New England Journal of Medicine MARCH 07, 2024

Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer (EV-302/KEYNOTE-A39)

Thomas Powles, Yohann Loriot, Michiel S. van der Heijden, et al.

Bottom Line

The EV-302 phase 3 trial demonstrated that the combination of enfortumab vedotin and pembrolizumab significantly improves progression-free and overall survival compared to platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma.

Key Findings

1. The combination of enfortumab vedotin and pembrolizumab reduced the risk of death by 53% compared to standard platinum-based chemotherapy (hazard ratio 0.47, P<0.001) at the primary analysis.

2. Median overall survival was significantly longer with the combination therapy (31.5 months) compared to chemotherapy (16.1 months).

3. Median progression-free survival was improved with the combination therapy (12.5 months) compared to chemotherapy (6.3 months), representing a 55% reduction in the risk of disease progression or death.

4. The confirmed objective response rate was markedly higher with the combination regimen at 67.7% (with 29.1% achieving a complete response) compared to 44.4% (with 12.5% achieving a complete response) in the chemotherapy arm.

5. Updated analysis with a median follow-up of 29.1 months reinforced these benefits, with a median overall survival now reaching 34 months and a consistent hazard ratio of 0.51.

Study Design

Design

RCT

Open-Label

Sample

886

Patients

Duration

29.1 mo

Median

Setting

Multicenter, global

Population Patients aged 18 years or older with previously untreated locally advanced or metastatic urothelial carcinoma and an ECOG performance status of 2 or less.

Intervention Enfortumab vedotin (1.25 mg/kg) on days 1 and 8 plus pembrolizumab (200 mg) on day 1 of 3-week cycles.

Comparator Gemcitabine plus either cisplatin or carboplatin for a maximum of 6 cycles.

Outcome Overall survival and progression-free survival (as assessed by blinded independent central review).

Study Limitations

• The trial was open-label, which may introduce observer bias, particularly in the assessment of subjective endpoints.

• While the study spanned multiple countries, the majority of the population was White, potentially limiting the global generalizability of the results across more diverse ethnic groups.

• The study required patients to have a performance status of 2 or less, excluding those with higher burden of disease or poorer performance status who are commonly seen in clinical practice.

• The management of specific adverse events, such as skin toxicity and peripheral neuropathy, requires focused clinical expertise and may impact long-term treatment adherence.

Clinical Significance

This study establishes enfortumab vedotin plus pembrolizumab as the new global standard of care for first-line treatment of locally advanced or metastatic urothelial carcinoma, effectively displacing platinum-based chemotherapy, which had been the standard for over four decades.

Historical Context

For over 40 years, platinum-based combination chemotherapy (gemcitabine with cisplatin or carboplatin) served as the primary treatment for advanced urothelial carcinoma. Despite advancements like maintenance avelumab, survival outcomes remained suboptimal, prompting an urgent need for more effective systemic therapies. The success of the EV-302 trial represents a paradigm shift in the management of this malignancy.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the mechanism of action of Enfortumab Vedotin, and why is Nectin-4 an ideal target for this antibody-drug conjugate in patients with urothelial carcinoma?

Key Response

Enfortumab Vedotin (EV) is an antibody-drug conjugate (ADC) targeting Nectin-4, a cell surface protein highly expressed in urothelial cancers but limited in normal tissue. The ADC delivers monomethyl auristatin E (MMAE), a microtubule-disrupting agent, directly into the cell, leading to cell cycle arrest and apoptosis. Understanding ADCs is foundational for modern oncology pharmacology.

Resident

In light of the EV-302 trial results, what are the most critical adverse events specific to the EV-Pembrolizumab combination that a clinician must monitor, compared to traditional platinum-based chemotherapy?

Key Response

While traditional chemotherapy is limited by myelosuppression and nephrotoxicity, EV-Pembrolizumab introduces unique toxicities: EV is associated with severe skin reactions (including Stevens-Johnson syndrome), peripheral neuropathy, and hyperglycemia, while Pembrolizumab adds the risk of immune-related adverse events (irAEs) like pneumonitis and colitis. Early recognition of these is vital for managing patients on this new standard of care.

Fellow

How does the survival benefit observed in EV-302 impact the treatment paradigm for patients who were previously considered 'cisplatin-ineligible,' and does PD-L1 status still play a role in frontline decision-making?

Key Response

EV-302 included both cisplatin-eligible and ineligible patients, showing a consistent benefit (Hazard Ratio for OS: 0.47). This trial effectively renders the 'cisplatin-eligibility' distinction less relevant for first-line therapy selection, as EV-Pembro outperformed platinum-based therapy regardless of cisplatin fitness or PD-L1 expression levels, displacing the previous dependence on PD-L1 testing for ICI-monotherapy eligibility.

Attending

With EV-Pembrolizumab moving to the first-line setting, how should we re-evaluate the sequencing of therapies upon progression, specifically regarding the utility of platinum-based chemotherapy and the role of Sacituzumab Govitecan?

Key Response

Since EV-302 moves both an ADC and an ICI to the first line, the traditional second-line options are exhausted early. Platinum-based chemotherapy, previously the first-line standard, now becomes a subsequent-line option. Clinicians must now determine if the 'platinum-free interval' impacts the efficacy of salvage chemotherapy and where newer ADCs like Sacituzumab Govitecan (targeting Trop-2) fit into the post-EV-Pembro landscape.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

From a trial design perspective, what are the implications of the unprecedented Hazard Ratio for Overall Survival (0.47) on the statistical power and ethical feasibility of future frontline trials seeking to challenge EV-Pembrolizumab?

Key Response

An OS HR of 0.47 is rare in solid tumors, creating a very high 'bar' for future experimental arms. This poses a challenge for drug developers, as future Phase 3 trials will require massive sample sizes or extremely long follow-up to demonstrate superiority or even non-inferiority against such a potent control arm, potentially shifting the research focus toward novel triplet combinations or biomarker-defined niches.

Journal Editor

Given that EV-302 was an open-label trial, what specific methodological safeguards were employed to prevent assessment bias for the primary endpoint of Progression-Free Survival (PFS), and how does the magnitude of the OS benefit mitigate concerns regarding the lack of blinding?

Key Response

Open-label trials are susceptible to investigator bias in tumor measurement. EV-302 utilized Blinded Independent Central Review (BICR) for PFS assessment to ensure objectivity. Furthermore, the objective nature of the Overall Survival endpoint (which cannot be influenced by investigator 'hope' or 'bias') confirms the PFS findings, providing the high level of evidence required for publication in a top-tier journal like NEJM.

Guideline Committee

How do the results of EV-302 necessitate a revision of the NCCN and EAU guidelines regarding 'Avelumab Maintenance' therapy, and should platinum-based chemotherapy remain a 'preferred' option for any specific patient subgroup?

Key Response

Current guidelines (e.g., NCCN) have already updated to list EV-Pembrolizumab as the Category 1 Preferred recommendation. The JAVELIN Bladder 100 paradigm (platinum followed by Avelumab) is now relegated to a secondary option for those who cannot receive EV or Pembrolizumab. The committee must decide if the OS benefit is so profound that platinum-based chemotherapy should no longer be considered an equivalent 'alternative' but rather a 'second-choice' therapy.

Clinical Landscape

Noteworthy Related Trials

2020

IMvigor130

n = 1,213 · Lancet

Tested

Atezolizumab plus platinum-based chemotherapy

Population

Untreated locally advanced or metastatic urothelial carcinoma

Comparator

Platinum-based chemotherapy alone

Endpoint

Progression-free survival and overall survival

Key result: The addition of atezolizumab to chemotherapy did not provide a statistically significant benefit in overall survival compared to chemotherapy alone in the intention-to-treat population.

2020

JAVELIN Bladder 100

n = 700 · NEJM

Tested

Avelumab maintenance therapy

Population

Patients with advanced urothelial carcinoma who had not progressed with first-line platinum-based chemotherapy

Comparator

Best supportive care

Endpoint

Overall survival

Key result: Avelumab as a first-line maintenance treatment significantly improved overall survival compared to best supportive care alone in patients with advanced urothelial carcinoma.

2021

KEYNOTE-361

n = 1,010 · JCO

Tested

Pembrolizumab plus platinum-based chemotherapy

Population

Untreated metastatic or locally advanced urothelial carcinoma

Comparator

Platinum-based chemotherapy alone

Endpoint

Overall survival and progression-free survival

Key result: Pembrolizumab plus chemotherapy did not meet the prespecified criteria for statistical significance in improving overall survival or progression-free survival compared with chemotherapy alone.

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