ctDNA Is Prognostic Regardless of Therapy in Cisplatin-Eligible MIBC

At the 2026 European Society for Medical Oncology (ESMO) Congress, Jonathan Chatzkel, MD, an assistant professor of medicine in the Division of Hematology and Oncology at the University of Florida College of Medicine, University of Florida Health, presented an exploratory analysis of circulating tumor DNA (ctDNA) from the phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124), wherein clearance of ctDNA before surgery was more common with perioperative enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) than with neoadjuvant cisplatin and gemcitabine among patients with MIBC.¹

In KEYNOTE-B15, perioperative enfortumab vedotin plus pembrolizumab with radical cystectomy and pelvic lymph node dissection significantly improved event-free survival (EFS), overall survival, and pathologic complete response (pCR) rates compared with neoadjuvant cisplatin and gemcitabine followed by surgery.² Based on those results, the FDA approved the combination as neoadjuvant and adjuvant treatment for adults with MIBC who are eligible for cisplatin-based chemotherapy.³

At baseline, ctDNA was detected in 52.4% (n = 133/254) of evaluable patients in the enfortumab vedotin arm and 56.8% (n = 134/236) in the chemotherapy arm. Among patients with detectable ctDNA at baseline, the 24-month EFS rate was 71.2% with enfortumab vedotin plus pembrolizumab vs 54.2% with chemotherapy (HR, 0.54; 95% CI, 0.37-0.80). Among those without detectable ctDNA, the 24-month EFS rates were 86.1% and 82.7%, respectively (HR, 0.68; 95% CI, 0.37-1.26).

Before surgery, ctDNA had cleared in 82.1% (n = 69/84) of patients in the enfortumab vedotin arm who were ctDNA positive at baseline, compared with 66.7% (n = 68/102) in the chemotherapy arm. Patients whose ctDNA cleared had better outcomes than those whose ctDNA remained detectable. The 24-month EFS rates were:

• Enfortumab vedotin plus pembrolizumab: 94.6% for patients negative at both time points, 81.1% for those who cleared ctDNA, and 33.3% for those who remained positive.
• Chemotherapy: 87.8%, 63.2%, and 35.3%, respectively.

Presurgery ctDNA status was also linked to pathologic response. Among patients who were ctDNA negative before cystectomy, the pCR rate was 72.4% (n = 131/181) with enfortumab vedotin plus pembrolizumab and 43.7% (n = 80/183) with chemotherapy. Among patients who remained ctDNA positive, pCR rates were 3.7% (n = 1/27) and 2.2% (n = 1/45), respectively.

After surgery, ctDNA was detected in 4.8% (n = 10/209) of evaluable patients in the enfortumab vedotin arm and 13.5% (n = 30/223) in the chemotherapy arm. Among patients with undetectable ctDNA after surgery, the 24-month EFS rates were 89.9% with enfortumab vedotin plus pembrolizumab and 82.2% with chemotherapy (HR, 0.48; 95% CI, 0.29-0.81). Outcomes were poor in both arms for patients with detectable ctDNA after surgery: the 24-month EFS rate was 10.0% in each arm, and 90% of patients in each arm had an event (HR, 0.63; 95% CI, 0.30-1.35).

The KEYNOTE-B15 investigators randomly assigned 808 adults with clinical stage T2-T4aN0M0 or T1-T4aN1M0 MIBC who were eligible for cisplatin. Of these, 405 received perioperative enfortumab vedotin plus pembrolizumab and 403 received neoadjuvant cisplatin and gemcitabine followed by surgery and observation. Adjuvant nivolumab (Opdivo) was permitted in the control arm beginning in February 2023 when clinically indicated and regionally available.

The primary end point was EFS by blinded independent central review. Evaluating EFS and pCR by pretreatment and on-treatment ctDNA status was an exploratory end point.

Plasma ctDNA was assessed with the Signatera assay at 4 time points:

• baseline;
• before surgery, at week 13;
• after surgery, at week 6;
• during adjuvant therapy, at weeks 30 to 34.

The ctDNA-evaluable population included all randomly assigned patients with ctDNA results at 1 or more time points. The median follow-up was 33.6 months (range, 22.5-53.6) at the October 27, 2025, data cutoff.

Fewer samples were available at the adjuvant time point: 17.0% of the enfortumab vedotin arm and 29.5% of the chemotherapy arm. The investigators attributed this to expected attrition, more test failures from insufficient cell-free DNA, and differences in procedure timelines between arms. More frequent assay failures or missed collections in the enfortumab vedotin arm may have contributed to its higher attrition.

The investigators concluded that ctDNA was strongly prognostic regardless of therapy in this study. They also concluded that perioperative enfortumab vedotin plus pembrolizumab showed favorable EFS vs cisplatin and gemcitabine regardless of ctDNA status at baseline or after surgery.

Disclosures

Chatzkel reported research funding to his institution from Allogene Therapeutics, Arsenal Biosciences, Aveo, Eisai, Exelixis, Genentech, Merck Sharp & Dohme LLC, and Prometheus, and personal travel, accommodations, or expenses from DAVA Oncology and Signatera.

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 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract 4734O.
2. Galsky MD, Valderrama BP, Maruzzo M, et al. Enfortumab vedotin and pembrolizumab in cisplatin-eligible bladder cancer. N Engl J Med. 2026;395(4):338-348. doi:10.1056/NEJMoa2601486
3. FDA approves pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph each with enfortumab vedotin-ejfv for muscle invasive bladder cancer. News release. FDA. July 10, 2026. Accessed October 23, 2026. https://tinyurl.com/ywwuhr5k