Japanese Approval Sought for Enfortumab Vedotin Plus Pembrolizumab in Urothelial Cancer

Ahsan Arozullah, MD, MPH

A supplemental new drug application (sNDA) seeking the approval of enfortumab vedotin-ejfv (Padcev) combined with pembrolizumab (Keytruda) in the first-line treatment of adult patients with locally advanced or metastatic urothelial cancer has been submitted to Japan’s Ministry of Health, Labour, and Welfare (MHLW).¹

The sNDA is based on findings from the phase 3 EV-302/KEYNOTE-A39 study (NCT04223856) in which the doublet (n = 442) resulted in a 53% reduction in the risk of death vs standard-of-care chemotherapy (n = 444; HR, 0.47; 95% CI, 0.38-0.58; P < .00001).² The median overall survival (OS) experienced with enfortumab vedotin plus pembrolizumab was 31.5 months (95% CI, 25.4-not reached [NR]) vs 16.1 months (95% CI, 13.9-18.3) with chemotherapy. The 18-month OS rates were 69.5% and 44.7%, respectively.

Moreover, those who received the doublet experienced a 55% reduction in the risk of disease progression or death vs those given chemotherapy. The median progression-free survival (PFS) in the combination arm was 12.5 months (95% CI, 10.4-16.6) by blinded independent central review (BICR) vs 6.3 months (95% CI, 6.2-6.5) in the chemotherapy arm (HR, 0.45; 95% CI, 0.38-0.54; P < .00001). The 18-month PFS rates were 43.9% and 11.7%, respectively.

“The initiation of MHLW’s review of our application for enfortumab vedotin and pembrolizumab is encouraging, as we are working to improve upon current treatment options for patients in Japan with advanced stage urothelial cancer, who face poor outcomes at the advanced stage,” Ahsan Arozullah, MD, MPH, senior vice president and head of the Oncology Department at Astellas Pharma, Inc., stated in a press release.¹ “This submission brings us one step closer to the possibility of offering these patients a treatment that demonstrated improved survival and slowed disease progression compared to platinum-containing chemotherapy.”

EV-302/KEYNOTE-A39 enrolled patients with previously untreated locally advanced or metastatic urothelial carcinoma who were able to receive platinum-based chemotherapy, enfortumab vedotin, and pembrolizumab, and who had not had prior exposure to a PD-(L)1 inhibitor.² Patients were required to have a glomerular filtration rate of at least 30 mL/min and an ECOG performance status ranging from 0 to 2.

A total of 886 patients were randomly assigned 1:1 to receive intravenous (IV) enfortumab vedotin at 1.25 mg/kg on days 1 and 8 plus 200 mg of IV pembrolizumab on day 1 of every 3-week cycle or chemotherapy comprised of gemcitabine paired with cisplatin or carboplatin for up to 6 cycles. The maximum number of immunotherapy cycles was 35.

OS and PFS by BICR served as the trial’s primary end points. Objective response rate (ORR) by RECIST v1.1 criteria and BICR and investigator assessment and safety.

Within those who were cisplatin eligible, patients who received enfortumab vedotin plus pembrolizumab (n = 240) experienced a median OS of 31.5 months (95% CI, 25.4-NR) vs 18.4 months (95% CI, 16.4-27.5) with chemotherapy (n = 242; HR, 0.53; 95% CI, 0.39-0.72). In the cisplatin-ineligible patients, the median OS with the doublet was NR (95% CI, 20.7-NR) vs 12.7 months (95% CI, 11.4-15.5) with chemotherapy (HR, 0.43; 95% CI, 0.31-0.59).

OS benefit with enfortumab vedotin plus pembrolizumab over chemotherapy was also consistent irrespective of PD-L1 expression. In those with a PD-L1 combined positive score (CPS) of 10 or higher, enfortumab vedotin/pembrolizumab resulted in a median OS of 31.5 months (95% CI, 25.4-NR) vs 16.6 months (95% CI, 13.1-20.6) with chemotherapy (HR, 0.49; 95% CI, 0.37-0.66). In those with a PD-L1 CPS of less than 10, the doublet resulted in a median OS of NR (95% CI, 22.3-NR) vs 15.5 months (95% CI, 12.9-17.7) with chemotherapy (HR, 0.44; 95% CI, 0.31-0.61).

Enfortumab vedotin plus pembrolizumab induced a confirmed ORR of 67.7% (95% CI, 63.1%-72.1%) vs 44.4% (95% CI, 39.7%-49.2%) with chemotherapy (P < .00001). In the doublet arm, the ORR was comprised of a complete response rate of 29.1% and a partial response rate of 38.7%; 18.8% had stable disease, 8.7% had disease progression, and 4.8% were not evaluable for response. The median duration of response with the doublet was NR (95% CI, 20.2-NR) vs 7.0 months (95% CI, 6.2-10.2).

The incidence of grade 3 or higher adverse effects (AEs) was 56% with enfortumab vedotin plus pembrolizumab vs 70% with chemotherapy. The most common grade 3 or higher AEs reported in these respective arms were peripheral sensory neuropathy (3.6% vs 0%), pruritus (1.1% vs 0%), alopecia (0.5% vs 0.2%), maculopapular rash (7.7% vs 0%), fatigue (3.0% vs 4.2%), diarrhea (3.6% vs 0.7%), decreased appetite (1.1% vs 1.4%), nausea (1.1% vs 2.8%), anemia (3.4% vs 31.4%), neutropenia (4.8% vs 30.0%), and thrombocytopenia (0.5% vs 19.4%).

In December 2023, the FDA approved enfortumab vedotin plus pembrolizumab for use in patients with locally advanced or metastatic urothelial carcinoma.³ In January 2024, the European Medicines Agency validated a type II application seeking approval of the combination in the same indication.⁴ Both decisions were based on findings from EV-302/KEYNOTE-A39.

References

1. Astellas submits supplemental new drug application in Japan for Padcev (enfortumab vedotin [genetic recombination]) with Keytruda (pembrolizumab [genetical recombination]) for first-line treatment of advanced bladder cancer. News release. Astellas Pharma, Inc. January 31, 2024. Accessed February 1, 2024. https://www.astellas.com/en/news/28851
2. Powles TB, Valderrama BP, Gupta S, et al. EV-302/KEYNOTE-A39: open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Ann Oncol. 2023;34(suppl 2):S1340. doi:10.1016/j.annonc.2023.10.106
3. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed February 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer
4. European Medicines Agency validates type II variation application for Padcev (enfortumab vedotin) with Keytruda (pembrolizumab) for first-line treatment of advanced bladder cancer. News release. Astellas. January 29, 2024. Accessed February 1, 2024. https://www.astellas.com/en/news/28801