Merck’s Keytruda-Padcev combo becomes first PD-1/ADC regimen for cisplatin-ineligible bladder cancer

Edited by Robert McTiernan··3 min read

The European Commission has approved Keytruda (pembrolizumab) in combination with Padcev (enfortumab vedotin) as perioperative treatment for adults with resectable muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy — marking the first PD-1 inhibitor plus antibody-drug conjugate regimen authorized in this setting across all 27 EU member states. The decision, which follows a positive CHMP recommendation in May 2026, extends a November 2025 US FDA approval to the European market and positions Merck (NYSE: MRK) alongside co-developers Pfizer and Astellas in a disease area where surgery alone has been the longstanding standard of care for cisplatin-ineligible patients.

Clinical evidence

The approval rests on data from KEYNOTE-905/EV-303 (NCT03924895), an open-label, randomized Phase III trial enrolling 595 patients with cisplatin-ineligible resectable MIBC. Patients in the combination arm received three neoadjuvant cycles of pembrolizumab plus enfortumab vedotin before radical cystectomy, followed by six adjuvant cycles of the combination and then eight cycles of pembrolizumab alone. The primary endpoint was event-free survival (EFS) versus surgery alone.

The combination reduced the risk of EFS events by 60% (HR=0.40; 95% CI, 0.28–0.57; p<0.0001), with median EFS not reached versus 15.7 months for surgery alone. Overall survival data were similarly statistically significant, with a 50% reduction in the risk of death (HR=0.50; 95% CI, 0.33–0.74; p=0.0002). Pathologic complete response rate reached 57.1% in the combination arm versus 8.6% with surgery alone — a difference that carries practical relevance given the established association between pCR and long-term outcomes in MIBC.

Mechanism and combination rationale

Pembrolizumab blocks the PD-1 receptor, restoring T-cell-mediated antitumor immunity, while enfortumab vedotin delivers a cytotoxic payload — monomethyl auristatin E — directly to tumor cells via a Nectin-4-targeting antibody. Nectin-4 is broadly expressed in urothelial carcinoma, and the two mechanisms are considered complementary: ADC-mediated tumor cell death may enhance antigen release and immune priming, potentially amplifying checkpoint inhibitor activity.

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Competitive context

The approval arrives in a bladder cancer landscape that is becoming increasingly competitive across disease stages. Bristol Myers Squibb’s nivolumab (Opdivo) holds FDA approval for adjuvant treatment of high-risk urothelial carcinoma following radical resection, including in cisplatin-ineligible patients, but covers only the post-surgical phase without a neoadjuvant component. The perioperative arc of the pembrolizumab plus enfortumab vedotin regimen — spanning both pre- and post-surgical treatment — has no direct approved equivalent in this cisplatin-ineligible population.

AstraZeneca’s durvalumab (Imfinzi) in combination with enfortumab vedotin is being evaluated in the same cisplatin-ineligible MIBC setting in the VOLGA trial, as previously reported, representing the closest active clinical comparator to KEYNOTE-905. Meanwhile, Genentech’s atezolizumab (Tecentriq) recently received FDA approval as adjuvant therapy for MIBC, adding further regulatory momentum to the checkpoint inhibitor field in this disease. Enfortumab vedotin’s role is also expanding: Astellas has indicated that Padcev is central to its post-Xtandi growth strategy, with an FDA priority review underway for the cisplatin-eligible MIBC setting based on the EV-304 trial (PDUFA August 17, 2026).

For Merck, the EU authorization consolidates pembrolizumab’s position across the MIBC continuum and adds a major market to an indication where the clinical differentiation from surgery alone is among the most pronounced reported in perioperative bladder cancer trials to date.

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