| Indication | Resectable muscle-invasive bladder cancer (MIBC) |
| Drug | Pembrolizumab and Enfortumab vedotin-ejfv |
| Mechanism of Action | PD-1 inhibitor and antibody-drug conjugate |
| Company | Merck |
| Trial Phase | Phase 3 |
| Trial Acronym | KEYNOTE-B15 |
| NCT ID | NCT04700124 |
| Category | Regulatory Milestone |
| Sub Category | Approval Granted |
| Therapeutic Area | Oncology |
| Regulatory Agency | European Commission |
| Approved Region | European Union, Iceland, Liechtenstein, Norway |
| Approval Date | October 21, 2026 |
| CHMP Recommendation Date | September 2026 |
| Comparator Regimen | Neoadjuvant chemotherapy (gemcitabine and cisplatin) and surgery |
| Patient Population Details | Adults with resectable MIBC, including cisplatin-eligible patients |
| Primary Endpoint Result (EFS) | Reduced risk by 47% (HR=0.53 [95% CI, 0.41-0.70]; p<0.0001) |
| Overall Survival Result (OS) | Reduced risk of death by 35% (HR=0.65 [95% CI, 0.48-0.89]; p=0.0029) |
| Pathologic Complete Response Rate | 55.8% (KEYTRUDA + Padcev) vs 32.5% (chemotherapy) (p<0.0001) |
| US Approval Status | Approved in July 2026 |
European Commission Approves KEYTRUDA Plus Padcev for Resectable MIBC
The European Commission (EC) has approved Merck's KEYTRUDA (pembrolizumab) in combination with Padcev (enfortumab vedotin-ejfv) as a perioperative treatment for adults with resectable muscle-invasive bladder cancer (MIBC). This marks the first and only PD-1 inhibitor plus antibody-drug conjugate (ADC) regimen approved in the EU for MIBC patients, regardless of cisplatin eligibility. The approval is based on the Phase 3 KEYNOTE-B15 trial, which demonstrated a statistically significant improvement in event-free survival (EFS) by 47% (HR=0.53) and overall survival (OS) by 35% (HR=0.65) compared to neoadjuvant chemotherapy and surgery. The regimen also showed a superior pathologic complete response (pCR) rate of 55.8% versus 32.5%. This expands treatment options for a patient population facing high recurrence rates and limited alternatives, especially for those ineligible for cisplatin.
- The European Commission's approval establishes KEYTRUDA plus Padcev as the first and only PD-1 inhibitor and antibody-drug conjugate regimen available in the European Union for resectable muscle-invasive bladder cancer. This is a crucial development as it extends a chemotherapy-free perioperative treatment option to patients regardless of their cisplatin eligibility, addressing a significant unmet need for those who cannot receive standard cisplatin-based chemotherapy and have limited alternatives.
- Results from the Phase 3 KEYNOTE-B15 trial underpinned the approval, demonstrating robust efficacy. The KEYTRUDA plus Padcev regimen significantly reduced the risk of event-free survival (EFS) events by 47% (HR=0.53 [95% CI, 0.41-0.70]; p<0.0001) and the risk of death (OS) by 35% (HR=0.65 [95% CI, 0.48-0.89]; p=0.0029) in cisplatin-eligible patients with MIBC, compared to neoadjuvant chemotherapy and surgery. These statistically significant improvements highlight the regimen's substantial clinical benefit.
- Beyond survival benefits, the KEYNOTE-B15 trial also reported a statistically significant improvement in the pathologic complete response (pCR) rate. Patients treated with KEYTRUDA plus Padcev achieved a pCR rate of 55.8% (95% CI: 50.8, 60.7), which was significantly higher than the 32.5% (95% CI: 28.0, 37.3) observed in the neoadjuvant chemotherapy arm (p<0.0001). A higher pCR rate indicates a greater likelihood of complete cancer eradication in the removed tissue, serving as a strong prognostic marker for long-term patient outcomes.
The Persistent Challenges in Resectable MIBC Treatment
Resectable muscle-invasive bladder cancer remains potentially curable when organ confined, yet approximately half of patients will relapse across prognostic groups, and up to 50% of patients undergoing radical cystectomy experience recurrence within the first two years, with a 5-year overall survival reaching 50%-60%. Despite radical cystectomy as standard of care and cisplatin-based chemotherapy improving outcomes, substantial morbidity, limited eligibility, and modest systemic benefits continue to constrain treatment.
Substantial surgical morbidity and postoperative complications: Open radical cystectomy remains the gold standard for treatment of muscle-invasive bladder cancer, but is associated with significant morbidity, and postoperative morbidity remains high, partly because of the complexity of the procedures; more than half of all patients (52%) developed one or more complications within 30 days after surgery in a comparative perioperative protocol analysis.
Limited reduction in locoregional recurrence and ineffective salvage: Despite the use of neoadjuvant chemotherapy, clinical trials have failed to attain a considerable reduction in the risk of locoregional recurrence, which remains a major clinical challenge due to the limited and largely ineffective salvage treatment options.
Narrow eligibility and practical barriers to cisplatin-based chemotherapy: Neoadjuvant cisplatin-based combination chemotherapy improves overall survival and should be offered to eligible ≥cT2N0 patients, with choice of cisplatin- or carboplatin-based regimens determined on the basis of criteria including performance status and renal function, while logistical and socioeconomic barriers limiting neoadjuvant chemotherapy delivery and multiday schedule reduces practicality in resource-constrained settings.
Modest and contradictory benefits of perioperative immunotherapy: PD-1/PD-L1 checkpoint-directed immunotherapy has been established for use in advanced disease with modest overall improvements in survival outcomes, with disease-free survival demonstrated for adjuvant nivolumab, but not atezolizumab, and no overall survival benefit has yet been confirmed; Grade ≥3 treatment-related AEs occurred in 16-26% of patients in adjuvant-only trials and 41-71% in perioperative trials, and high heterogeneity in treatment regimens, endpoint definitions, and follow-up durations limits interpretability of pooled estimates.
Unresolved surgical approach, diversion choice, and functional outcomes: Robotic radical cystectomy continues to be associated with longer surgical times and higher costs, data on long-term oncologic outcomes are insufficient, there is a lack of consensus on the type of approach and urinary diversion that is optimal, and there is a paucity of rigorous, standardized studies on health-related quality of life for continent versus incontinent diversion.
Lack of validated predictive biomarkers and limited options for variant histology: Treatment strategies for bladder cancer are still largely based on clinicopathologic characteristics, development of properly validated predictive biomarkers has proven challenging, and patients with predominant variant histology, defined as involving >50 % of the tumor specimens, are typically excluded from clinical trials, and for these patients, the efficacy of standard chemotherapy is limited.
KEYNOTE-B15: Unpacking the Efficacy and Design for MIBC
Neoadjuvant and perioperative strategies for resectable muscle-invasive bladder cancer span cisplatin-based chemotherapy, chemo-immunotherapy combinations, and immunotherapy alone for cisplatin-ineligible patients. Key trials differ in phase, randomization, eligibility by cisplatin fitness and clinical stage, and primary endpoints centered on pathological response and event-free survival.
| Trial | Design & Population | Perioperative Regimen | Primary Endpoints & Key Outcomes |
|---|---|---|---|
| ABACUS | Multicenter, single-arm, neoadjuvant, phase 2 trial, including patients with MIBC (T2-4aN0M0) who were ineligible for or refused neoadjuvant cisplatin-based chemotherapy | Two cycles of atezolizumab prior to radical cystectomy | Primary endpoints of pathological complete response (pCR) rate and dynamic changes to T-cell biomarkers; secondary outcomes were 2-yr DFS and OS; pCR rate was 31% (27/88; 95% CI 21-41); Two-year DFS and OS were 68% (95% CI 58-76) and 77% (95% CI 68-85), respectively |
| SWOG S1314 (NCT02177695) | Randomized Phase II Study; eligibility included cT2-T4a N0 M0, urothelial bladder cancer, ≥ 5 mm of viable tumor, cisplatin eligible, with plan for cystectomy; 237 patients were randomized | Dose-dense methotrexate-vinblastine-adriamycin-cisplatin (ddMVAC), given every 14 days for four cycles, and gemcitabine-cisplatin (GC), given every 21 days for four cycles | Primary objective assessed prespecified dichotomous treatment-specific COXEN score as predictive of pT0 rate or ≤ pT1 (downstaging) at surgery; pT0 rates for ddMVAC and GC were 28% and 30%; downstaging was 47% and 40%, respectively |
| SAKK 06/19 | Open-label single-arm phase II trial for cT2-T4a N0-1 MIBC eligible for cisplatin and radical cystectomy with lymphadenectomy (RC-LND); 47 patients included | Intravesical rBCG weekly x3 starting day 1; atezolizumab on day 1 for a total of 4 doses and cisplatin/gemcitabine started on day 22 for 4 cycles followed by RC-LND | Primary endpoint was centrally reviewed pathological complete response (pCR, ypT0 ypN0); centrally reviewed pCR was 68% (27/40; one-sided 95% CI lower boundary 53%) and pathological overall response (PaR, ≤ypT1 ypN0) was 83% (33/40; 95% CI 67% - 93%) |
| SAKK 06/17 | Investigator-initiated, open-label, single-arm phase II study including cisplatin-fit patients with stage cT2-T4a cN0-1 operable MIUC; 61 patients accrued | Four cycles of neoadjuvant GC in combination with four cycles of durvalumab (start with GC cycle 2), followed by radical surgery; adjuvant durvalumab for 10 cycles | Primary end point was event-free survival (EFS) at 2 years; EFS at 2 years of 76% (one-sided 90% CI [lower bound], 67%; two-sided 95% CI, 62 to 85); complete pathologic response in resected patients (N = 52) was achieved in 17 patients (33%), and 31 (60%) had pathologic response |
| NEMIO (NCT03549715) | Multicenter, randomized, noncomparative phase II trial in cT2-T4a N0-1 cisplatin-eligible MIBC planned for radical cystectomy (RC); 119 patients received treatment | ddMVAC once every 2 weeks × four cycles plus durvalumab ± tremelimumab (durvalumab 1,500 mg and tremelimumab 75 mg) once every 4 weeks × two doses before RC | Coprimary end points were pathologic complete response (pCR; ypT0N0) and grade ≥3 treatment-related adverse events (TRAEs); overall Bayesian posterior mean pCR rate was 48.70% (95% CI, 35.93 to 61.56) with doublet and 46.27% (95% CI, 33.92 to 58.85) with triplet |
| Neoadjuvant dose-dense GC Phase II | Prospective, multicenter phase II study in MIBC; 49 patients enrolled | ddGC (gemcitabine 2,500 mg/m on day 1 and cisplatin 35 mg/m on days 1 and 2) every 2 weeks for 6 cycles followed by RC | Primary end point was pathologic downstaging to non-muscle-invasive disease (< pT2N0); 57% of 46 evaluable patients downstaged to < pT2N0 |
| Neoadjuvant cabazitaxel + cisplatin Phase II | Single-arm phase II trial to recruit at least 26 evaluable patients with muscle-invasive transitional cell carcinoma of the urinary bladder | Cisplatin plus cabazitaxel before cystectomy | Primary endpoint, objective response rate defined as pathologic complete response plus partial response (pathologic downstaging); objective response was seen in 15 of 26 evaluable patients (57.7%) and 9/26; 34.6% achieved a pathologic complete response |
| VESPER (GETUG-AFU V05) | Randomized Phase III trial in muscle-invasive bladder cancer | Gemcitabine and cisplatin (GC, 4 cycles) or methotrexate, vinblastine, doxorubicin and cisplatin (dose dense [dd]-MVAC, 6 cycles) before surgery | Definition criteria for local control after neoadjuvant chemotherapy included pathological complete response (ypT0N0), pathological downstaging ( |
| Neoadjuvant gemcitabine-cisplatin + tislelizumab (ChiCTR2000037670) | Multicenter, single-arm, phase 2 trial; 65 participants with cT2-4aN0M0 MIBC; 57 underwent radical cystectomy (RC) | Neoadjuvant gemcitabine-cisplatin plus tislelizumab | Primary endpoint of pathologic complete response (pCR) rate was 50.9% (29/57, 95% confidence interval (CI) 37.3-64.4%) and pathologic downstaging rate was 75.4% (43/57, 95% CI 62.2-85.9%) in participants undergoing RC |
Redefining MIBC Standard of Care in Europe
Perioperative chemoimmunotherapy has demonstrated superiority over neoadjuvant chemotherapy alone in cisplatin-eligible muscle-invasive bladder cancer. In the phase 3 NIAGARA trial (NCT03732677), neoadjuvant durvalumab plus gemcitabine-cisplatin every 3 weeks for four cycles followed by radical cystectomy and adjuvant durvalumab every 4 weeks for eight cycles was compared with neoadjuvant gemcitabine-cisplatin followed by radical cystectomy alone in 533 versus 530 patients. The estimated event-free survival at 24 months was 67.8% (95% confidence interval [CI], 63.6 to 71.7) versus 59.8% (95% CI, 55.4 to 64.0) (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), and estimated overall survival at 24 months was 82.2% (95% CI, 78.7 to 85.2) versus 75.2% (95% CI, 71.3 to 78.8) (hazard ratio for death, 0.75; 95% CI, 0.59 to 0.93; P = 0.01). A network meta-analysis of 12 randomized controlled trials (5,026 patients) ranked neoadjuvant chemotherapy followed by surgery and adjuvant nivolumab as the most effective strategy (SUCRA: 99%, HR 0.43, 95% CrI 0.24-0.74), followed by perioperative durvalumab-based regimens (SUCRA: 82%) and dose-dense MVAC chemotherapy (SUCRA: 78%), with moderate heterogeneity (I² = 46%).
Indirect comparisons position enfortumab vedotin plus pembrolizumab and dose-dense MVAC relative to durvalumab plus gemcitabine-cisplatin. A systematic review and meta-analysis of 15 trials (n = 1,545) reported pooled pathological complete response (ypT0N0) of 57% (95% confidence interval [CI], 49%-65%) for enfortumab vedotin plus pembrolizumab (n = 170), 37% (34%-39%; I² = 33%) for immune checkpoint inhibitor-based regimens (13 studies, n = 1,353), and 36% (17%-59%) for enfortumab vedotin monotherapy (n = 22), with enfortumab vedotin plus pembrolizumab showing a higher pathological complete response rate than immune checkpoint inhibitor-based regimens (P < .0001). In cisplatin-ineligible patients, enfortumab vedotin plus pembrolizumab pathological complete response (57%) exceeded immune checkpoint inhibitor-based pathological complete response (29%; 22%-37%), with pooled radical cystectomy completion of 89%. In EV-303, enfortumab vedotin plus pembrolizumab versus surgery alone yielded event-free survival hazard ratio (HR) 0.40 (0.28-0.57) and overall survival HR 0.50 (0.33-0.74), while NIAGARA reported HRs of 0.68 and 0.75. A separate network meta-analysis of randomised controlled trials found dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (HR 0.75, 95% CI 0.58-0.98; p = 0.034) and durvalumab plus gemcitabine-cisplatin (HR 0.75, 95% CI 0.66-0.85; p < 0.001) improved overall survival versus gemcitabine-cisplatin, without differences between dose-dense MVAC and durvalumab plus gemcitabine-cisplatin (HR 0.99, 95% CI 0.75-1.33; p = 0.97). Immune checkpoint inhibitor-chemotherapy combination therapy was associated with higher pathological complete response versus chemotherapy alone (40.6% vs 17.9%; p < 0.01), and durvalumab plus gemcitabine-cisplatin achieved higher pathological complete response versus gemcitabine-cisplatin (OR 1.57, 95% CI 1.21-2.03; p < 0.001), whereas dose-dense MVAC did not.
Pathological response remains closely linked to long-term outcomes, and safety profiles differentiate regimens. In PURE-01, three cycles of pembrolizumab 200 mg followed by radical cystectomy in 155 patients with cT2-3b N0 M0 disease yielded 5-yr event-free survival of 68% and 5-yr overall survival of 77% in the intention-to-treat population, with 5-yr recurrence-free survival of 77% in the radical cystectomy cohort and 5-yr overall survival of ∼90% in the group achieving a complete or major response (p < 0.001). Neoadjuvant gemcitabine and split-dose cisplatin plus pembrolizumab in 39 patients achieved < pT2N0 in 22 of 39 patients (56% [95% CI, 40 to 72]) and pT0N0 in 14 of 39 (36% [95% CI, 21 to 53]), while gemcitabine, cisplatin, plus nivolumab in 76 patients achieved clinical complete response in 33 patients (43%, 95% CI: 32%, 55%) with positive predictive value of 0.97 (95% CI: 0.91, 1). Treatment-related adverse events of grade 3 or 4 occurred in 40.6% versus 40.9% in the NIAGARA durvalumab versus comparison groups, with treatment-related events leading to death in 0.6% in each group and radical cystectomy performed in 88.0% versus 83.2%, while dose-dense methotrexate + vinblastine + Adriamycin + cisplatin significantly increased grade ≥3 anemia (risk ratio [RR] 2.81, 95% CI 1.62-4.88) and asthenia (RR 3.46, 95% CI 1.68-7.14) versus gemcitabine-cisplatin, whereas durvalumab + gemcitabine + cisplatin did not.
Perioperative EVP: A Paradigm Shift in MIBC Treatment
The European Commission's approval of pembrolizumab in combination with enfortumab vedotin for resectable muscle-invasive bladder cancer (MIBC) marks a pivotal moment in the management of this aggressive disease. Historically, neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy has been the standard of care for eligible patients, offering modest survival benefits. However, a significant proportion of patients are ineligible for cisplatin due to comorbidities, leaving them with limited effective perioperative options and facing high recurrence rates. This new regimen, combining a PD-1 inhibitor with an antibody-drug conjugate, directly addresses this unmet need by demonstrating superior event-free survival, overall survival, and pathologic complete response rates compared to chemotherapy alone.
This approval underscores a broader trend in oncology towards integrating novel mechanisms of action, particularly targeted therapies and immunotherapies, into earlier disease settings. The robust efficacy observed with this combination, even in patients who might not tolerate traditional chemotherapy, positions it as a potential new standard. However, the clinical community must also consider the associated toxicity profile. While effective, enfortumab vedotin plus pembrolizumab is known to cause a high incidence of grade ≥3 adverse events, including skin reactions, peripheral neuropathy, and hyperglycemia. Careful patient selection, vigilant monitoring, and proactive management of these toxicities will be crucial to optimize patient outcomes and ensure treatment completion.
Furthermore, the long-term implications of Nectin-4 downregulation, a potential resistance mechanism to enfortumab vedotin observed in chemotherapy-resistant cells, warrant ongoing investigation. Understanding and mitigating such resistance pathways will be key to sustaining the benefits of this therapy. From a strategic perspective, the high cost of this innovative combination may present accessibility challenges, potentially influencing its integration into diverse healthcare systems. As the treatment landscape for MIBC continues to evolve, with other perioperative immune checkpoint inhibitor regimens also showing promise, the focus will increasingly shift towards personalized approaches, leveraging biomarkers to identify patients most likely to benefit from specific combinations while balancing efficacy, safety, and cost-effectiveness. This approval represents a significant step forward, offering new hope for patients with resectable MIBC.
Frequently Asked Questions
References
- [1] Culine S, Harter V et al.. Chemotherapy for Muscle-invasive Bladder Cancer: Impact of Cisplatin Delivery on Renal Function and Local Control Rate in the Randomized Phase III VESPER (GETUG-AFU V05) Trial. Clinical genitourinary cancer. 2021 Dec. 34602349
- [2] Matsukawa A, Cormio A et al.. Impact of Immune Checkpoint Inhibitors as Neoadjuvant Therapy for Muscle-invasive Bladder Cancer: A Systematic Review, Meta-analysis, and Network Meta-analysis. European urology oncology. 2025 Dec. 40288918
- [3] Cathomas R, Rothschild SI et al.. Perioperative Chemoimmunotherapy With Durvalumab for Muscle-Invasive Urothelial Carcinoma: Primary Analysis of the Single-Arm Phase II Trial SAKK 06/17. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023 Nov 20. 37590894
- [4] Nakagawa R, Naito R et al.. Real-World Efficacy of Postoperative Adjuvant Nivolumab in High-Risk Urothelial Carcinoma: A Retrospective Comparative Study in an Asian Population. Asia-Pacific journal of clinical oncology. 2026 Oct. 41220193
- [5] Fraslin A, Colrat F et al.. Characteristics, management and survival outcomes in patients with muscle-invasive bladder cancer at high risk of recurrence in France: a subgroup analysis from the coblance cohort. BMC urology. 2025 May 12. 40355842
- [6] Raychaudhuri R, Khaki AR et al.. Neoadjuvant Pembrolizumab and Accelerated Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Nonurothelial Histologic Subtypes of Muscle-invasive Bladder Cancer: A Phase 2 Trial. European urology. 2025 Dec. 40764177
- [7] De Lorenzis E, Albo G et al.. Current Knowledge on Genomic Profiling of Upper Tract Urothelial Carcinoma. Genes. 2021 Feb 25. 33668859
- [8] Laukhtina E, von Deimling M et al.. Urinary function in female patients after traditional, organ-sparing and nerve-sparing radical cystectomy for bladder cancer: a systematic review and pooled analysis. BJU international. 2024 Mar. 37562831
- [9] Meghani K, Frydenlund N et al.. A Spatial Comparison of Molecular Features Associated with Resistance to Pembrolizumab in BCG Unresponsive Bladder Cancer. medRxiv : the preprint server for health sciences. 2023 Nov 29. 38077072
- [10] Powles T, Catto JWF et al.. Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer. The New England journal of medicine. 2024 Nov 14. 39282910
- [11] Stewart TF, Chalfin H et al.. Perioperative Use of ctDNA to Guide Treatment for Urothelial Carcinoma: The Future is Now. Bladder cancer (Amsterdam, Netherlands). 2024. 39493820
- [12] Su ZT, Florissi IS et al.. Cost-Effectiveness of Perioperative Durvalumab With Neoadjuvant Gemcitabine/Cisplatin in Muscle-Invasive Bladder Cancer Treatment. Journal of the National Comprehensive Cancer Network : JNCCN. 2026 Mar 19. 41911914
- [13] Szabados B, Kockx M et al.. Final Results of Neoadjuvant Atezolizumab in Cisplatin-ineligible Patients with Muscle-invasive Urothelial Cancer of the Bladder. European urology. 2022 Aug. 35577646
- [14] Thibault C, Bennamoun M et al.. Neoadjuvant Durvalumab ± Tremelimumab in Combination With Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Muscle-Invasive Bladder Carcinoma: Results of the Phase I/II NEMIO Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2026 Jul 10. 42190158
- [15] Petrelli F, Dottorini L et al.. Comparison of adjuvant and neoadjuvant therapies for muscle invasive bladder cancer: A network meta-analysis. Urologic oncology. 2026 Jan. 40935764
- [16] Song B, Wu P et al.. Integrating single cell and bulk RNA sequencing data identifies RBM17 as a novel response biomarker for immunotherapy in bladder cancer. Virchows Archiv : an international journal of pathology. 2024 Dec. 39453457
- [17] Iwasawa T, Tsujino T et al.. Translational Advances in Urothelial Carcinoma: From Bench to Bedside. International journal of urology : official journal of the Japanese Urological Association. 2026 Jan. 41531330
- [18] Powles T, Assaf ZJ et al.. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature. 2021 Jul. 34135506
- [19] Guo X, Wang S et al.. Disitamab vedotin (RC48-ADC) combined with immunotherapy as neoadjuvant therapy for localized muscle-invasive bladder cancer: a multicenter real-world study. NPJ precision oncology. 2025 Dec 3. 41331072
Contact Us
Address
350 Springfield Avenue,
Suite #200 Summit, NJ 07901
For General Inquiry
info@pienomial.com
