Merck Receives Positive EU CHMP Opinion for KEYTRUDA® (pembrolizumab) Plus Padcev® (enfortumab vedotin-ejfv) as Perioperative Treatment for Adults With Resectable Muscle-Invasive Bladder Cancer (MIBC)

EU CHMP Recommends KEYTRUDA Plus Padcev for Resectable MIBC

Merck announced a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) for KEYTRUDA (pembrolizumab) in combination with Padcev (enfortumab vedotin-ejfv) as perioperative treatment for adults with resectable muscle-invasive bladder cancer (MIBC). This recommendation, which includes both IV and subcutaneous formulations, is based on the Phase 3 KEYNOTE-B15 trial. The trial demonstrated statistically significant improvements in event-free survival (EFS), reducing risk by 47% (HR=0.53), and overall survival (OS), reducing risk by 35% (HR=0.65), compared to neoadjuvant chemotherapy. It also showed a significantly improved pathologic complete response (pCR) rate of 55.8% versus 32.5%. If approved by the European Commission by Q4 2026, this regimen would be the first and only PD-1 inhibitor plus antibody-drug conjugate for MIBC patients in the EU, regardless of cisplatin eligibility.

• Regulatory Milestone Achieved: The European Medicines Agency’s CHMP has issued a positive opinion recommending approval for Merck’s KEYTRUDA (pembrolizumab) in combination with Padcev (enfortumab vedotin-ejfv). This recommendation covers the use of the regimen as neoadjuvant treatment followed by adjuvant treatment after radical cystectomy for adults with resectable muscle-invasive bladder cancer (MIBC). The opinion also includes KEYTRUDA SC (known as KEYTRUDA QLEX in the U.S.), expanding the potential administration options.
• Compelling Clinical Efficacy Data: The positive opinion is underpinned by robust results from the Phase 3 KEYNOTE-B15 trial. The study showed a statistically significant improvement in event-free survival (EFS), with a 47% reduction in the risk of EFS events (HR=0.53; 95% CI, 0.41-0.70; p<0.0001). Furthermore, the combination significantly improved overall survival (OS), reducing the risk of death by 35% (HR=0.65; 95% CI, 0.48-0.89; p=0.0029), and achieved a higher pathologic complete response rate of 55.8% compared to 32.5% for neoadjuvant chemotherapy.
• Expanded Treatment Paradigm for MIBC: This potential approval represents a significant advancement for patients with resectable MIBC in the European Union. The KEYTRUDA plus Padcev regimen would be the first and only PD-1 inhibitor plus antibody-drug conjugate available for this patient population, critically including those who are ineligible for cisplatin-based chemotherapy. This addresses a substantial unmet medical need, as recurrence remains a concern and many patients cannot receive standard cisplatin treatment.

Transforming MIBC Treatment: A New Regimen's Impact

The treatment landscape for resectable MIBC has undergone substantial evolution, driven by a convergence of more intensive chemotherapy regimens and the integration of immune checkpoint inhibitors (ICIs) into perioperative strategies. Cisplatin-based neoadjuvant chemotherapy remains the established standard of care, yet evidence has increasingly favored dose-dense regimens over conventional gemcitabine-cisplatin (GC). A systematic review and meta-analysis comparing ddMVAC with GC demonstrated a superior complete response rate (odds ratio 1.57; 95% CI, 1.10–2.25) and an overall survival hazard ratio of 0.47 (95% CI, 0.30–0.72) in favor of ddMVAC. The VESPER trial further corroborated these findings, showing that ddMVAC provided oncological benefits over GC in terms of pathological complete response rates, OS (HR: 0.71), and PFS (HR: 0.70). A network meta-analysis incorporating randomized controlled trials confirmed that both ddMVAC (HR 0.75; 95% CI, 0.58–0.98) and durvalumab plus gemcitabine-cisplatin (D-GC; HR 0.75; 95% CI, 0.66–0.85) improved overall survival versus GC, without a statistically significant difference between the two intensified regimens (HR 0.99; 95% CI, 0.75–1.33).

The addition of ICIs to neoadjuvant chemotherapy has emerged as one of the most consequential developments in this space. The NIAGARA trial demonstrated that perioperative durvalumab plus GC outperformed GC alone in pathological complete response rates, OS (HR: 0.75), and event-free survival (HR: 0.68). In parallel, neoadjuvant ICI monotherapy has shown meaningful activity: the ABACUS trial reported a 31% pCR with atezolizumab, pembrolizumab achieved 37% pCR (n = 42/114), and the NCT03520491 trial combining nivolumab and ipilimumab reached a pCR rate of up to 46%. Combination immunotherapy plus chemotherapy has pushed pCR rates further still — the KCT0003804 trial reported a 59% pCR and 81.8% 1-year disease-free survival. A meta-analysis of 15 prospective trials (n = 1,545) found pooled pCR rates of 37% (95% CI, 34%–39%; I² = 33%) for ICI-based regimens and 57% (95% CI, 49%–65%) for enfortumab vedotin plus pembrolizumab (EV+P), with EV+P demonstrating a statistically superior pCR rate versus ICI-based regimens (P < .0001). In the EV-303 trial, EV+P versus surgery alone yielded an event-free survival HR of 0.40 (95% CI, 0.28–0.57) and an overall survival HR of 0.50 (95% CI, 0.33–0.74).

In the adjuvant setting, ICIs have also secured a defined role for high-risk disease following cystectomy. A pairwise meta-analysis of three phase III randomized controlled trials evaluating adjuvant nivolumab, pembrolizumab, and atezolizumab demonstrated significant improvements in both DFS (HR: 0.77; 95% CI, 0.66–0.90) and OS (HR: 0.87; 95% CI, 0.76–1.00) versus placebo or observation. Network meta-analysis ranked pembrolizumab highest for DFS benefit (84% probability) and nivolumab highest for OS benefit (93% probability). Notably, the DFS benefit from adjuvant ICIs was most pronounced in patients who had received prior neoadjuvant chemotherapy (P = 0.041). Circulating tumor DNA (ctDNA) has also emerged as a promising biomarker in this perioperative context: a subgroup analysis of the phase 3 IMvigor010 trial showed that ctDNA-positive patients treated with adjuvant atezolizumab had a DFS hazard ratio of 3.36 (95% CI, 2.44–4.62), and ctDNA clearance after two cycles was associated with improved DFS (HR: 0.26; 95% CI, 0.12–0.56; P = 0.0014) and OS (HR: 0.14; 95% CI, 0.03–0.59), pointing toward a future of biomarker-guided patient selection across the perioperative continuum.

Addressing Unmet Needs in Resectable MIBC

Despite radical cystectomy remaining the gold standard for resectable MIBC, a substantial proportion of patients experience disease recurrence, and several structural, biological, and patient-level barriers continue to limit optimal outcomes. Perioperative chemotherapy improves survival, yet its delivery is inconsistent due to eligibility constraints and toxicity concerns. The following challenges define the current unmet need landscape in this setting.

• Cisplatin eligibility and nephrotoxicity: Consensus on cisplatin eligibility criteria in the neoadjuvant curative MIBC setting is still lacking, representing a substantial barrier to standardization of patient care and clinical trial design. Patients with normal renal function may experience nephrotoxicity after cisplatin administration, and renal function after neoadjuvant chemotherapy is significantly lower in cisplatin-based regimens than in carboplatin-based alternatives. Under-utilization of chemotherapy is associated with suboptimal cure rates.

• High recurrence rates after radical cystectomy: Disease recurrence was observed in 36% of patients in one cohort, with mortality rates of 93% for both local recurrence and distant metastasis. Independent predictors for recurrence include lymphovascular invasion (even in node-negative cases), high tumor grade, and high nodal stage — findings that raise the necessity for postoperative multimodality treatment to improve disease-free survival.

• Pathologic staging and downstaging uncertainty: While pathologic downstaging to non-muscle-invasive disease at radical cystectomy is associated with a significant reduction in cancer-specific mortality, even patients with residual non-invasive disease (pT0, pTa, or pTis) may suffer disease recurrence and require continued surveillance after surgery.

• Limited high-level evidence for bladder-sparing strategies: Trimodal therapy and chemoradiation protocols have demonstrated long-term efficacy, but due to the lack of randomized controlled trials, high-level evidence on bladder-sparing strategy efficacy compared to radical cystectomy remains absent. Adoption of these approaches is consequently still limited.

• Absence of validated predictive biomarkers: Historically, there were no predictive biomarkers to guide the clinical management and treatment of urothelial carcinoma, and biomarker development was an unmet need. While recent clinical trials have identified several promising tumor biomarkers — including PD-L1, FGFR, HER2, DDR mutations, and ctDNA — their clinical application remains in development.

• Surgical approach trade-offs: Robotic-assisted radical cystectomy reduces perioperative morbidity and length of stay compared to open radical cystectomy, but is associated with higher rates of uretero-ileal anastomosis stenosis and eventration at long term (25.5% vs. 3.6% and 23% vs. 2%, respectively), introducing distinct long-term complication profiles that require further evaluation.

KEYNOTE-B15: Clinical Evidence for Pembrolizumab Plus Enfortumab Vedotin

Several Phase III and meta-analytic studies have recently reported perioperative and adjuvant strategies for resectable MIBC, demonstrating meaningful improvements in event-free, disease-free, and overall survival across cisplatin-eligible and -ineligible populations. The findings collectively reflect a shift toward multimodal regimens integrating immune checkpoint inhibitors and antibody-drug conjugates alongside standard chemotherapy and radical cystectomy.

A New Horizon for Resectable Bladder Cancer Treatment

The positive CHMP opinion for KEYTRUDA in combination with Padcev for resectable muscle-invasive bladder cancer (MIBC) signals a pivotal moment in the treatment paradigm for this challenging disease. For years, neoadjuvant chemotherapy has been a cornerstone, but its efficacy is limited, and many patients are ineligible due to comorbidities. This new regimen, combining a PD-1 inhibitor with an antibody-drug conjugate, offers a compelling alternative, demonstrating superior event-free survival, overall survival, and pathologic complete response rates.

This development is particularly significant as it introduces a novel, non-chemotherapy-centric approach into the perioperative setting, potentially redefining the standard of care. The ability to offer this to patients regardless of cisplatin eligibility broadens the treatable population and addresses a critical unmet need. The strong clinical data could drive rapid adoption and influence future guideline recommendations, establishing a new benchmark for efficacy in MIBC.

However, as with any potent combination therapy, careful consideration of the safety profile is paramount. Enfortumab vedotin is associated with a range of adverse events, including dermatologic toxicities, peripheral neuropathy, and hyperglycemia, and has been linked to rare cases of myelodysplastic syndrome. While these are generally manageable, their incidence in a perioperative setting, potentially impacting surgical recovery, will be closely watched. Furthermore, while the overall benefits are clear, the literature suggests that immune checkpoint inhibitor efficacy can sometimes vary by sex in urothelial carcinoma, a factor that may warrant continued monitoring in real-world use. This approval underscores the ongoing evolution of urothelial carcinoma treatment, moving towards more targeted and immunotherapeutic strategies that aim to improve both survival and quality of life, including the potential for bladder preservation in select cases.