients who were ctDNA negative at both time points had respective 24-month EFS rates of 94.6% (n = 79) and 87.8% (n = 77).

“These findings show that ctDNA is strongly prognostic, regardless of therapy in this study, and that ctDNA clearance was higher with [enfortumab vedotin plus pembrolizumab] than with [gemcitabine plus cisplatin],” said presenting author Jonathan Chatzkel, MD, a medical oncologist in the Genitourinary Oncology Program at Moffitt Cancer Center in Tampa, Florida.

Based on the primary KEYNOTE-B15 results, the FDA approved pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex), each in combination with enfortumab vedotin, as neoadjuvant treatment followed by adjuvant treatment following cystectomy in adult patients with MIBC.²

How was the ctDNA analysis designed?

KEYNOTE-B15 enrolled adult patients with MIBC staged as T2-T4aN0M0 or T1-T4aN1M0 by central assessment who had urothelial histology of at least 50%, were eligible for radical cystectomy (RC) plus pelvic lymph node dissection (PLND), did not meet any Galsky criteria for cisplatin ineligibility, and had an ECOG performance status of 0 or 1.

Investigators randomly assigned patients 1:1 to receive neoadjuvant enfortumab vedotin plus pembrolizumabn followed by RC and PLND, then adjuvant enfortumab vedotin plus pembrolizumab (n = 405); or neoadjuvant gemcitabine plus cisplatin, followed by RC plus PLND, then observation (n = 403). Adjuvant nivolumab (Opdivo) was permitted in the control arm as of February 2023 when clinically indicated and regionally available.

The primary end point was EFS per blinded independent central review; EFS and pathologic complete response (pCR) by ctDNA status were exploratory end points.

ctDNA was assessed with the Signatera assay at baseline (week 1, day 1), presurgery (week 13 ± 7 days), postsurgery (week 6 ± 14 days), and an adjuvant time point (weeks 30-34). Across both arms, 490, 436, 432, and 188 patients, respectively, were evaluable at those time points, and median study follow-up was 33.6 months (range, 22.5-53.6).

The proportion of patients with ctDNA-positive status at baseline was 52.4% in the enfortumab vedotin plus pembrolizumab arm vs 56.8% in the chemotherapy arm. Rates of ctDNA positivity fell to 13.0% vs 19.7%, respectively, before surgery and 4.8% vs 13.5%, respectively, after surgery.

How did ctDNA status relate to EFS and pCR?

In patients who were ctDNA negative at baseline, the 24-month EFS rate was 86.1% with enfortumab vedotin plus pembrolizumab (n = 121) vs 82.7% with chemotherapy (n = 102; HR, 0.68; 95% CI, 0.37-1.26). Among patients who were ctDNA positive at baseline, the 24-month EFS rates were 71.2% (n = 133) and 54.2% (n = 134), respectively (HR, 0.54; 95% CI, 0.37-0.80).

After surgery, ctDNA-negative patients had 24-month EFS rates of 89.9% with enfortumab vedotin plus pembrolizumab (n = 199) vs 82.2% with chemotherapy (n = 193; HR, 0.48; 95% CI, 0.29-0.81). For patients who were ctDNA positive after surgery, the 24-month EFS rate was 10.0% in both the enfortumab vedotin plus pembrolizumab (n = 10) and chemotherapy (n = 30) groups (HR, 0.63; 95% CI, 0.30-1.35).

Among patients who were ctDNA negative before surgery and underwent RC, the pCR rate was 72.4% with enfortumab vedotin plus pembrolizumab (n = 181) vs 43.7% with chemotherapy (n = 183). Patients who were ctDNA positive before surgery had pCR rates of 3.7% (n = 27) and 2.2% (n = 45), respectively.

What do the findings mean for ctDNA-guided treatment?

ctDNA is a strongly prognostic biomarker in perioperative localized bladder cancer, and the IMvigor011 and TOMBOLA trials support ctDNA-guided adjuvant immunotherapy after cystectomy, Chatzkel noted; however, it remains unclear whether that approach can be applied to patients receiving perioperative regimens such as EV/pembrolizumab.

“While the hazard ratio numerically favored [enfortumab vedotin plus pembrolizumab], both of these groups did relatively poorly, unfortunately,” Chatzkel said of patients with detectable ctDNA after surgery. “This arguably represents an important unmet medical need.”

References

1. Chatzkel J, Galsky MD, Gómez de Liaño A, et al. ctDNA analysis of the phase 3 KEYNOTE-B15 trial: neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab for participants with muscle-invasive bladder cancer who are eligible for cisplatin. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract 4734O.
2. FDA approves pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph each with enfortumab vedotin-ejfv for muscle invasive bladder cancer. FDA. July 10, 2026. Accessed October 23, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-or-pembrolizumab-and-berahyaluronidase-alfa-pmph-each-enfortumab-vedotin