FDA Grants Regular Approval to Enfortumab Vedotin, Expands Indication for Locally Advanced or Metastatic Urothelial Cancer

The FDA has granted a regular approval to enfortumab vedotin-ejfv (Padcev) and has expanded the agent's indication to include adult patients with locally advanced or metastatic urothelial cancer who are ineligible for cisplatin-containing chemotherapy and who have received 1 or more prior lines of therapy.^1,2

The conversion from the accelerated approval to a regular approval was supported by 2 supplemental biologics license applications that included data from the phase 3 EV-301 trial (NCT03474107).

Results from the trial indicated that at the time of the prespecified interim analysis, the median overall survival (OS) in those who received the ADC was 12.9 months (95% CI, 10.6-15.2) vs 9.0 months (95% CI, 8.1-10.7) with chemotherapy (HR, 0.70; 95% CI, 0.56-0.89; P = .001); this translated to a 3.9-month benefit with enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer who received prior treatment with a platinum-based chemotherapy and a PD-1 inhibitor.

“With [enfortumab vedotin], for the first time, physicians can treat advanced urothelial cancer following treatment with a platinum-containing therapy and immunotherapy using an FDA-approved therapy that has demonstrated an OS benefit compared with chemotherapy," Andrew Krivoshik, MD, PhD, senior vice president and Oncology Therapeutic Area Head at Astellas Pharma Inc., stated in a press release.

The open-label, multicenter phase 3 EV-301 trial was required to confirm the clinical benefit that supported the accelerated approval. A total of 608 patients with locally advanced or metastatic urothelial cancer who had previously received a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy were enrolled to the trial.

Participants were randomized 1:1 to receive the antibody-drug conjugate (ADC) at a dose of 1.24 mg/kg on days 1, 8, and 15 of a 28-day treatment cycle (n = 301) or investigator's choice of single-agent chemotherapy in the form of docetaxel, paclitaxel, or vinflunine (n = 307).

The primary end point of the trial was OS, and important secondary end points comprised investigator-assessed progression-free survival and overall response rate (ORR) per RECIST v1.1 criteria.

Additional findings from the trial showed that the median PFS was 5.6 months (95% CI, 5.3-5.8) in the investigative arm and 3.7 months (95% CI, 3.5-3.9) in the control arm (HR, 0.62; 95% CI, 0.51-0.75; P <.0001). Additionally, enfortumab vedotin elicited an ORR of 40.6% (95% CI, 34.9%-46.5%) in this population vs 17.9% (95% CI, 13.7%-22.8%) with chemotherapy (P <.0001).

Previously, in December 2019, the regulatory agency granted an accelerated approval to enfortumab vedotin for use in adult patients with locally advanced or metastatic urothelial cancer who have received a prior PD-1/L1 inhibitor and a platinum-containing chemotherapy either before or after surgery, or in a locally advanced or metastatic urothelial cancer setting.³

The decision had been supported by data from the phase 2 EV-201 trial (NCT03219333), which examined the efficacy of the agent in a total of 125 patients with locally advanced or metastatic urothelial cancer who previously received a PD-1 or PD-L1 inhibitor and were not candidates for cisplatin-containing chemotherapy.

For this trial, the primary end point was confirmed ORR per blinded independent central review. The secondary efficacy end point was duration of response (DOR).

Results indicated that the ADC induced an ORR of 44% (95% CI, 35.1%-53.2%) in patients with locally advanced or metastatic urothelial cancer; this included a 12% complete response rate and a 32% partial response rate. The estimated median DOR with the agent was 7.6 months (95% CI, 6.3–not estimable [NE]).³

Among 89 patients who comprised cohort 2 of the trial, the confirmed ORR was 51% (95% CI, 39.8%-61.3%); this included a CR rate of 22%. The median DOR in this population was 13.8 months (95% CI, 6.4–NE).²

Regarding safety, the most frequent toxicities, including laboratory abnormalities, comprised rash, increased aspartate aminotransferase, increased glucose, increased creatinine, fatigue, peripheral neuropathy, decreased lymphocytes, alopecia, decreased appetite, decreased hemoglobin, and diarrhea.

Additional common adverse reactions include decreased sodium, nausea, pruritus, decreased phosphate, dysgeusia, increased alanine aminotransferase, anemia, decreased albumin, decreased neutrophils, increased urate, increased lipase, decreased platelets, reduced weight, and dry skin.

References

1. US FDA grants approval and expands indication for PADCEV (enfortumab vedotin-ejfv) for patients with locally advanced or metastatic urothelial cancer. News release. Seagen Inc. and Astellas Pharma Inc. July 9, 2021. Accessed July 9, 2021. https://bit.ly/3r7jzJ2
2. FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer. News release. FDA. July 9, 2021. Accessed July 9, 2021. https://bit.ly/3xxXlSC
3. FDA grants accelerated approval to enfortumab vedotin-ejfv for metastatic urothelial cancer. News release. FDA. December 18, 2019. Accessed July 9, 2021. https://bit.ly/3htZCJ5