EV/pembrolizumab under review in China for advanced urothelial carcinoma

The China National Medical Products Administration (NMPA)’s Center for Drug Evaluation (CDE) has accepted a supplemental biologics license application (sBLA) for the combination of enfortumab vedotin-ejfv (Padcev; EV) and pembrolizumab (Keytruda) for the treatment of patients with previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC), according to a news release from Astellas Pharma.¹

At a median follow-up of 17.2 months, patients treated with EV/pembrolizumab demonstrated a median overall survival of 31.5 months, compared with 16.1 months among patients treated with chemotherapy.

"Locally advanced or metastatic urothelial cancer is a life-threatening condition in China with nearly half of those diagnosed succumbing to the disease. The CDE's acceptance of our sBLA for enfortumab vedotin and pembrolizumab brings us one step closer to delivering a much-needed, innovative new treatment option for this patient population,” said Ahsan Arozullah, MD, MPH, senior vice president and head of oncology development at Astellas, in the news release.¹

The sBLA is supported by findings from the phase 3 EV-302 trial (NCT04223856), which showed that treatment with EV plus pembrolizumab extended overall survival (OS) and progression-free survival (PFS) vs platinum-based chemotherapy in patients with la/mUC.²

Overall, the EV-302 trial met its dual primary end points of OS and PFS.

At a median follow-up of 17.2 months, treatment with EV plus pembrolizumab reduced the rate of death by 53% vs chemotherapy. Patients in the combination arm demonstrated a median OS of 31.5 months compared with 16.1 months among patients treated with chemotherapy (HR, 0.47; 95% CI, 0.38 to 0.58; P < .001).

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

Regarding the trial’s key secondary end points, the confirmed overall response rate (ORR) was 67.7% (95% CI, 63.1-72.1) in the EV/pembro arm, compared with 44.4% (95% CI, 39.7%-49.2%) in the chemotherapy arm (P < .001). The ORR in the EV/pembro cohort consisted of a complete response (CR) rate of 29.1%, vs a CR rate of 12.5% in the chemotherapy cohort.

The median duration of response was not reached in the combination arm and was 7.0 months in the chemotherapy arm. The median time to pain progression was 14.2 months among patients receiving EV/pembro vs 10.0 months among patients receiving chemotherapy, although the difference did not reach statistical significance (HR, 0.92; 95% CI, 0.72 to 1.17; P = .48).

Regarding safety, 55.9% of patients in the combination arm experienced treatment-related adverse events (TRAEs) of grade 3 or higher, vs 69.5% of patients in the chemotherapy group. TRAEs that led to a discontinuation of treatment occurred among 35% of patients receiving EV/pembro and 18.5% of patients receiving chemotherapy.

In total, the global, open-label EV-302 trial included 886 adult patients with previously untreated la/mUC. Patients were randomly assigned 1:1 to receive EV/pembro (n = 442) or chemotherapy (n = 444). Patients in the EV/pembro cohort received a median of 12 cycles (range, 1-46) of treatment vs 6 (range, 1-6) cycles in the chemotherapy cohort.
"In China, the recommended first-line treatment for advanced urothelial cancer is platinum-based chemotherapy, and there are currently no other treatments approved in the first-line setting. Given the efficacy brought by chemotherapy, alternate treatment options are extremely needed to extend survival benefits and potentially improve the prognosis of those patients. The results of the EV-302 study demonstrated that enfortumab vedotin in combination with pembrolizumab, as the first non-platinum first-line treatment, can achieve a clinically meaningful improvement in response rate, nearly double the median progression-free survival, and significantly improve the overall survival benefit of patients with locally advanced or metastatic urothelial cancer compared to chemotherapy,” said Guo Jun, MD, in the news release.¹ Jun is the principle investigator in China for the EV-302 trial, the director of the department of melanoma and urological oncology at Beijing Cancer Hospital, and an executive board member of the Chinese Society Of Clinical Oncology.

In addition to the sBLA for EV plus pembrolizumab, the NMPA is also currently reviewing EV as a treatment option for patients with la/mUC who have received prior treatment with a PD-1/L1 inhibitor and platinum-based chemotherapy.³

EV plus pembrolizumab was granted FDA approval in December 2023 for the treatment of patients with la/mUC.⁴ The treatment regimen is also currently under review for this patient population in Japan and the European Union.

References

1. China's National Medical Products Administration accepts Astellas and Pfizer's supplemental biologics license application for enfortumab vedotin with KEYTRUDA (pembrolizumab) for first-line treatment of advanced bladder cancer. News release. Astellas Pharma, Inc. Published online and accessed March 28, 2024. https://www.astellas.com/en/news/28961

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. Astellas and Seagen announce China’s National Medical Products Administration accepts Biologics License Application for enfortumab vedotin in certain patients with locally advanced or metastatic urothelial cancer. News release. March 10, 2023. Accessed March 28, 2024. https://www.astellas.com/en/news/27441

4. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. News release. US Food and Drug Administration. Published online December 15, 2023. Accessed March 28, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer