Enfortumab vedotin plus pembrolizumab approved in Japan for urothelial carcinoma

Japan’s Ministry of Health, Labour, and Welfare (MHLW) has approved the combination of enfortumab vedotin-ejfv (EV, Padcev) and pembrolizumab (Keytruda) for the first-line treatment of adult patients with radically unresectable urothelial carcinoma, Astellas Pharma announced in a news release.¹

The approval was supported by findings from the phase 3 EV-302 trial.

According to the company, this marks the first combination treatment regimen approved in Japan to offer an alternative to platinum-containing chemotherapy for this patient population. The combination was previously granted a priority review designation from the MHLW.
"Today's approval by Japan's MHLW expands the benefits of treatment with enfortumab vedotin in combination with pembrolizumab to patients living with radically unresectable urothelial carcinoma in Japan,” said Ahsan Arozullah, MD, MPH, senior vice president and head of oncology development at Astellas, in the news release.¹ “These patients will now have an alternative to platinum-containing chemotherapy to treat this devastating disease, helping to improve patient outcomes, extend lives, and give further hope to the patients and families that we serve."

The approval by the MHLW was supported by findings 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/pembrolizumab 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 objective 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.

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. Patients were eligible for enrollment in the trial regardless of eligibility for cisplatin-based chemotherapy or PD-L1 status. 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

In August 2024, the European Commission granted approval to EV plus pembrolizumab in the European Union for patients with unresectable or metastatic urothelial cancer who are eligible for platinum-containing chemotherapy. The US FDA also approved the combination in December 2023 for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma.

References

1. Japan's Ministry of Health, Labour and Welfare approves PADCEV (enfortumab vedotin) with KEYTRUDA (pembrolizumab) for first-line treatment of radically unresectable urothelial carcinoma. News release. Astellas Pharma Inc. Published online and accessed September 24, 2024. https://www.astellas.com/en/news/29451

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 July 26, 2024. Accessed September 24, 2024. https://clinicaltrials.gov/study/NCT04223856