FDA Approves Enfortumab Vedotin for Urothelial Cancer

The FDA granted an accelerated approval to enfortumab vedotin-ejfv (Padcev) for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have received prior treatment with a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy.

The approval is based on results from the first cohort of patients in the phase II EV-201 trial, which showed that enfortumab vedotin elicited an overall response rate (ORR) of 44% in patients with locally advanced or metastatic urothelial cancer, which included a 12% complete response rate, and a 32% partial response rate.²

“Antibody-drug conjugates are strategic tools in the targeted treatment of cancer. These conjugates combine the ability of monoclonal antibodies to target specific receptors on cancer cells and then deliver a drug to the cancer cell,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, said in statement. “Padcev is an antibody-drug conjugate that targets Nectin-4, a cell surface protein expressed on bladder cancer cells and a cell-killing agent, monomethyl auristantin E.”

Enfortumab vedotin is a novel investigational antibody-drug conjugate that targets Nectin-4, a protein that is highly expressed in urothelial cancers.

In the single-arm, phase II EV-201 trial, investigators administered enfortumab vedotin to patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1/PD-L1 inhibitor, including those who have also been treated with a platinum-containing chemotherapy (cohort 1) and those who have not received a platinum-containing chemotherapy and who are ineligible for cisplatin (cohort 2). A total 128 patients were enrolled at multiple centers internationally for cohort 1, in which enfortumab vedotin was given at 1.25 mg/kg enfortumab vedotin intravenously on days 1, 8, and 15 of each 28-day cycle.

Seventy percent of the 125 patients treated with enfortumab vedotin were male and the median age was 69 years (range, 40-84). Patients received a median of 3 lines (range, 1-6) of prior systemic treatments in the locally advanced or metastatic setting but had not received treatment for ≥2 weeks prior to enrolling in the study. Moreover, the combined positive scores of PD-L1 expression were <10 in 65% and ≥10 in 35%.

The primary endpoint is confirmed ORR per blinded independent central review, while secondary endpoints include duration of response (DOR), disease control rate, progression-free survival (PFS), overall survival (OS), safety, and tolerability. Patients are continuing to be enrolled in cohort 2.

Additional results showed that the OS was 11.7 months (95% CI, 9.1—not reached), the median PFS was 5.8 months (95% CI, 4.9-7.5), and the median DOR was 7.6 months (range, 0.95-11.30+).

Responses were observed across all subgroups, irrespective of response to prior PD-1/PD-L1 inhibitors or presence of liver metastases (ORR, 38%; 95% CI, 24.7%-52.8%). The median time to response was 1.8 months (range, 1.2-9.2), with 44% of responses ongoing.

Regarding safety, the most common treatment-related adverse events (TRAEs) of any grade were fatigue (50%), alopecia (49%), and decreased appetite (44%), while TRAEs of interest include any case of rash (all grade, 48%; grade ≥3, 12%), any peripheral neuropathy (all grade, 50%; grade ≥3, 3%), and any hyperglycemia (all grade, 11%; grade ≥3, 6%).

The treatment discontinuation rate due to a TRAE was 12%, which was mostly due to peripheral neuropathy. One treatment-related death was reported, which was caused by interstitial lung disease, but was confounded by a suspected pulmonary infection, as per the investigator.

The FDA previously granted enfortumab vedotin a breakthrough therapy designation in March 2018 for patients with locally advanced or metastatic urothelial cancer whose disease has progressed during or following checkpoint inhibitor therapy, based on the EV-101 data.

The accelerated approval of enfortumab vedotin in this setting is contingent on the results of a confirmatory trial.

References

1. Seattle Genetics and Astellas Announce US FDA Grants Priority Review for Enfortumab Vedotin Biologics License Application in Locally Advanced or Metastatic Urothelial Cancer. Seattle Genetics. Published September 16, 2019. https://bit.ly/2mbJ9Ps. Accessed September 16, 2019.
2. Petrylak DP, Balar AV, O'Donnell PH, et al. EV-201: results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and immune checkpoint inhibitors. J Clin Oncol. 2019;37(suppl; abstr LBA4505). doi: 10.1200/JCO.2019.37.18_suppl.LBA4505.