Keytruda + Padcev Perioperative MIBC — PatSnap Eureka
Keytruda + Padcev Perioperative Therapy in Cisplatin-Eligible Muscle-Invasive Bladder Cancer
KEYNOTE-B15 is testing enfortumab vedotin plus pembrolizumab as a perioperative regimen around radical cystectomy in cisplatin-eligible MIBC — extending the EV+P paradigm established in metastatic urothelial carcinoma to the curative-intent surgical setting.
From Metastatic Success to Perioperative Strategy in Muscle-Invasive Bladder Cancer
Muscle-invasive bladder cancer (MIBC) represents a clinically aggressive disease where the standard of care has long been neoadjuvant cisplatin-based chemotherapy — regimens such as MVAC or GC — followed by radical cystectomy. Pathologic complete response (pCR) achieved at surgery is a validated surrogate for long-term survival outcomes, making the neoadjuvant phase a critical window for therapeutic innovation.
KEYNOTE-B15 represents the next frontier: applying the enfortumab vedotin plus pembrolizumab (EV+P) combination — which demonstrated transformative efficacy in locally advanced and metastatic urothelial carcinoma — to the perioperative setting in cisplatin-eligible patients. The trial follows the structural framework pioneered by KEYNOTE-671 in resectable NSCLC: neoadjuvant systemic therapy, surgery, then adjuvant continuation of the checkpoint inhibitor.
The scientific rationale builds on two converging bodies of evidence. First, the PURE-01 phase II study demonstrated that neoadjuvant pembrolizumab monotherapy achieved a pCR rate of 42.0% and pathologic downstaging in 54.0% of MIBC patients, with PD-L1 expression (CPS ≥10%) and tumor mutational burden identified as significant predictive biomarkers. Second, EV-103 Cohort K established proof-of-concept for neoadjuvant EV+P in cisplatin-ineligible MIBC, reporting a pCR rate of 40.0% for the combination versus 36.4% for EV monotherapy. According to FDA precedent, pCR can support accelerated approval pathways in the perioperative setting when linked to event-free survival data.
KEYNOTE-B15 now tests whether this combination can outperform cisplatin-based neoadjuvant chemotherapy — the established standard — in the cisplatin-eligible population, where the bar for improvement is higher and the competitive landscape more defined. Explore the full patent and clinical evidence landscape on PatSnap Eureka.
Key Efficacy Data Across the EV+Pembrolizumab Trial Programme
Pathologic response and survival outcomes from the trials informing the KEYNOTE-B15 perioperative design in muscle-invasive bladder cancer.
Neoadjuvant pCR Rates: EV+P vs EV Monotherapy vs Pembrolizumab Alone
EV-103 Cohort K (cisplatin-ineligible MIBC) and PURE-01 (pembrolizumab monotherapy) pCR benchmarks informing KEYNOTE-B15 design.
EV-302/KEYNOTE-A39: Survival Outcomes vs Chemotherapy (Metastatic UC)
Phase III data in 886 patients showing EV+pembrolizumab nearly doubling OS and more than doubling PFS versus chemotherapy — the efficacy foundation for KEYNOTE-B15.
Nectin-4 ADC Plus PD-1 Blockade: Scientific Rationale and Patent Coverage
The complementary mechanisms of enfortumab vedotin and pembrolizumab underpin the combination's activity in urothelial carcinoma, supported by extensive IP filings from Seagen and Merck.
Enfortumab Vedotin: Anti-Nectin-4 ADC Mechanism
Enfortumab vedotin is an anti-Nectin-4 antibody-drug conjugate comprising an anti-Nectin-4 antibody, an auristatin moiety, and a linker moiety. Nectin-4 is highly expressed on urothelial carcinoma cells, enabling targeted delivery of cytotoxic auristatin payload. Seagen's core patent covers the ADC construct and its combination with PD-1/PD-L1 checkpoint inhibitors for bladder cancer treatment across locally advanced, metastatic, platinum-ineligible, and platinum-failed settings.
Seagen Inc. · Anti-Nectin-4 ADC PatentsPembrolizumab: PD-1 Blockade in Urothelial Carcinoma
Pembrolizumab is an anti-PD-1 antibody that restores anti-tumor immune activity by blocking the PD-1/PD-L1 axis. Merck's patent portfolio covering pembrolizumab in urothelial carcinoma extends to neoadjuvant and adjuvant use in muscle-invasive bladder cancer, with biomarker-based patient selection including PD-L1 expression and tumor mutational burden (TMB). The KEYNOTE-057 trial established pembrolizumab's activity in BCG-unresponsive NMIBC with a 41% complete response rate at 3 months and a median duration of response of 16.2 months.
Merck Sharp & Dohme LLC · Anti-PD-1 PatentsComplementary Mechanisms Drive Synergistic Activity
The EV+P combination provides dual mechanisms: enfortumab vedotin delivers direct cytotoxic killing to Nectin-4-expressing tumor cells, while pembrolizumab enables immune-mediated tumor clearance. In EV-302/KEYNOTE-A39, this combination achieved an objective response rate of 67.7% versus 44.4% for chemotherapy across all pre-specified subgroups, regardless of cisplatin eligibility and PD-L1 status — suggesting the combination is not dependent on a single biomarker pathway. Learn more about life sciences innovation intelligence.
ORR 67.7% · Subgroup-consistent benefitKEYNOTE-671 Precedent: Perioperative Checkpoint Inhibition
The perioperative design of KEYNOTE-B15 mirrors the approach validated in KEYNOTE-671 for resectable early-stage non-small-cell lung cancer, where pembrolizumab combined with platinum-based chemotherapy in the neoadjuvant setting, followed by adjuvant pembrolizumab, demonstrated significant improvement in event-free survival and pCR rates. According to EMA and FDA regulatory frameworks, this perioperative structure — treating before and after surgery — is increasingly accepted as a path to regulatory approval when linked to pCR and EFS data.
KEYNOTE-671 · Perioperative EFS + pCR frameworkKey Trials Informing the KEYNOTE-B15 Perioperative MIBC Programme
From phase II neoadjuvant studies to the phase III metastatic foundation, this evidence base shapes the regulatory and clinical expectations for KEYNOTE-B15.
Track every MIBC trial update in real time
PatSnap Eureka monitors clinical trial registries, patent filings, and regulatory submissions across the urothelial carcinoma landscape.
What KEYNOTE-B15 Means for the MIBC Treatment Landscape
Key strategic and clinical implications of the perioperative EV+pembrolizumab programme for oncology teams, IP professionals, and R&D strategists.
Cisplatin-Eligible Population: A Higher Bar
Unlike EV-103 Cohort K, which targeted cisplatin-ineligible patients where chemotherapy is not an option, KEYNOTE-B15 must demonstrate superiority or non-inferiority against established cisplatin-based neoadjuvant regimens — a significantly more competitive benchmark for a new perioperative regimen.
pCR as Regulatory Surrogate Endpoint
The PURE-01 study established that pCR rate and pathologic downstaging (≤pT1N0, achieved in 54.0% of patients) are clinically meaningful endpoints in MIBC. FDA has accepted pCR as a basis for accelerated approval in perioperative settings when linked to event-free survival, creating a potential regulatory pathway for KEYNOTE-B15 results.
FDA Decision Framework for Perioperative EV+Pembrolizumab in MIBC
The FDA regulatory pathway for KEYNOTE-B15 builds on established precedents across two tumour types. In FDA's perioperative oncology framework, pCR achieved at surgery and event-free survival (EFS) are the co-primary endpoints most likely to support approval in the neoadjuvant/adjuvant setting. The KEYNOTE-671 approval in NSCLC demonstrated that this perioperative structure — neoadjuvant systemic therapy followed by surgery then adjuvant continuation — is an accepted regulatory path when EFS benefit is demonstrated.
For KEYNOTE-B15 in cisplatin-eligible MIBC, the comparison arm is cisplatin-based neoadjuvant chemotherapy (such as dose-dense MVAC or gemcitabine-cisplatin), which already achieves meaningful pCR rates. The MIBC standard of care review from ESMO guidelines contextualises pCR rates with cisplatin-based regimens as the benchmark against which EV+P must demonstrate superiority or non-inferiority.
Merck's anti-PD-1 patent portfolio explicitly describes neoadjuvant and adjuvant use of pembrolizumab in muscle-invasive bladder cancer, and biomarker-based patient selection using PD-L1 expression and TMB. The PatSnap customer case studies demonstrate how pharma R&D teams use Eureka to monitor competitor regulatory filings and anticipate FDA submission timelines in oncology. Track KEYNOTE-B15 regulatory signals and patent activity through PatSnap Analytics.
KEYNOTE-B15 & Perioperative MIBC — key questions answered
KEYNOTE-B15 is a perioperative phase III trial evaluating enfortumab vedotin plus pembrolizumab in cisplatin-eligible muscle-invasive bladder cancer patients, combining neoadjuvant and adjuvant treatment phases around radical cystectomy. EV-103 Cohort K was an earlier phase II study focused specifically on cisplatin-ineligible MIBC patients, reporting pCR rates of 40.0% for the EV+pembrolizumab combination and 36.4% for EV monotherapy. KEYNOTE-B15 extends this approach to the cisplatin-eligible population, which represents the standard-of-care surgical candidate group.
In EV-103 Cohort K, neoadjuvant enfortumab vedotin plus pembrolizumab achieved a pathologic complete response (pCR) rate of 40.0% in cisplatin-ineligible MIBC patients, compared to 36.4% for enfortumab vedotin monotherapy. The PURE-01 trial with neoadjuvant pembrolizumab monotherapy reported a pCR rate of 42.0% and a pathologic downstaging rate of 54.0% in MIBC, with PD-L1 expression (CPS ≥10%) and tumor mutational burden identified as significant biomarkers.
EV-302/KEYNOTE-A39 was a phase III trial of 886 patients with previously untreated locally advanced or metastatic urothelial carcinoma. Enfortumab vedotin plus pembrolizumab significantly improved overall survival (median 31.5 vs 16.1 months; HR 0.47; P<0.00001) and progression-free survival (median 12.5 vs 6.3 months; HR 0.45; P<0.00001) versus chemotherapy, with an objective response rate of 67.7% versus 44.4%. The benefit was consistent across subgroups regardless of cisplatin eligibility and PD-L1 status.
Enfortumab vedotin is an anti-Nectin-4 antibody-drug conjugate (ADC) comprising an anti-Nectin-4 antibody, an auristatin moiety, and a linker moiety. Nectin-4 is highly expressed on urothelial carcinoma cells. The ADC delivers cytotoxic auristatin payload directly to Nectin-4-expressing tumor cells. When combined with pembrolizumab, a PD-1 checkpoint inhibitor, the combination provides complementary mechanisms: direct tumor cell killing via the ADC and immune-mediated tumor clearance via checkpoint blockade.
Based on the PURE-01 study, PD-L1 expression (CPS ≥10%) and tumor mutational burden (TMB) were identified as significant biomarkers for pathologic complete response to neoadjuvant pembrolizumab in muscle-invasive bladder cancer. The Merck anti-PD-1 patent portfolio also describes biomarker-based patient selection including PD-L1 expression and TMB for identifying patients most likely to benefit from pembrolizumab treatment in urothelial carcinoma.
KEYNOTE-671 evaluated perioperative pembrolizumab in resectable early-stage non-small-cell lung cancer, combining pembrolizumab with platinum-based chemotherapy in the neoadjuvant setting followed by adjuvant pembrolizumab. This trial demonstrated significant improvement in event-free survival and pathologic complete response rates compared to chemotherapy alone. This perioperative framework — neoadjuvant systemic therapy followed by surgery then adjuvant continuation — is the same structural approach being applied in KEYNOTE-B15 for muscle-invasive bladder cancer, adapted with enfortumab vedotin replacing platinum chemotherapy.
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References
- EV-302/KEYNOTE-A39 Phase III Trial — Powles T et al. Enfortumab vedotin plus pembrolizumab versus chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. Lancet. 2024 Feb 8.
- EV-103 Cohort K (2023) — Hoimes CJ et al. Antitumor activity of enfortumab vedotin monotherapy or in combination with pembrolizumab as neoadjuvant treatment for cisplatin-ineligible patients with muscle-invasive bladder cancer. J Clin Oncol. 2023 Jun.
- EV-103 Cohort K (2024) — Flaig TW et al. Neoadjuvant Enfortumab Vedotin+Pembrolizumab for Cisplatin-ineligible Muscle-invasive Bladder Cancer. 2024 May 28.
- PURE-01 Phase II Study — Necchi A et al. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer. J Clin Oncol. 2018 Nov.
- KEYNOTE-671: Perioperative Pembrolizumab in NSCLC — Wakelee H et al. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med. 2023 Oct 5.
- KEYNOTE-057: Pembrolizumab in BCG-unresponsive NMIBC — Balar AV et al. Pembrolizumab for High-Risk Non-Muscle-Invasive Bladder Cancer Unresponsive to BCG. J Clin Oncol. 2021 Dec 9.
- Seagen Inc. — Anti-Nectin-4 ADC Patent (2021) — Anti-Nectin-4 Antibody Drug Conjugates and Treatment of Bladder Cancer. Published 2021-08-05.
- Merck Sharp & Dohme LLC — Anti-PD-1 in Urothelial Carcinoma Patent (2023) — Anti-PD-1 Antibody for Treatment of Urothelial Carcinoma. Published 2023-09-14.
- U.S. Food and Drug Administration (FDA) — Oncology regulatory guidance on perioperative endpoints including pCR and event-free survival.
- European Society for Medical Oncology (ESMO) — Clinical practice guidelines for muscle-invasive and metastatic bladder cancer.
- European Medicines Agency (EMA) — Regulatory framework for perioperative oncology approvals in urothelial carcinoma.
All data and statistics on this page are sourced from the references above and from PatSnap's proprietary innovation intelligence platform, PatSnap Eureka.
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