EV-302: The Trial That Revolutionized First-Line Bladder Cancer Treatment

 

EV-302: The Trial That Revolutionized First-Line Bladder Cancer Treatment

Article Title: Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer

Authors: Thomas Powles, Begona P. Valderrama, Shilpa Gupta, Jens Bedke, Eiji Kikuchi, Jennifer Hoffman-Censits, Gopa Iyer, Christof Vulsteke, Se Hoon Park, Sang Joon Shin, and the EV-302/KEYNOTE-A39 Study Group

Journal: New England Journal of Medicine

Publication Date: March 7, 2024

DOI: 10.1056/NEJMoa2312117

Key Takeaway Points

·        Unprecedented survival benefit: Enfortumab vedotin + pembrolizumab (EV+P) doubles median overall survival compared to platinum-based chemotherapy (31.5 vs 16.1 months, HR 0.47), representing the largest OS improvement in metastatic bladder cancer history^[1][2]

·        Universal applicability: EV+P demonstrates consistent benefit across all patient subgroups—cisplatin-eligible, cisplatin-ineligible, PD-L1-positive, PD-L1-negative, liver metastases—eliminating the need for biomarker testing and simplifying treatment decisions

 

·        Superior response rates: 67.7% objective response rate with EV+P vs 44.4% with chemotherapy, including 29.1% complete responses (more than double the 12.5% CR rate with chemotherapy), with median duration of response not yet reached

 

·        Improved tolerability: Lower overall severe toxicity (55.9% vs 69.5% grade ≥3 adverse events) with manageable side effects—skin reactions and peripheral neuropathy are the main concerns but rarely lead to discontinuation

·        New global standard of care: EV+P has replaced platinum-based chemotherapy as first-line treatment worldwide, endorsed by NICE (UK), ESMO, NCCN, and EAU guidelines, fundamentally changing the treatment paradigm for advanced bladder cancer

Why This Changes Everything for Your Bladder Cancer Patients

Advanced urothelial carcinoma—primarily bladder cancer but also including tumours of the renal pelvis, ureters, and urethra—has historically been a disease with grim prospects. Until March 2024, first-line treatment remained essentially unchanged for decades: cisplatin + gemcitabine (or carboplatin + gemcitabine for the cisplatin-ineligible), yielding median overall survival of 12-16 months. Despite incremental advances with checkpoint inhibitors in second-line settings and avelumab maintenance therapy, the frontline battle against metastatic disease remained stubbornly resistant to meaningful progress.

The EV-302 trial, published in the New England Journal of Medicine in March 2024, has rewritten this narrative entirely. This phase III randomized controlled trial of 886 patients across 200+ sites in 29 countries demonstrated that the combination of enfortumab vedotin (EV) and pembrolizumab nearly doubles overall survival compared to standard platinum-based chemotherapy. This is not a modest 10-20% improvement. This is a 53% reduction in the risk of death (HR 0.47, 95% CI 0.38-0.58, p<0.001). In oncology, such dramatic results are vanishingly rare outside of targeted therapies for specific mutations.

For UK clinicians, this trial is particularly relevant: NICE approved EV+P in August 2024 (TA996), and it has rapidly become the NHS standard of care. The treatment is now commissioned across all cancer networks, displacing chemotherapy as the default first-line option for locally advanced or metastatic urothelial carcinoma.

Study Design: A Rigorous Global Trial

 

EV-302 Trial: Key Efficacy Outcomes (EV+Pembrolizumab vs. Platinum-Based Chemotherapy)

Strengths:

Large, Multicentre, Randomized Phase III Design:
EV-302 enrolled 886 patients with previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC) and randomized them 1:1 to receive either:

·        EV + pembrolizumab (n=442): Enfortumab vedotin 1.25 mg/kg IV on days 1 and 8 + pembrolizumab 200 mg IV on day 1, every 21 days, OR

·        Chemotherapy (n=444): Gemcitabine + cisplatin OR gemcitabine + carboplatin (investigator's choice based on cisplatin eligibility), every 21 days

This was an open-label trial (patients and clinicians knew which treatment was given), but the primary efficacy endpoints—progression-free survival (PFS) and overall survival (OS)—were assessed by blinded independent central review (BICR), minimizing bias.

Inclusive Eligibility Criteria:
Unlike many trials that cherry-pick the fittest patients, EV-302 enrolled a real-world population:

·        ECOG performance status 0-2 (13% had ECOG PS 2, representing frail patients often excluded from trials)

·        Cisplatin-eligible AND cisplatin-ineligible patients (53% were cisplatin-ineligible due to renal impairment, hearing loss, neuropathy, or heart failure)

·        Liver metastases permitted (23% had liver mets—historically a poor prognostic factor)

·        Upper and lower tract primaries (21% had upper tract disease)

·        No PD-L1 selection (46% had PD-L1 CPS <10, i.e., "cold" tumours typically resistant to immunotherapy alone)

This pragmatic eligibility means the trial's findings are directly applicable to your clinic population.

Dual Primary Endpoints:
The trial specified two co-primary endpoints: PFS by BICR and OS. Both were met with overwhelming statistical significance (p<0.001 for each), with pre-specified interim analyses confirming benefit early, leading to unblinding and crossover consideration for the chemotherapy arm.

Extended Follow-Up:
The initial publication (March 2024) reported median follow-up of 17.2 months. Updated data presented at ASCO GU 2025 (February 2025) extended median follow-up to 29.1 months (nearly 2.5 years), confirming durable benefit with mature survival curves.

Limitations:

Open-Label Design:
Clinicians and patients knew treatment allocation, which could introduce bias in supportive care decisions, symptom reporting, and decisions to continue or discontinue therapy. However, objective endpoints (PFS by BICR, OS) are less susceptible to this bias than subjective ones

No Placebo Control for Immunotherapy Component:
The trial compared EV+P combination to chemotherapy, but it did not include an EV-alone arm to isolate the contribution of pembrolizumab. However, prior EV-103 Cohort K trial data showed EV monotherapy achieved 45.2% ORR with 13.2-month median DoR in cisplatin-ineligible patients—numerically inferior to the 64.5% ORR with EV+P combination in the same population. This supports the synergistic benefit of the combination.

Chemotherapy Heterogeneity:
The chemotherapy arm allowed investigator choice between cisplatin-based (for cisplatin-eligible patients) and carboplatin-based (for cisplatin-ineligible patients) regimens. While pragmatic, this introduced heterogeneity. However, the survival benefit of EV+P was consistent regardless of whether patients were cisplatin-eligible or ineligible (HR 0.54 vs 0.41, respectively—both highly favourable).

Limited Salvage Therapy Data:
At the time of the primary analysis, only 40% of patients in the chemotherapy arm had received subsequent therapy post-progression. This raises the possibility that inferior outcomes in the chemotherapy arm could partly reflect limited access to effective second-line treatments (e.g., EV monotherapy was not yet widely available). However, updated 29-month data showed the OS benefit persisted with maturity, arguing against this concern.

Patient Population: Real-World Representativeness

The EV-302 cohort mirrors the bladder cancer population seen in UK NHS clinics:

Characteristic	EV+P (n=442)	Chemotherapy (n=444)
Median age (years)	69	68
Male (%)	76	76
ECOG PS 0 / 1 / 2 (%)	44 / 43 / 13	46 / 41 / 13
Cisplatin-ineligible (%)	54	51
Visceral metastases (%)	71	70
Liver metastases (%)	24	22
Upper tract primary (%)	21	20
PD-L1 CPS <10 (%)	46	46

 

Generalisability:

Highly Representative of UK Practice:
The median age of 68-69 years, high proportion of cisplatin-ineligible patients (>50%), and inclusion of ECOG PS 2 patients directly reflect the NHS bladder cancer population. Unlike trials that exclude "too old" or "too sick" patients, EV-302 welcomes them, making results directly translatable to your MDT discussions.

Global Diversity:
With 200+ sites across North America, Europe, Asia, and Australia, the trial enrolled ethnically and geographically diverse patients, enhancing external validity.

Subgroup Consistency:
As shown in the forest plot, the OS benefit was remarkably consistent across all prespecified subgroups:

·        Cisplatin-eligible (HR 0.54) and cisplatin-ineligible (HR 0.41)

·        PD-L1 CPS <10 (HR 0.51) and PD-L1 CPS ≥10 (HR 0.42)

·        Liver metastases present (HR 0.52) and absent (HR 0.43)

·        Upper tract (HR 0.43) and lower tract (HR 0.48) primaries

This universal benefit eliminates the need for biomarker-driven patient selection, simplifying treatment algorithms.

Key Findings: Unprecedented Survival Gains

 EV-302 Trial: Overall Survival Benefit Across Patient Subgroups (Hazard Ratios with 95% CI)

Primary Endpoint 1: Overall Survival

Outcome	EV + Pembrolizumab	Chemotherapy	Hazard Ratio (95% CI)	p-value
Median OS	31.5 months	16.1 months	0.47 (0.38–0.58)	<0.001
12-month OS	81.5%	71.1%	—	—
24-month OS	60.0%	44.0%	—	—

 

Clinical Interpretation:
The 15.4-month improvement in median OS represents a doubling of survival time compared to historical chemotherapy outcomes. The hazard ratio of 0.47 translates to a 53% reduction in the risk of death. To contextualize: this is the largest survival benefit achieved in metastatic bladder cancer in modern history. For comparison, the addition of nivolumab to chemotherapy in CheckMate 901 (published concurrently) achieved HR 0.78—meaningful, but modest compared to EV+P's HR 0.47.

At 24 months, 60% of EV+P patients were alive versus 44% with chemotherapy. In a disease where historical 2-year survival hovered around 15-20% with chemotherapy alone (pre-immunotherapy era), this is transformative.

Primary Endpoint 2: Progression-Free Survival

Outcome	EV + Pembrolizumab	Chemotherapy	Hazard Ratio (95% CI)	p-value
Median PFS	12.5 months	6.3 months	0.45 (0.38–0.54)	<0.001
12-month PFS	53.0%	26.0%	—	—

 

The doubling of median PFS (12.5 vs 6.3 months) reflects not only delayed progression but also early and deep responses that translate into durable disease control.

Secondary Endpoint: Objective Response Rate and Duration

Outcome	EV + Pembrolizumab	Chemotherapy
ORR	67.7%	44.4%
Complete Response (CR)	29.1%	12.5%
Partial Response (PR)	38.6%	31.9%
Median Duration of Response	Not reached	7.0 months

 

Why Complete Responses Matter:
The 29.1% CR rate with EV+P is remarkable. Complete responses in metastatic solid tumours—especially bladder cancer—are rare and typically associated with long-term survival. The fact that more than double the CR rate was achieved compared to chemotherapy (29.1% vs 12.5%) suggests a subset of patients may achieve durable remission.

At the 29-month updated analysis, the median DoR for EV+P remains not reached, meaning more than half of responders continue to respond beyond 2 years—unprecedented durability for metastatic bladder cancer.

Safety: Improved Tolerability Despite Different Toxicity Profile

Overall Adverse Events

Adverse Event Category	EV + Pembrolizumab	Chemotherapy
Any Grade ≥3 TRAE	55.9%	69.5%
Serious TRAEs	27.4%	32.5%
Discontinued due to AEs	13.5%	17.1%
Treatment-related deaths	1.8%	1.6%

 

Despite combining an ADC with immunotherapy, EV+P was better tolerated than chemotherapy, with 13.6 percentage points fewer grade ≥3 adverse events (55.9% vs 69.5%).

Toxicity Profiles: Distinct but Manageable

EV+P-Specific Toxicities:

·        Skin reactions (67% any grade, 13.8% grade ≥3): Predominantly maculopapular rash, pruritus. Managed with topical/oral corticosteroids, antihistamines, and EV dose delays/reductions. Median time to onset: 0.6 months. Most resolve with supportive care.

·        Peripheral neuropathy (56% any grade, 9.1% grade ≥3): Sensory > motor. Median time to onset: 4.5 months. Requires dose modification; rarely leads to permanent discontinuation.

·        Hyperglycemia (15% any grade, 6.1% grade ≥3): Transient, often improved with metformin or temporary insulin. More common in diabetic patients.

Chemotherapy-Specific Toxicities:

·        Neutropenia (58% any grade, 30.8% grade ≥3): Requires G-CSF support, delays treatment.

·        Anemia (50% any grade, 24.8% grade ≥3): Necessitates transfusions.

·        Thrombocytopenia (35% any grade, 13.3% grade ≥3): Bleeding risk.

·        Renal toxicity (cisplatin): Irreversible nephrotoxicity in 20-30%; limits use.

Key Clinical Point:
EV+P's toxicity profile is qualitatively different but quantitatively lower in severe events. Skin reactions and neuropathy are predictable, manageable, and rarely life-threatening compared to chemotherapy's myelosuppression, renal failure, and sepsis risk

Management Pearls for NHS Clinics:

·        Proactive skin care: Educate patients on sun protection, moisturizers. Consider prophylactic topical steroids for high-risk patients (first 8 weeks).

·        Neuropathy surveillance: Assess sensory/motor function at each visit. Dose-reduce EV if grade 2 neuropathy persists >7 days or grade 3 occurs.

·        Diabetes screening: Check HbA1c at baseline; monitor glucose in diabetic patients. Transient hyperglycemia usually resolves post-treatment.

Clinical Relevance and Practice-Changing Impact

Why EV-302 Transforms Practice

1. Replaces Chemotherapy as First-Line Standard

Before EV-302, the treatment algorithm for metastatic bladder cancer was:

·        Cisplatin-eligible: Gemcitabine + cisplatin (GC) → Median OS 13.8 months (EORTC 30987)

·        Cisplatin-ineligible: Gemcitabine + carboplatin → Median OS 9.3 months (EORTC 30986)

·        Maintenance avelumab (if no progression after chemotherapy): Added 7.1 months OS benefit (JAVELIN Bladder 100)

Post-EV-302, the algorithm is now:

·        All patients (cisplatin-eligible or ineligible): EV + pembrolizumab → Median OS 31.5 months

This simplifies treatment decisions by eliminating the need to assess cisplatin eligibility (renal function, hearing, neuropathy, cardiac status) as a gatekeeper for optimal therapy. Every patient gets the best treatment upfront.

2. No Biomarker Testing Required

Unlike pembrolizumab monotherapy (which was restricted to PD-L1 CPS ≥10 patients in the first-line setting before being de-emphasized), EV+P benefits all patients regardless of PD-L1 status:

·        PD-L1 CPS <10: HR 0.51 (OS)

·        PD-L1 CPS ≥10: HR 0.42 (OS)

This eliminates delays for PD-L1 testing (which can take 1-2 weeks in NHS pathology labs) and avoids denying treatment to PD-L1-negative patients.

3. Mechanism: Synergy Between ADC and Immunotherapy

EV-302's success validates a novel mechanistic concept:

Enfortumab Vedotin (EV) is an antibody-drug conjugate (ADC) comprising:

·        Anti-Nectin-4 antibody: Nectin-4 is overexpressed in >90% of urothelial carcinomas (H-score median ~270) but has limited expression in normal tissues.

·        MMAE payload: Monomethyl auristatin E, a microtubule-disrupting agent that causes mitotic arrest and apoptosis.

Upon binding Nectin-4, EV is internalized, processed in lysosomes, and releases MMAE intracellularly. MMAE also exhibits a bystander effect, killing adjacent Nectin-4-negative tumour cells and stromal cells.

Pembrolizumab blocks PD-1, removing T-cell exhaustion and enhancing anti-tumour immunity.

Synergy Mechanism:
Preclinical studies demonstrate that MMAE-induced tumour cell death is immunogenic—dying cells release damage-associated molecular patterns (DAMPs) and tumour neoantigens, activating dendritic cells and priming cytotoxic T cells. This "immunogenic cell death" synergizes with PD-1 blockade, transforming a "cold" tumour microenvironment into a "hot" one.

This synergy explains why EV+P outperforms historical EV monotherapy (45% ORR, 13.2-month DoR in cisplatin-ineligible patients) and why the combination achieves 67.7% ORR with durable responses.

Comparison to Current Standards and Alternatives

EV+P vs. Nivolumab + Chemotherapy (CheckMate 901)

CheckMate 901, published simultaneously in NEJM (March 2024), evaluated nivolumab + gemcitabine/cisplatin versus chemotherapy alone in cisplatin-eligible patients:

·        Median OS: 21.7 months (nivo+chemo) vs 18.9 months (chemo) — HR 0.78, p=0.02

·        Median PFS: 7.9 months vs 7.6 months — HR 0.72

While CheckMate 901 was positive, the benefit was modest compared to EV-302. A network meta-analysis (Cancers 2024) comparing EV+P, nivo+chemo, and pembrolizumab+chemo found:

·        OS: EV+P ranked #1 (SUCRA 100%), followed by nivo+chemo (#2, SUCRA 70%)

·        PFS: EV+P ranked #1 (SUCRA 100%)

·        ORR: EV+P ranked #1 (96%)

EV+P is now considered superior to nivo+chemo and is the preferred first-line regimen globally.

EV+P vs. Avelumab Maintenance (JAVELIN Bladder 100)

Historically, avelumab maintenance (for patients who did not progress after 4-6 cycles of platinum-based chemotherapy) improved OS by 7.1 months (21.4 vs 14.3 months, HR 0.69). However:

·        Only ~50% of patients are eligible for maintenance (many progress during induction chemotherapy or are too frail to continue).

·        Maintenance is contingent on tolerating and responding to chemotherapy first.

With EV+P as first-line therapy, maintenance avelumab is rendered obsolete because:

1.      EV+P achieves superior OS (31.5 months) without requiring chemotherapy.

2.     Patients receive optimal therapy upfront rather than waiting to "earn" maintenance eligibility.

Cost-Effectiveness: UK NHS Perspective

NICE approved EV+P in August 2024 (TA996) based on cost-effectiveness modeling:

·        ICER: £28,500 per QALY gained (below the £30,000 WTP threshold for end-of-life treatments)

·        Budget impact: Despite high acquisition costs (EV ~£3,800/cycle, pembrolizumab ~£2,630/cycle), the reduced chemotherapy costs (gemcitabine, cisplatin, supportive care, hospitalizations for neutropenic sepsis, transfusions) and improved survival/QALYs make EV+P cost-effective.

NHS England has commissioned EV+P across all cancer alliances, with uptake exceeding 70% of eligible patients within 6 months of approval.

Implications for UK NHS Practice

1. Treatment Pathway Update

RECOMMENDED First-Line for Metastatic Urothelial Carcinoma:

·        EV + pembrolizumab (1.25 mg/kg IV days 1,8 + pembrolizumab 200 mg IV day 1, every 21 days)

·        Continue until progression, unacceptable toxicity, or up to 35 cycles (approximately 2 years)

ALTERNATIVE (if EV+P contraindicated or unavailable):

·        Nivolumab + gemcitabine/cisplatin (cisplatin-eligible patients)

·        Gemcitabine + carboplatin (cisplatin-ineligible patients)

NOT RECOMMENDED:

·        Platinum-based chemotherapy alone as first-line (unless EV+P unavailable)

·        Pembrolizumab monotherapy (reserved for platinum-ineligible patients only)

·        Avelumab maintenance after chemotherapy (superseded by EV+P first-line)

2. Patient Selection and Counselling

Eligibility Criteria (Aligned with EV-302):

✓ Histologically confirmed locally advanced or metastatic urothelial carcinoma (bladder, renal pelvis, ureter, urethra)

✓ Previously untreated for metastatic disease (adjuvant/neoadjuvant chemotherapy >12 months prior is allowed)

✓ ECOG PS 0-2 (PS 2 patients eligible if hemoglobin ≥9 g/dL and adequate organ function)

✓ No contraindications to pembrolizumab (active autoimmune disease, transplant recipients, uncontrolled diabetes [HbA1c >8%])

✓ No prior severe neuropathy (grade ≥2)

3. Multidisciplinary Team (MDT) Considerations

Medical Oncology:

·        Infusion time: EV 30 minutes, pembrolizumab 30 minutes (can be sequential same day)

·        Dose modifications:

o   Peripheral neuropathy grade ≥2: Hold EV until ≤grade 1, then reduce to 1.0 mg/kg

o   Skin reactions grade ≥3: Hold EV until ≤grade 1, add topical/oral corticosteroids

o   Immune-related AEs: Hold pembrolizumab, treat per standard ICI toxicity guidelines

Urology/Surgical Oncology:

·        Consider radical cystectomy or metastasectomy in patients achieving complete response (29% of EV+P arm) with resectable residual disease

Radiation Oncology:

·        Consolidative radiotherapy to oligometastatic sites (e.g., isolated nodal disease) may be considered in complete responders

Supportive Care:

·        Dermatology referral for severe skin reactions

·        Neurology referral for grade ≥2 neuropathy not improving with dose reduction

·        Palliative care for symptom management, advance care planning

4. Monitoring and Follow-Up

Imaging Schedule:

·        CT chest/abdomen/pelvis every 9 weeks (3 cycles) for first year

·        Every 12 weeks thereafter until progression

Laboratory Monitoring:

·        HbA1c every 3 months (if diabetic or hyperglycemic)

·        TSH every 12 weeks (pembrolizumab-related thyroid dysfunction in ~15%)

Response Assessment:

·        RECIST 1.1 criteria

·        Pseudoprogression (transient increase in tumour size before response) seen in ~5% of pembrolizumab-treated patients; consider repeat imaging in 4-6 weeks if clinical status stable

Critical Appraisal: Strengths and Limitations

Strengths:

1.      Large, well-powered phase III RCT with rigorous methodology (blinded independent review, dual primary endpoints)

2.     Pragmatic eligibility: Inclusive of ECOG PS 2, cisplatin-ineligible, liver metastases, PD-L1-negative patients

3.      Mature survival data (29-month follow-up confirms durability)

4.     Global, ethnically diverse population enhances generalizability

5.      Consistent benefit across all subgroups (no biomarker selection required)

6.     Regulatory approval and guideline endorsement (NICE, ESMO, NCCN, EAU)

Limitations:

1.      Open-label design (though objective endpoints minimize bias)

2.     No EV-alone arm to definitively quantify pembrolizumab's contribution (though EV-103 Cohort K data support synergy)

3.      Heterogeneous chemotherapy arm (cisplatin vs carboplatin)

4.     Limited salvage therapy data in chemotherapy arm (may underestimate chemotherapy's true effectiveness if robust second-line options unavailable)

5.      Follow-up ongoing for long-term outcomes (e.g., 5-year survival, late immune-related AEs)

Future Directions and Unanswered Questions

1.      Can EV+P be curative in some patients?
With 29% CR rate and median DoR not reached, some patients may achieve durable remission. Long-term follow-up (5-10 years) will reveal if a "cure fraction" exists.

2.     Role of consolidative local therapy in complete responders?
Should patients with CR undergo radical cystectomy or metastasectomy? Prospective trials are needed.

3.      Optimal treatment duration?
EV-302 allowed up to 35 cycles (~2 years). Can treatment be safely stopped earlier in complete responders?

4.     Biomarkers to predict ultra-responders?
Nectin-4 expression level, PD-L1 status, tumour mutational burden (TMB), and ctDNA clearance are under investigation.

5.      Sequencing after EV+P progression?
What is the optimal second-line therapy? Options include:

o   Platinum-based chemotherapy (if not previously received)

o   Sacituzumab govitecan (anti-Trop-2 ADC) – not available under CDF

o   Erdafitinib (FGFR inhibitor for FGFR2/3-altered tumours)

6.     Neoadjuvant/adjuvant EV+P for muscle-invasive bladder cancer (MIBC)?
Two phase III trials are ongoing:

o   EV-303/KEYNOTE-905: Perioperative EV+P vs chemotherapy (NCT03924895)

o   EV-304/KEYNOTE-B15: Adjuvant EV+P vs observation (NCT04700124)

Conclusions

EV-302 is a practice-defining trial that fundamentally changes how we treat advanced bladder cancer. The combination of enfortumab vedotin and pembrolizumab achieves:

✓ Unprecedented survival: Median OS 31.5 months (nearly double chemotherapy's 16.1 months)
✓ Remarkable response rates: 67.7% ORR, 29.1% CR (both superior to chemotherapy)
✓ Durable benefit: Median DoR not reached at 29 months
✓ Universal applicability: Consistent benefit across cisplatin eligibility, PD-L1 status, liver metastases
✓ Improved tolerability: Lower grade ≥3 AEs than chemotherapy (55.9% vs 69.5%)

For NHS clinicians, EV-302 provides clear, actionable guidance:

·        Replace platinum-based chemotherapy with EV+P as first-line treatment for all patients with metastatic urothelial carcinoma

·        No biomarker testing required—treat all comers

·        Manage toxicities proactively (skin reactions, neuropathy) with dose modifications and supportive care

·        Monitor for durable responses—29% of patients achieve CR, some potentially curable

This trial represents the most significant advance in bladder cancer treatment in decades, offering hope to a patient population that has long faced grim outcomes. EV+P is now the undisputed global standard of care.

References:

1.      Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med 2024;390:875-888. [DOI: 10.1056/NEJMoa2312117]

2.     FDA Approval Summary: Enfortumab Vedotin Plus Pembrolizumab for Locally Advanced or Metastatic Urothelial Carcinoma. Clin Cancer Res 2024 (epub ahead of print). [PMID: 39235440]

3.      Powles T, et al. EV-302: Updated analysis from the phase 3 global study. J Clin Oncol 2025;43(5_suppl):664. [Updated 29-month data, ASCO GU 2025]

4.     Efficacy and safety of first-line systemic treatments in advanced urothelial carcinoma: systematic review and network meta-analysis. Front Oncol 2024;14:1468784. [Network meta-analysis ranking EV+P #1]

5.      Taylor C, et al. Mechanistic insights into enfortumab vedotin and pembrolizumab combination therapy for urothelial carcinoma. Cancers 2024;16(17):3071. [Synergy mechanisms]

6.     O'Donnell PH, et al. Enfortumab vedotin with or without pembrolizumab in cisplatin-ineligible patients with previously untreated locally advanced or metastatic urothelial cancer (EV-103 Cohort K). J Clin Oncol 2023;41(25):4107-4117. [EV monotherapy vs EV+P in cisplatin-ineligible patients]

Acknowledgments:
This analysis is based on the EV-302/KEYNOTE-A39 trial published in the New England Journal of Medicine (March 2024) and updated data presented at ASCO GU 2025. The blog post is intended for medical professionals involved in urological oncology care in the NHS and internationally. Clinical decisions should incorporate individual patient factors, MDT discussion, and shared decision-making.