EV-302: Long-term subgroup analysis from the phase 3 global study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC).
Abstract
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Background: EV-302/KEYNOTE-A39 (NCT04223856) demonstrated superior efficacy of first-line (1L) EV+P vs chemo and established EV+P as the standard of care (SOC). EV+P is included in global treatment guidelines for patients (pts) with untreated la/mUC. After ≈2.5 years of median follow-up, the benefit of EV+P was sustained; median OS was maintained for > 2.5 years. We present long-term efficacy and safety analyses in the following prespecified subgroups: primary disease site of origin (upper and lower tracts), lymph node (LN)–only disease, and presence of liver metastases (mets) (present and absent).
Methods: Pts with previously untreated la/mUC were randomized 1:1 to receive EV (1.25 mg/kg; Days 1 and 8; IV) and P (200 mg; Day 1; IV) or chemo (gemcitabine with cisplatin or carboplatin) every 3 wk. Primary endpoints were progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS). A genAI tool (01/09/25; Pfizer; GPT-4o) developed the 1st draft; authors assume content responsibility.
Results: Pts (N = 886) were randomized to receive EV+P (n = 442) or chemo (n = 444) and were analyzed according to the subgroups shown in the Table. At data cutoff (Aug 8, 2024), median follow-up was 29.1 mo (95% CI, 28.5-29.9). PFS by BICR, OS, duration of response, and objective response rate continued to demonstrate sustained benefit of EV+P vs chemo across prespecified subgroups after long-term follow-up (Table). For EV+P, treatment-related adverse events (TRAEs) occurred in 96.0-98.5% and Grade ≥3 TRAEs in 53.4-60.7% of pts across prespecified subgroups, generally consistent with previous reports.
Conclusions: EV+P continues to demonstrate superior long-term efficacy vs chemo in key subgroups with both favorable and poor prognoses. There were no new safety signals, and AE rates in prespecified subgroups were consistent with the overall population after an additional year of follow-up. This reinforces EV+P as the SOC for the 1L treatment of pts with la/mUC. Clinical trial information: NCT04223856.
By: Giandomenico Roviello, MD, Phd Associate Profess | University of florence
To the Editor,
We read with great interest the recent Viewpoint by Dr. Satya Das, which insightfully outlines the evolving landscape of oncology drug development and the emerging promise of antibody-drug conjugates (ADCs). While we agree that ADCs have the potential to reshape therapeutic strategies across several tumor types, it is crucial to critically examine their limitations—particularly when juxtaposed with immune checkpoint inhibitors (ICIs).
A timely example comes from the EV-302 trial, which investigated the combination of the ADC enfortumab vedotin and the anti–PD-1 agent pembrolizumab in untreated patients with advanced urothelial carcinoma. The study reported impressive results: a median overall survival of 31.5 months versus 16.1 months with chemotherapy, a median PFS of 12.5 months, and an objective response rate (ORR) of 68%, including complete responses in nearly 30% of patients. Notably, clinical benefit was observed independently of PD-L1 expression and visceral disease status.
However, these outcomes were achieved through a synergistic approach, combining the cytotoxic potency of the ADC with the long-term immunologic engagement of the ICI3. On their own, ADCs are limited by their dependency on target antigen expression and its stability over time. Tumor heterogeneity or antigen downregulation can lead to therapeutic escape. Moreover, despite their targeted delivery, ADCs frequently cause systemic toxicities, including myelosuppression, neuropathy, and interstitial lung disease, sometimes rivalling those of traditional chemotherapy.
Perhaps most critically, ADCs do not elicit immunologic memory. Unlike ICIs—which, in a subset of responders, can produce durable and potentially curative responses—ADCs lack the ability to modify the tumor microenvironment or generate long-term immune surveillance.
Therefore, while ADCs represent an important advance, the EV-302 data reinforce the notion that their optimal use may lie in strategic combination with immunotherapies, rather than in therapeutic isolation. Future development should focus on integrative approaches, leveraging the strengths of both modalities to maximize clinical outcomes.
We read with great interest the recent Viewpoint by Dr. Satya Das, which insightfully outlines the evolving landscape of oncology drug development and the emerging promise of antibody-drug conjugates (ADCs). While we agree that ADCs have the potential to reshape therapeutic strategies across several tumor types, it is crucial to critically examine their limitations—particularly when juxtaposed with immune checkpoint inhibitors (ICIs).
A timely example comes from the EV-302 trial, which investigated the combination of the ADC enfortumab vedotin and the anti–PD-1 agent pembrolizumab in untreated patients with advanced urothelial carcinoma. The study reported impressive results: a median overall survival of 31.5 months versus 16.1 months with chemotherapy, a median PFS of 12.5 months, and an objective response rate (ORR) of 68%, including complete responses in nearly 30% of patients. Notably, clinical benefit was observed independently of PD-L1 expression and visceral disease status.
However, these outcomes were achieved through a synergistic approach, combining the cytotoxic potency of the ADC with the long-term immunologic engagement of the ICI3. On their own, ADCs are limited by their dependency on target antigen expression and its stability over time. Tumor heterogeneity or antigen downregulation can lead to therapeutic escape. Moreover, despite their targeted delivery, ADCs frequently cause systemic toxicities, including myelosuppression, neuropathy, and interstitial lung disease, sometimes rivalling those of traditional chemotherapy.
Perhaps most critically, ADCs do not elicit immunologic memory. Unlike ICIs—which, in a subset of responders, can produce durable and potentially curative responses—ADCs lack the ability to modify the tumor microenvironment or generate long-term immune surveillance.
Therefore, while ADCs represent an important advance, the EV-302 data reinforce the notion that their optimal use may lie in strategic combination with immunotherapies, rather than in therapeutic isolation. Future development should focus on integrative approaches, leveraging the strengths of both modalities to maximize clinical outcomes.
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