FDA approves enfortumab vedotin plus pembrolizumab for urothelial carcinoma

The FDA has approved enfortumab vedotin-ejfv (Padcev, Astellas Pharma) in combination with pembrolizumab (Keytruda, Merck) for the treatment of patients with locally advanced or metastatic urothelial cancer (UC).¹

Median PFS with the combination was 12.5 months, compared with 6.3 months among patients who received platinum-based chemotherapy.

The approval is supported by findings from the phase 3 EV-302 trial (NCT04223856), which showed that the combination led to significant improvements in overall survival (OS) and progression-free survival (PFS) compared with chemotherapy in this patient population.²

"Today's FDA approval represents a paradigm change in the treatment of advanced bladder cancer and provides hope to the thousands of Americans impacted by this aggressive disease. This achievement is notable, as it is the first regimen approved in advanced urothelial cancer that has demonstrated superiority to platinum chemotherapy, the gold standard of care for decades," said Ahsan Arozullah, MD, MPH, Senior Vice President and Head of Oncology Development at Astellas Pharma, in a news release on the approval.³

In total, the EV-302 trial enrolled 886 patients with locally advanced or metastatic UC who had not been previously treated with systemic therapy. Patients were randomly assigned 1:1 to receive enfortumab vedotin-ejfv with pembrolizumab (n = 442) or standard-of-care platinum-based chemotherapy consisting of gemcitabine plus either cisplatin or carboplatin (n = 444). The primary efficacy end points were OS and PFS based on blinded independent central review.⁴

At a median follow-up of 17.2 months, treatment with enfortumab vedotin plus pembrolizumab (EVP) reduced the risk of death by 53% vs treatment with chemotherapy. The median OS was 31.5 months (95% CI, 25.4-not estimable) in the EVP arm compared with 16.1 months (95% CI, 13.9-18.3) in the chemotherapy arm (HR, 0.47; 95% CI, 0.38-0.58; P < .00001). The OS benefit was observed regardless of whether patients in the control arm received cisplatin or carboplatin, and was not impacted by PD-L1 status or existence of visceral metastases.

Median PFS with the combination was 12.5 months (95% CI: 10.4, 16.6), compared with 6.3 months among patients who received platinum-based chemotherapy (HR, 0.45; 95% CI, 0.38-0.54; P < .0001).

The confirmed objective response rate (ORR) was 67.7% in the EVP arm compared with 44.4% in the chemotherapy arm. The ORR in the EVP group consisted of a complete response (CR) rate of 29.1% and a partial response (PR) rate of 38.7%. The stable disease (SD) rate was 18.8%, and the progressive disease (PD) rate was 8.7%. In the chemotherapy arm, the ORR consisted of a CR rate of 12.5% and a PR rate of 32%. The SD rate was 33.8% and the PD rate 13.6%.

Regarding safety, 56% of patients receiving EVP and 70% of patients receiving chemotherapy experienced grade 3 or greater treatment-related adverse events (TRAEs). Serious TRAEs occurred in 27.7% vs 19.6% of patients in the 2 arms, respectively. Adverse event (AE)-related discontinuations occurred in 21.9% and 14.0% of patients in the 2 arms, respectively.²

The recommended dose of enfortumab vedotin in combination with pembrolizumab is 1.25 mg/kg (up to a maximum of 125 mg for patients of ≥ 100 kg) via intravenous (IV) infusion over 30 minutes on day 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicity. The recommended dose of pembrolizumab when given with enfortumab vedotin is 200 mg via IV infusion every 3 weeks, or 400 mg given every 6 weeks until disease progression, unacceptable toxicity, or 2 years of treatment.

Also commenting on the approval in the news release, Thomas Powles, MRCP, MD, professor of Genitourinary Oncology at Queen Mary University of London; director, Barts Cancer Center, London, stated, "Advanced bladder cancer is a common cause of cancer-related death. The overall survival benefit seen in the EV-302 trial demonstrates the potential for Padcev in combination with pembrolizumab to impact first-line treatment of patients with locally advanced or metastatic urothelial carcinoma. In my opinion, this is a meaningful advancement over platinum-based chemotherapy in the systemic treatment of these patients."

References

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

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). Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain. Abstract LBA6

3. PADCEV (enfortumab vedotin-ejfv) with KEYTRUDA (pembrolizumab) approved by FDA as the first and only ADC plus PD-1 to treat advanced bladder cancer. News release. Astellas. Published online and accessed December 15, 2023. https://newsroom.astellas.us/2023-12-15-PADCEV-R-enfortumab-vedotin-ejfv-with-KEYTRUDA-R-pembrolizumab-Approved-by-FDA-as-the-First-and-Only-ADC-Plus-PD-1-to-Treat-Advanced-Bladder-Cancer

4. Enfortumab vedotin and pembrolizumab vs. chemotherapy alone in untreated locally advanced or metastatic urothelial cancer (EV-302). ClinicalTrials.gov. Last updated December 6, 2023. Accessed December 15, 2023. https://clinicaltrials.gov/study/NCT04223856