EMA Validates Application for First-Line Enfortumab Vedotin Plus Pembrolizumab in Urothelial Cancer

Roger Dansey, MD

The European Medicines Agency (EMA) has validated a type II application seeking approval of enfortumab vedotin (Padcev) in combination with pembrolizumab (Keytruda) in the frontline treatment of adult patients with previously untreated locally advanced or metastatic urothelial cancer.¹

The application was supported by results from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), in which treatment-naive patients who received the doublet experienced statistically significant and clinically meaningful improvements in overall survival (OS) and progression-free survival (PFS) vs platinum-containing chemotherapy. Primary results were reported at the 2023 ESMO Congress.²

At a median follow-up of 17.2 months, the median overall survival (OS) with the combination was 31.5 months (95% CI, 25.4-not reached [NR]) vs 16.1 months (95% CI, 13.9-18.3) with chemotherapy alone (HR, 0.47; 95% CI, 0.38-0.58; P < .00001). The combination regimen led to a median PFS of 12.5 months (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5) with chemotherapy (HR, 0.45; 95%, 0.38-0.54; P < .00001). OS and PFS benefits were observed across prespecified subgroups defined by cisplatin eligibility, PD-L1 status, and visceral metastases.

“The EV-302 pivotal trial demonstrated the benefits of combining Padcev with pembrolizumab for advanced bladder cancer,” Roger Dansey, MD, the chief development officer of Oncology at Pfizer, stated in the press release.¹ “Patients with bladder cancer in Europe face poor outcomes at the advanced stage, and innovative therapies that extend survival are needed. This acceptance brings us closer to our mission: delivering breakthroughs that help address the unmet needs of patients and reshape the advanced urothelial cancer treatment landscape.”

The open-label, randomized study enrolled 886 patients with previously untreated locally advanced or metastatic urothelial cancer who were eligible for platinum-containing chemotherapy, enfortumab vedotin, and pembrolizumab. Eligibility criteria required patients to be naive to PD-(L)1 inhibitors, have a glomerular filtration rate of at least 30 mL/min, and have an ECOG performance status of 2 or less. Notably, patients were eligible for enrollment regardless of PD-L1 status.^1,2

Patients were randomly assigned 1:1 to receive either 1.25 mg/kg of intravenous (IV) enfortumab vedotin on days 1 and 8 plus 200 mg of IV pembrolizumab on day 1 of a 3-week cycle (n = 442) or gemcitabine plus cisplatin or carboplatin for a maximum of 6 cycles (n = 444). A maximum of 35 cycles of pembrolizumab was allowed.²

The dual primary end points of the trial were OS and PFS per blinded independent central review (BICR) and by RECIST v1.1 criteria. Select secondary end points included overall response rate (ORR) per BICR and RECIST v1.1 criteria and safety.

Additional data presented at the 2023 ESMO Congress indicated that enfortumab vedotin plus pembrolizumab elicited an ORR of 67.7% (95% CI, 63.1%-72.1%), which was comprised of a complete response rate of 29.1% and a partial response rate of 38.7%; 18.8% of patients achieved stable disease (SD), 8.7% experienced progressive disease (PD), and 4.8% were not response evaluable. The median duration of response (DOR) with the doublet was NR (95% CI, 20.2-NR). Chemotherapy resulted in an ORR of 44.4% (95% CI, 39.7%-49.2%), which consisted of a 12.5% CR rate and a 32.0% PR rate; the SD and PD rates were 33.8% and 13.6%, respectively, and 8.2% of patients were not evaluable. The median DOR in this arm was 7.0 months (95% CI, 6.2-10.2).

Regarding safety, grade 3 or greater treatment-related adverse effects (TRAEs) were seen in 55.9% of patients who received the combination and 69.5% of those who were given chemotherapy. Serious TRAEs occurred in 27.7% vs 19.6% of patients in these respective arms.

In December 2023, the FDA approved the combination for patients with locally advanced or metastatic urothelial cancer based on primary results from EV-302.3 The regimen had previously received accelerated approval in April 2023 for use in patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin-containing chemotherapy based on previously reported data from cohorts A and K of the phase 1b/2 EV-103/KEYNOTE-869 trial (NCT03288545).⁴

The EV-302 and EV-103 trials are ongoing, and the combination is being evaluated across multiple stages of urothelial cancer and other solid tumors as part of the phase 3 EV-304/KEYNOTE-B15 (NCT04700124) and EV-303/KEYNOTE-905 (NCT03924895) trials in muscle-invasive bladder cancer.¹

“Patients in Europe need better treatment options for advanced-stage urothelial cancer, and we look forward to working with the EMA on their review of the combination of enfortumab vedotin and pembrolizumab,” said Ahsan Arozullah, MD, MPH, the senior vice president and head of Oncology Development at Astellas, in the press release. “If approved, the combination would be the first alternative to a chemotherapy-based treatment for this patient population. This milestone is another opportunity to affirm our commitment to helping patients with advanced urothelial cancer live longer.”

References

1. European Medicines Agency validates type II variation application for PADCEVTM (enfortumab vedotin) with KEYTRUDA® (pembrolizumab) for first-line treatment of advanced bladder cancer. News release. Astellas. January 29, 2024. Accessed January 30, 2024. https://www.astellas.com/en/news/28801
2. Powles TB, Perez Valderrama B, 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 grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. FDA. April 3, 2023. Accessed January 30, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
4. FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. FDA. April 3, 2023. Accessed January 30, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic