# EV-302: enfortumab vedotin plus pembrolizumab replaces chemotherapy as first treatment for advanced bladder cancer

Source: https://onco.cc/key-papers/paper-ev-302-nejm-2024/  
OnCo record `paper-ev-302-nejm-2024` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Combining the Nectin-4 antibody-drug conjugate enfortumab vedotin with pembrolizumab nearly doubled survival compared with platinum chemotherapy in advanced urothelial cancer, the biggest advance in this disease in 40 years.

## Summary

Open-label phase 3 trial of 886 patients with untreated locally advanced or metastatic urothelial carcinoma, eligible for cisplatin or carboplatin, randomised to enfortumab vedotin plus pembrolizumab or gemcitabine plus platinum. Dual primary endpoints were PFS by blinded review and OS.

Median PFS was 12.5 vs 6.3 months (HR 0.45) and median OS 31.5 vs 16.1 months (HR 0.47), with benefit regardless of cisplatin eligibility or PD-L1 expression. It displaced platinum chemotherapy as first-line standard of care, the first regimen to do so since the 1980s, and is the first ADC plus checkpoint inhibitor combination to become a first-line standard in any cancer.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: New England Journal of Medicine
- Year: 2024
- DOI: 10.1056/NEJMoa2312117
- Authors: Powles T, Valderrama BP, Gupta S, et al.
- Findings: Median PFS 12.5 vs 6.3 months; HR 0.45 (95% CI 0.38-0.54).; Median overall survival 31.5 vs 16.1 months; HR 0.47 (95% CI 0.38-0.58).; Objective response 67.7% vs 44.4%; complete response 29.1% vs 12.5%.; Benefit consistent in cisplatin-eligible and -ineligible patients and in PD-L1 high and low tumours.; Grade 3 or higher treatment-related adverse events 55.9% vs 69.5%; skin reactions, peripheral neuropathy and hyperglycaemia were the characteristic toxicities of enfortumab vedotin.
- What it means: Almost every patient newly diagnosed with advanced bladder or urothelial cancer should now be offered enfortumab vedotin plus pembrolizumab rather than chemotherapy, with median survival extended from about 16 months to over two and a half years. Neuropathy and skin toxicity need monitoring and dose adjustment, and patients with severe diabetes or pre-existing neuropathy need care. Platinum chemotherapy remains an option for those who cannot receive the combination.
- Caveats: Open-label; PFS by blinded review.; Only about 30% of chemotherapy patients received maintenance avelumab, which is standard, so the control arm may have underperformed.; Peripheral neuropathy is cumulative and often persistent, affecting quality of life in long survivors.; Very high cost; access outside high-income countries is limited.

## Sources

- NEJM 2024: https://doi.org/10.1056/NEJMoa2312117
- ClinicalTrials.gov NCT04223856: https://clinicaltrials.gov/study/NCT04223856

## Connected records

- cancers: [Bladder & urothelial cancer](https://onco.cc/cancers/urothelial/), [Muscle-invasive and advanced bladder cancer](https://onco.cc/cancers/muscle-invasive-bladder-cancer/)
- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/)
- targets: [Nectin-4](https://onco.cc/targets/nectin4/), [PD-1](https://onco.cc/targets/pd1/)
- drugs: [Enfortumab vedotin](https://onco.cc/drugs/enfortumab-vedotin/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- companies: [Astellas](https://onco.cc/companies/astellas/), [Merck & Co. (MSD)](https://onco.cc/companies/merck/), [Pfizer (incl. Seagen)](https://onco.cc/companies/pfizer/)
- terms: [Lines of therapy](https://onco.cc/terms/first-line/), [Objective response rate (ORR)](https://onco.cc/terms/orr/), [Overall survival (OS)](https://onco.cc/terms/os/), [Payload (ADC)](https://onco.cc/terms/payload/), [Progression-free survival (PFS)](https://onco.cc/terms/pfs/), [Standard of care](https://onco.cc/terms/standard-of-care/)
- trials: [EV-302 / KEYNOTE-A39](https://onco.cc/trials/ev-302/)
- people: [Jonathan E. Rosenberg](https://onco.cc/people/jonathan-rosenberg/), [Sang Joon Shin](https://onco.cc/people/shin-sang-joon/), [Shilpa Gupta](https://onco.cc/people/shilpa-gupta/), [Thomas Powles](https://onco.cc/people/thomas-powles/)
- bottlenecks: [Prices and value](https://onco.cc/bottlenecks/b-drug-pricing/), [Too many combinations to test](https://onco.cc/bottlenecks/b-combination-space/), [Toxicity and quality of life are undervalued](https://onco.cc/bottlenecks/b-toxicity-qol/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)
- ideas: [Bladder preservation for MIBC after perioperative EV + pembrolizumab complete response](https://onco.cc/ideas/idea-bladder-preservation-mibc/)

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