Japan's Ministry of Health, Labour and Welfare (MHLW) has approved enfortumab vedotin-ejfv (Padcev) in combination with pembrolizumab (Keytruda) as a first-line treatment for adult patients with radically unresectable urothelial carcinoma. This approval marks a significant advancement in the treatment landscape for this aggressive cancer, offering an alternative to platinum-containing chemotherapy.
The approval was primarily supported by the results of the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), a study that evaluated the efficacy and safety of the combination therapy against platinum-containing chemotherapy (cisplatin or carboplatin plus gemcitabine) in patients with previously untreated locally advanced or metastatic urothelial carcinoma. The findings, published in the New England Journal of Medicine, demonstrated a statistically significant improvement in both progression-free survival (PFS) and overall survival (OS).
Significant Survival Benefits
The study data revealed a progression-free survival (PFS) benefit of 12.5 months (95% CI, 10.4-16.6) with the enfortumab vedotin combination therapy compared to 6.3 months (95% CI, 6.2-6.5) with chemotherapy (HR, 0.45; 95% CI, 0.38-0.54; P < .001). Additionally, an overall survival (OS) benefit was reported at 31.5 months (95% CI, 25.4-not reached) with enfortumab vedotin plus pembrolizumab versus 16.1 months (95% CI, 13.9-18.3) with platinum-containing chemotherapy plus gemcitabine (HR, 0.47; 95% CI, 0.38-0.58; P < .001).
Dr. Ahsan Arozullah, Senior Vice President and Head of Oncology Development at Astellas, emphasized the importance of this approval, stating, "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. 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."
Trial Details and Outcomes
The international, open-label phase 3 EV-302 trial randomly assigned 866 patients 1:1 to receive either enfortumab vedotin in combination with pembrolizumab (n = 442) or platinum-based chemotherapy plus gemcitabine (n = 444). Patients assigned to the combination arm received 3-week cycles of intravenous enfortumab vedotin at 1.25 mg/kg on days 1 and 8 plus intravenous pembrolizumab at 200 mg on day 1. The chemotherapy arm received intravenous gemcitabine at 1000 mg/m2 plus intravenous cisplatin at 70 mg/m2 or carboplatin at area under the curve of 4.5 to 5 mg/mL/minute.
The dual primary end points for the study were PFS per RECIST v 1.1 criteria and OS. Secondary end points included overall response rate (ORR), duration of response (DOR), time to pain progression, and safety.
Additional findings included an ORR benefit in the combination therapy at 67.7% (95% CI, 63.1%-72.1%) vs 44.4% (95% CI, 39.7%-49.2%) in the chemotherapy arm (P < .001). Complete responses were reported in 29.1% and 12.5% of patients in each cohort, respectively.
Estimated 12-month OS rates were 78.2% (95% CI, 73.9%-81.9%) and 61.4% (95% CI, 56.6%-65.9%) in each cohort, respectively. Median DOR was not reached in the combination therapy arm, with 67.3% and 59.6% having ongoing response rates at 12 and 18 months; median DOR was 7 months with chemotherapy, with 35.2% and 19.3% experiencing ongoing responses at 12 and 18 months, respectively.
Safety Profile
Any-grade treatment-related adverse effects (TRAEs) were reported in 97.0% and 95.6% of the combination and chemotherapy cohorts. The grade 3 or higher TRAE rate was 55.9% and 69.5% in the respective arms. Dose reductions due to TRAEs occurred in 40.7% and 37.9% of each cohort, with 4 deaths in the combination therapy arm related to individual instances of multiple organ dysfunction syndrome, immune-mediated lung disease, diarrhea, and asthenia.
Global Regulatory Landscape
Based on the phase 3 EV-302 findings, the combination of enfortumab vedotin plus pembrolizumab was approved by the FDA in December 2023 for use in this patient population. Additionally, the combination therapy gained European approval as a treatment for unresectable or metastatic urothelial carcinoma in August 2024.
