FDA Approves Enfortumab Vedotin Plus Pembrolizumab for Locally Advanced or Metastatic Urothelial Carcinoma

The FDA has granted accelerated approval to enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.

The regulatory decision was supported by data from the combined dose-escalation/cohort A and cohort K of the phase 1/2 EV-103/KEYNOTE-869 study (NCT03288545).

In these cohorts (n = 121), the doublet elicited a confirmed objective response rate (ORR) of 68% (95% CI, 59%-76%) by RECIST v1.1 criteria and blinded independent central review (BICR). Among those who responded, 12% achieved a complete response and 55% had a partial response.

Moreover, the median duration of response (DOR) in the dose-escalation cohort plus cohort A was 22.1 months (range, 1.0+ to 46.3+) and not yet reached (range, 1.2 to 24.1+) for cohort K.

“The accelerated approval for the combination of PADCEV and pembrolizumab marks an important milestone for the approximately 8,000 to 9,000 patients in the United States with locally advanced or metastatic urothelial cancer who are not eligible for cisplatin-containing chemotherapy,” Ahsan Arozullah, MD, MPH, senior vice president and head of Oncology Development at Astellas, stated in a press release. “This patient population now has an additional treatment option to treat advanced bladder cancer at first diagnosis of metastatic disease.”

The open-label, multi-cohort study enrolled patients with locally advanced or metastatic urothelial cancer who were not eligible to receive cisplatin-based chemotherapy.³ Patients could not have received previous systemic therapy for locally advanced or metastatic disease.

Other exclusion criteria included having active central nervous system metastases, ongoing sensory or motor neuropathy that was at least grade 2 in severity, or having uncontrolled diabetes defined as hemoglobin A1C (HbA1c) of at least 8% or HbA1c of at least 7% with associated diabetes symptoms.

Those in the dose-escalation cohort (n = 5), cohort A (n = 40), and cohort K (n = 76) were administered enfortumab vedotin at 1.25 mg/kg intravenously over the course of 30 minutes on days 1 and 8 of each 21-day treatment cycle. This was followed by pembrolizumab, which was also given intravenously at a dose of 200 mg on day 1 of each cycle about 30 minutes after enfortumab vedotin.

Treatment continued until progressive disease or intolerable toxicity.

In the 121 patients, the median age was 71 years (range, 51-91); most patients were male (74%) and White (85%). Regarding ECOG performance status, 45% had a status of 1 and 15% had a status of 2. Moreover, just under half of patients (47%) had a documented HbA1c of less than 5.7% at baseline.

Reasons for being ineligible for cisplatin comprised the following: baseline creatinine clearance of 30 mL/min to 59 mL/min (60%), ECOG performance status of 2 (10%), and grade 2 or higher hearing loss (13%). Sixteen percent of patients had more than one cisplatin-ineligibility criteria.

At baseline, 97.5% of patients had metastatic disease and 2.5% had locally advanced disease. Moreover, 37% of patients had upper tract disease and 84% had visceral metastasis at baseline, including 22% with liver metastases. Additionally, 39% of patients had transitional cell carcinoma (TCC) histology; 13% had TCC with squamous differentiation and 48% had TCC with other histologic variants.

ORR and DOR by RECIST v1.1 criteria and BICR served as the major efficacy outcome measures of the trial.

The median follow-up for combined dose-escalation/cohort A cohort and cohort K was 44.7 months (range, 0.7-52.4) and 14.8 months (range, 0.6-26.2), respectively. The median number of treatment cycles received in these cohorts was 9 lines and 11 lines, respectively.

The most common toxicities with the regimen, occurring in over 20% of patients, included increased glucose, increased aspartate aminotransferase, rash, decreased hemoglobin, increased creatinine, peripheral neuropathy, decreased lymphocytes, fatigue, increased alanine aminotransferase, decreased sodium, and increased lipase.¹

Other adverse effects included decreased albumin, alopecia, decreased phosphate, decreased weight, diarrhea, pruritus, decreased appetite, nausea, dysgeusia, decreased potassium, decreased neutrophils, urinary tract infection, constipation, potassium increased, calcium increased, peripheral edema, dry eye, dizziness, arthralgia, and dry skin.

The clinical benefit of enfortumab vedotin plus pembrolizumab in patients with previously treated advanced urothlial cancer is being further evaluated in the phase 3 EV-302 trial (NCT04223856), which will serve as the confirmatory trial for the accelerated approval in the United States.² Data from the study are also intended to serve as the basis for global registrations, according to Seagen, Inc. and Astellas Pharma, Inc.

Global enrollment to the trial has been completed. The China extension of the study is currently enrolling participants.

References

1. FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. FDA. April 3, 2023. Accessed April 3, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
2. FDA grants approval for Padcev (enfortumab vedotin-ejfv) with Keytruda (pembrolizumab) for first-line treatment of locally advanced or metastatic urothelial cancer. News release. Seagen, Inc. and Astellas Pharma, Inc. April 3, 2023. Accessed April 3, 2023. https://investor.seagen.com/press-releases/news-details/2023/
3. Enfortumab vedotin-ejfv. Prescribing information. Seagen Inc. Updated April 2023. Accessed April 3, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761137s018.pdf