Perioperative ADC-IO Wins on Survival But Faces Payer and Toxicity Scrutiny

European Commission Approves KEYTRUDA Plus Padcev for Resectable MIBC

Merck announced that the European Commission (EC) has approved KEYTRUDA (pembrolizumab) in combination with Padcev (enfortumab vedotin-ejfv) as perioperative treatment for adults with resectable muscle-invasive bladder cancer (MIBC). This approval, based on the Phase 3 KEYNOTE-B15 trial, marks the first and only PD-1 inhibitor plus antibody-drug conjugate (ADC) regimen available for MIBC patients in the EU, regardless of cisplatin eligibility. The regimen demonstrated a statistically significant improvement in event-free survival (EFS), reducing the risk of EFS events by 47% (HR=0.53; p<0.0001), and overall survival (OS), reducing the risk of death by 35% (HR=0.65; p=0.0029), compared to neoadjuvant chemotherapy and surgery. It also showed a significantly higher pathologic complete response (pCR) rate of 55.8% versus 32.5%.

• First-in-Class EU Approval for Perioperative MIBC: The European Commission's approval of KEYTRUDA plus Padcev represents a significant advancement as the first and only PD-1 inhibitor and antibody-drug conjugate combination for perioperative treatment of resectable muscle-invasive bladder cancer in the European Union. This broadens treatment options for adults with MIBC, crucially extending to patients regardless of their cisplatin eligibility, addressing a critical unmet need where recurrence remains a challenge.
• Superior Efficacy in KEYNOTE-B15 Trial: The approval is underpinned by robust data from the Phase 3 KEYNOTE-B15 trial, which showed KEYTRUDA plus Padcev significantly improved event-free survival (EFS). The regimen reduced the risk of EFS events (disease progression, recurrence, or death) by 47% (HR=0.53 [95% CI, 0.41-0.70]; p<0.0001) in cisplatin-eligible patients compared to standard neoadjuvant chemotherapy and surgery.
• Significant Overall Survival and Pathologic Response Benefits: Beyond EFS, the KEYNOTE-B15 trial also demonstrated a statistically significant improvement in overall survival (OS), reducing the risk of death by 35% (HR=0.65 [95% CI, 0.48-0.89]; p=0.0029). Furthermore, the combination achieved a substantially higher pathologic complete response (pCR) rate of 55.8% compared to 32.5% for neoadjuvant chemotherapy (p<0.0001), indicating a strong pathological benefit.
• Global Regulatory Milestones: This EC approval follows a positive recommendation from the European Medicines Agency’s CHMP in September 2026. It also builds on the U.S. Food and Drug Administration (FDA) approval in July 2026 for the same indication and patient population, solidifying the global recognition of this combination therapy for MIBC.

Transforming MIBC Care: The New Standard for Cisplatin-Ineligible Patients

The current treatment paradigm for muscle-invasive bladder cancer (MIBC) consists of cisplatin-based neoadjuvant chemotherapy followed by local definitive therapy, or local definitive therapy alone for cisplatin-ineligible patients. Neoadjuvant MVAC or gemcitabine-cisplatin (GC) in cT2-T4N0 MIBC patients fit for cisplatin is still recommended based on OS benefit shown in meta-analyses, which indicated a small, but significant 5% improvement in overall survival in T2-T4N0M0 MIBC patients. The VESPER trial demonstrated that dd-MVAC provided oncological benefits over GC alone in terms of pCR rates, OS (HR: 0.71), and PFS (HR: 0.70), with six cycles of neoadjuvant dose-dense MVAC superior to four cycles of gemcitabine/cisplatin. Recently, the NIAGARA trial showed that perioperative durvalumab plus GC outperformed GC alone in terms of pCR rates, OS (HR: 0.75), and EFS (HR: 0.68).

In the adjuvant setting, no study provided the OS benefit from adjuvant chemotherapy, however, only adjuvant nivolumab had significant DFS and OS benefits compared to placebo. Nivolumab is the only ICI recommended as adjuvant therapy in patients who harbored adverse pathologic outcomes. Adjuvant cisplatin-based chemotherapy may be considered in selected, chemo-naïve pT3-T4N1-3M0 MIBC patients, including pT3-T4N+ patients. Pathologic high risk of recurrence following radical cystectomy (RC) and pelvic lymph node dissection (PLND) is defined as ypT2-T4a or ypN+ and pT3-4a or pN+.

Radical cystectomy (RC) has historically been the standard treatment for MIBC and remains the most commonly used definitive local treatment, although cisplatin eligibility criteria in the neoadjuvant, curative MIBC setting lack consensus. Cisplatin eligibility criteria are defined for patients with metastatic bladder cancer by the Galsky criteria, which include creatinine clearance ≥60 ml/min. Among bladder-sparing alternatives, trimodal therapy (TMT), comprising maximal transurethral resection of bladder tumour (TURBT) followed by concurrent chemotherapy and radiotherapy (chemoRT) using radiosensitising agents, has become a guideline accepted alternative to RC in appropriately selected patients with MIBC.

Overcoming Recurrence and Cisplatin Ineligibility in MIBC

Despite cisplatin-based neoadjuvant chemotherapy (NAC) demonstrating an overall survival (OS) benefit in muscle-invasive bladder cancer (MIBC), current approaches for resectable disease remain limited by modest efficacy, narrow eligibility, and significant morbidity. Radical cystectomy is the standard of care for patients with localized muscle-invasive bladder cancer, yet 50 percent of patients still relapse in distant sites following surgery.

• Incomplete response to NAC and modest survival gain: Only a subset of patients (25-50%) have a pathologic complete response at cystectomy, and meta-analyses undertaken for neoadjuvant cisplatin-based combination chemotherapy show a 5% benefit in overall survival. Pathologic complete remission may be an intermediate surrogate for survival, but requires further validation.

• Narrow cisplatin eligibility and low uptake: Use of neoadjuvant chemotherapy is low, and is attributable to patient and physician choice because of limited benefit, advanced age, and comorbidities including renal and/or cardiac dysfunction. Performance status, presence of comorbidities and renal function were key considerations in offering NC, with NC not offered if performance status ≥2, age >80, or glomerular filtration rate ≤40 mL/min. Carboplatin cannot be substituted for cisplatin in fit patients, and many patients are ineligible for or refuse cisplatin.

• Undefined adjuvant role and chemoresistance: Evidence is insufficient to justify its role in the adjuvant setting despite a possible benefit, and approved regimens for subsequent-line therapy do not exist. Nrf2 overexpression in bladder cancer is associated with clinically relevant cisplatin resistance, with expression associated with unfavorable overall (median = 0.65 vs. 2.11 y, P = 0.045), bladder cancer-specific, and recurrence-free survival in those patients who also received neoadjuvant cisplatin-based chemotherapy.

• Substantial surgical morbidity: In 128 patients undergoing radical cystectomy, 58 patients (45.31%) had complications, with 51 (39.84%) minor complications and 7 (5.47%) major complications. Wound dehiscence or unhealing (22.66%), infection (20.31%) and ileus (17.19%) were the most common complications, while benign uretero-ileal anastomotic stricture (UIAS) is a major complication following radical cystectomy (RC) and ileal orthotopic bladder substitution.

KEYNOTE-B15: Demonstrating Efficacy in Perioperative MIBC Treatment

Recent perioperative trials in resectable muscle-invasive bladder cancer have evaluated immunotherapy alone and in combination with chemotherapy or antibody-drug conjugates. Phase 3 trials including NIAGARA and CheckMate 274 have reported event-free, disease-free and overall survival benefits, while phase 2 studies have explored bladder-sparing and chemoimmunotherapy strategies.

• NIAGARA — perioperative durvalumab plus gemcitabine-cisplatin: In cisplatin-eligible patients, 533 patients were assigned to the durvalumab group and 530 to the comparison group. The estimated event-free survival at 24 months was 67.8% (95% confidence interval [CI], 63.6 to 71.7) in the durvalumab group and 59.8% (95% CI, 55.4 to 64.0) in the comparison group (hazard ratio for progression, recurrence, not undergoing radical cystectomy, or death from any cause, 0.68; 95% CI, 0.56 to 0.82; P<0.001 by stratified log-rank test). The estimated overall survival at 24 months was 82.2% (95% CI, 78.7 to 85.2) in the durvalumab group and 75.2% (95% CI, 71.3 to 78.8) in the comparison group (hazard ratio for death, 0.75; 95% CI, 0.59 to 0.93; P = 0.01 by stratified log-rank test). Treatment-related adverse events of grade 3 or 4 in severity occurred in 40.6% of the patients in the durvalumab group and in 40.9% of those in the comparison group; treatment-related adverse events leading to death occurred in 0.6% in each group. Radical cystectomy was performed in 88.0% of the patients in the durvalumab group and in 83.2% of those in the comparison group.

• CheckMate 274 — adjuvant nivolumab versus placebo: This phase III, randomized, double-blind trial evaluated adjuvant nivolumab for muscle-invasive urothelial carcinoma at high risk of recurrence after radical resection. At an extended median follow-up of 36.1 months in the intent-to-treat (ITT) population, disease-free survival benefit with nivolumab versus placebo was observed in both the ITT (hazard ratio [HR], 0.71 [95% CI, 0.58 to 0.86]) and tumor PD-L1 expression ≥1% (HR, 0.52 [95% CI, 0.37 to 0.72]) patients. The HR for overall survival with nivolumab versus placebo was 0.76 (95% CI, 0.61 to 0.96) in the ITT population and 0.56 (95% CI, 0.36 to 0.86) in the PD-L1 ≥1 population. No new safety signals were reported.

• SURE-02 — neoadjuvant sacituzumab govitecan plus pembrolizumab, followed by adjuvant pembrolizumab: This single-arm, phase 2 study enrolled 49 patients with stage cT2-T3bN0M0 disease deemed ineligible for or declined cisplatin-based neoadjuvant chemotherapy. Patients received four cycles of intravenous pembrolizumab 200 mg on day 1 and intravenous sacituzumab govitecan 7·5 mg/kg on day 1 and day 8, every 3 weeks, followed by radical cystectomy or redo-transurethral resection of the bladder tumour and 13 cycles of postsurgical pembrolizumab 200 mg, every 3 weeks. After a median follow-up of 14 months (IQR 8-18), 19 (39% [95% CI 25-54]) patients had a clinical complete response, defined as negative imaging and no viable tumour at re-TURBT in patients not undergoing radical cystectomy. Grade 3 treatment-related adverse-events occurred in eight patients (16%), the most common being diarrhoea (in four [8%]). There were no treatment-related deaths. Serious treatment-related adverse events were reported in three patients (6%); bullous pemphigoid in two and colitis in one patient respectively.

• NEMIO — neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) combined with durvalumab ± tremelimumab: This multicenter, randomized, noncomparative phase II trial enrolled cT2-T4a N0-1 cisplatin-eligible patients planned for radical cystectomy. The overall Bayesian posterior mean pathologic complete response (pCR; ypT0N0) rate was 48.70% (95% CI, 35.93 to 61.56) with doublet (ddMVAC + durvalumab) and 46.27% (95% CI, 33.92 to 58.85) with triplet (ddMVAC + durvalumab + tremelimumab). Bayesian posterior mean grade ≥3 treatment-related adverse events occurred in 40.95% (95% CI, 32.50 to 49.69) overall (30.48% [95% CI, 20.00 to 42.08] doublet; 49.63% [95% CI, 37.55 to 61.73] triplet); immune-related adverse events occurred in 26.9% (grade ≥3 4.2%). Two-year event-free survival and overall survival rates were 75% and 85% in the doublet arm, and 77% and 88% in the triplet arm, respectively.

The Evolving Landscape of Perioperative MIBC Therapies

Other PD-1/PD-L1 immune checkpoint inhibitors and Nectin-4-directed antibody-drug conjugates are being investigated in locally advanced or metastatic urothelial carcinoma. Nivolumab and avelumab reflect the same PD-1/PD-L1 inhibitor class as pembrolizumab, while 9MW2821 is a next-generation Nectin-4 targeting antibody-drug conjugate delivering monomethylauristatin E (MMAE) to cells expressing Nectin-4.

The knowledge base does not have sufficient information on this aspect.

Perioperative MIBC: The EV+P Combination Redefines Care

The European Commission's endorsement of the KEYTRUDA and Padcev combination for resectable muscle-invasive bladder cancer (MIBC) marks a pivotal moment in the treatment landscape. This approval, based on robust Phase 3 data, introduces the first PD-1 inhibitor plus antibody-drug conjugate (ADC) regimen for perioperative MIBC in the EU, setting a new benchmark for efficacy. The significant improvements in event-free survival, overall survival, and pathologic complete response rates observed in the KEYNOTE-B15 trial underscore the transformative potential of this combination.

Crucially, this regimen is approved regardless of cisplatin eligibility, addressing a long-standing unmet need for a substantial portion of MIBC patients who cannot tolerate or are ineligible for traditional platinum-based chemotherapy. While neoadjuvant cisplatin-based chemotherapy has been the standard, its limitations have left many patients with suboptimal options. This new combination offers a powerful alternative, broadening access to highly effective systemic therapy.

However, this advancement also brings important considerations for clinical practice and market strategy:

• Toxicity Management: The combination therapy is associated with a higher incidence of grade 3 or higher adverse events compared to chemotherapy, requiring vigilant patient management and supportive care strategies.

• Economic Impact: The cost-effectiveness of novel ICI-based therapies remains a critical factor for healthcare systems, potentially influencing reimbursement decisions and patient access.

• Biomarker Development: While effective, ongoing research emphasizes the need for more refined biomarkers to predict response and optimize patient selection, ensuring the right therapy for the right patient.

This approval not only reshapes the treatment algorithm for MIBC but also validates the synergistic potential of ADC-ICI combinations, paving the way for further innovation in oncology. As the treatment paradigm evolves, a focus on individualized, biomarker-driven strategies will be essential to maximize patient outcomes and navigate the complexities of these advanced therapies.