Enfortumab Vedotin Demonstrates Durable Responses in Advanced Urothelial Cancer

Enfortumab vedotin-ejfv (Padcev) elicited durable responses in patients with locally advanced or metastatic urothelial cancer who received previous treatment with a PD-1/PD-L1 inhibitor, have not been given a platinum-containing chemotherapy, and are not eligible for cisplatin, according to topline results from the second cohort of patients in the phase 2 EV-201 trial (NCT03219333).¹

Results from the trial showed that the antibody-drug conjugate (ADC) resulted in an objective response rate (ORR) of 52% (95% CI, 40.8-62.4) via blinded independent central review (BICR), with a median duration of response (DOR) of 10.9 months. With regard to safety, the most commonly experienced adverse effects (AEs) that occurred in 5% of patients and were grade 3 or higher included neutropenia, rash, fatigue, increased lipase, diarrhea, decreased appetite, anemia, and hyperglycemia.

Seagen, Inc. and Astellas Pharma, Inc. announced that the results from cohort 2 of EV-201 will be submitted for presentation at an upcoming medical meeting; the data will also be discussed with regulatory authorities.

“This is the first trial to report objective responses in patients with advanced urothelial cancer who had previously received immunotherapy but were ineligible for cisplatin in this setting due to inadequate kidney function or other conditions,” said Roger Dansey, MD, chief medical officer at Seagen, Inc.¹ “These promising new data from EV-201 may support a regulatory application to extend use of [enfortumab vedotin] in US patients whose cancer has progressed after immunotherapy and who are ineligible for cisplatin.”

In the single-arm phase 2 EV-201 trial, investigators set out to examine enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor. Patients included in cohort 1 of the trial had also been treated with a platinum-containing chemotherapy, and those in cohort 2 had not received a platinum-containing chemotherapy in this setting but were ineligible for cisplatin. A total of 128 participants were enrolled to cohort 1 of the trial, while 91 patients comprised cohort 2.

In the trial, enfortumab vedotin was administered intravenously at a dose of 1.25 mg/kg on days 1, 8, and 15 of each 28-day treatment cycle. The primary end point of the trial was ORR per BICR, while key secondary end points included DOR, disease control rate, progression-free survival (PFS), overall survival (OS), and safety.

In December 2019, the FDA granted an accelerated approval to enfortumab vedotin for use in adult patients with locally advanced or metastatic urothelial cancer who received previous treatment with a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy based on data from the first cohort of patients in EV-201.²

In cohort 1, the ADC resulted in an ORR of 44%; this was comprised of a 12% complete response rate and a 32% partial response rate. Moreover, the OS achieved with the agent was 11.7 months (95% CI, 9.1–not reached) and the median PFS was 5.8 months (95% CI, 4.9-7.5). The median DOR reported with enfortumab vedotin was 7.6 months (range, 0.95-11.30+).

Notably, responses were reported across all subgroups analyzed, regardless of response to previous treatment with PD-1/PD-L1 inhibitors or the presence of liver metastases (ORR, 38%; 95% CI, 24.7%-52.8%). Additionally, the median time to response was 1.8 months and just under half, or 44%, of responses were ongoing.

With regard to safety, the most frequently reported all-grade treatment-related AEs (TRAEs) included fatigue (50%), alopecia (49%), and decreased appetite (44%). TRAEs of interest included rash (all grade, 48%; grade 3 or higher, 12%), any peripheral neuropathy (all grade, 50%; grade 3 or higher, 3%), and any hyperglycemia (all grade, 11%; grade 3 or higher, 6%).

Additionally, TRAEs resulted in a treatment discontinuation rate of 12%; this was mostly attributed to peripheral neuropathy. Moreover, 1 death determined to be related to treatment was reported, and this was caused by interstitial lung disease; however, this was confounded by a suspected pulmonary infection per investigator assessment.

References

1. Seagen and Astellas announces positive topline results from second cohort of patients in phase 2 pivotal trial of PADCEV (enfortumab vedotin-ejfv) in advanced urothelial cancer. News release. Seagen Inc and Astellas Pharma Inc. October 12, 2020. Accessed October 12, 2020. https://bit.ly/2GH1D5f.
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 15):LBA4505. doi:10.1200/JCO.2019.37.18_suppl.LBA4505