EV plus pembrolizumab approved in China for advanced urothelial carcinoma

China’s National Medical Products Administration (NMPA) has approved the combination of enfortumab vedotin-ejfv (EV; Padcev) and pembrolizumab (Keytruda) for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma.¹

The combination was approved in the US in December 2023.

"The current first-line treatment strategy for advanced urothelial carcinoma in China is platinum-based chemotherapy, with very limited clinical options available,” said Huang Jian, lead primary investigator of the EV-302 study in China, chairman of the Urology Subcommittee of the Chinese Medical Association, professor in the department of urology at Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China, in a news release.¹ “The approval of enfortumab vedotin in combination with pembrolizumab represents the first treatment regimen in the past 20-30 years that has shown superiority over platinum-based chemotherapy in the entire population. We hope that this combination could become the future standard of care treatment."

The NMPA’s approval was supported by data from the phase 3 EV-302 trial (KEYNOTE-A39 trial; NCT04223856), in which the combination of EV plus pembrolizumab significantly extended overall survival (OS) and progression-free survival (PFS) vs platinum-based chemotherapy (gemcitabine plus cisplatin or carboplatin) in patients with previously untreated locally advanced or metastatic urothelial carcinoma.²

Specifically, at a median follow-up of 17.2 months, treatment with EV plus pembrolizumab resulted in a 53% lower risk of death vs chemotherapy. Patients in the combination arm demonstrated a median OS of 31.5 months (95% CI, 25.4-NR) compared with 16.1 months (95% CI, 13.9-18.3) among patients treated with chemotherapy (HR, 0.47; 95% CI, 0.38 to 0.58; P < .001).

Additionally, the median PFS was 12.5 months with EV/pembro vs 6.3 months with chemotherapy, translating to a 55% lower risk of disease progression or death with the combination (HR, 0.45; 95% CI, 0.38 to 0.54; P < .001).

The combination of EV plus pembrolizumab also demonstrated significant improvements on the trial’s secondary end points of overall response rate (ORR) and duration of response (DOR). In the combination arm, the confirmed ORR by blinded independent central review was 67.7% (95% CI, 63.1%-72.1%), vs 44.4% (95% CI, 39.7%-49.2%) in the chemotherapy arm (P < .001). At the time of data analysis, the median DOR had not yet been reached in the combination arm; in the chemotherapy arm, the median DOR was 7 months.

Additionally, the median time to pain progression was 14.2 months in the EV/pembro arm and 10.0 months in the chemotherapy arm. However, the difference between the 2 arms did not reach statistical significance (HR, 0.92; 95% CI, 0.72 to 1.17; P = .48)

The safety profile for the combination was consistent with previously reported safety findings from the phase 1/2 EV-103 trial (NCT03288545) in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma. In EV-302, treatment-related adverse events of grade 3 or higher were experienced by 55.9% of patients in the combination arm and 69.5% of those in the chemotherapy arm.

In total, the open-label EV-302 trial enrolled 886 patients with previously untreated locally advanced or metastatic urothelial carcinoma. The median age of participants was 69 years (range, 22-91).

Those included in the trial were randomly assigned 1:1 to receive EV plus pembrolizumab (n = 442) or to chemotherapy (n = 444). Patients in the EV plus pembrolizumab cohort received a median of 12 cycles (range, 1-46) of treatment vs 6 cycles (range, 1-6) in the chemotherapy cohort.

The dual primary end points for the trial were PFS per blinded independent central review and OS. Secondary outcome measures included ORR, DOR, time to pain progression, and the incidence of adverse events.

The EV-302 trial remains ongoing to assess long-term outcomes. Final completion of the trial is anticipated for November 2027.³

EV plus pembrolizumab was approved last year in the European Union, Canada, and Japan. The combination was granted approval in the US in December 2023 for patients with locally advanced or metastatic urothelial carcinoma.

References

1. China's National Medical Products Administration (NMPA) approves PADCEV in combination with KEYTRUDA (pembrolizumab) for the treatment of advanced bladder cancer. News release. Astellas Pharma Inc. Published online and accessed January 8, 2025. https://www.prnewswire.com/news-releases/chinas-national-medical-products-administration-nmpa-approves-padcev-in-combination-with-keytruda-pembrolizumab-for-the-treatment-of-advanced-bladder-cancer-302345641.html

2. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial carcinoma. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117

3. Enfortumab vedotin and pembrolizumab vs. chemotherapy alone in untreated locally advanced or metastatic urothelial cancer (EV-302). ClinicalTrials.gov. Last updated September 27, 2024. Accessed January 8, 2025. https://clinicaltrials.gov/study/NCT04223856