FDA Grants Priority Review to 2 sBLAs for Enfortumab Vedotin in Locally Advanced or Metastatic Urothelial Cancer

The FDA has granted priority review to 2 supplemental biologics license applications (sBLAs) for enfortumab vedotin-ejfv (Padcev) for the treatment of select patients with locally advanced or metastatic urothelial cancer.¹

The first application is based on data from the phase 3 EV-301 trial (NCT03474107), which seeks to convert the accelerated approval of the antibody-drug conjugate (ADC) into a regular approval. Here, the agent showcased superior efficacy and a survival advantage over chemotherapy in this population. The median overall survival (OS) with the ADC was 12.88 months (95% CI, 10.58-15.21) vs 8.97 months (95% CI, 8.05-10.74) with chemotherapy (HR, 0.70; 95% CI, 0.56-0.89; P = .00142).²

The second application is based on findings from cohort 2 of the phase 3 EV-201 trial (NCT03219333), which seeks to expand the current indication of the agent to include patients with locally advanced or metastatic urothelial cancer who had prior PD-1/PD-L1 treatment and are not eligible for cisplatin. The ADC elicited the highest response rates observed for any regimen evaluated in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who had previously received PD-1/PD-L1 inhibition.³ The confirmed objective response rate (ORR) with the agent was 52.0% (95% CI, 40.8%-62.4%).

The FDA will make a decision on the applications by the target action date of August 17, 2021.

“With our recent regulatory submissions, we intend to provide the highest level of clinical evidence supporting [enfortumab vedotin] use – OS data from a randomized phase 3 trial – and expand availability in multiple countries where there is unmet medical need,” Andrew Krivoshik, MD, PhD, senior vice president and head of Oncology Therapeutic Area at Astellas, stated in a press release.

Enfortumab vedotin was granted accelerated approval from the FDA in December 2019 for the treatment of adult patients with locally advanced or metastatic urothelial cancer who had previously received a PD-1/PD-L1 inhibitor and platinum-based chemotherapy. The regulatory decision was based on findings from the first cohort of EV-201, in which the ADC induced a 44.0% ORR, which comprised a complete response (CR) rate of 12.0% and a partial response rate of 32.0%.⁴

In the open-label, confirmatory EV-301 trial, investigators compared the ADC with chemotherapy in a total of 608 patients with locally advanced or metastatic urothelial cancer who had previously received platinum-based chemotherapy and a PD-1/PD-L! inhibitor. To be eligible for enrollment, patients had to have an ECOG performance status of 0 to 1.

Study patients were randomized in a 1:1 fashion to enfortumab vedotin (n = 301) at a dose of 1.25 mg/kg on days 1, 8, and 15 of every 28-day treatment cycle or a chemotherapy regimen of docetaxel ay 75 mg/m², paclitaxel at 175 mg/m², or vinflunine at 320 mg/m², each given on day 1 of every 21-day treatment cycle (n = 307). Patients were stratified based on performance status (0 or 1), region of the world, and liver metastasis (present or absent).

The primary end point of EV-301 was OS and key secondary end points included investigator-assessed progression-free survival (PFS), ORR, and disease control rate (DCR) in accordance with RECIST v1.1 criteria. Safety of the ADC was also examined in the population.

The baseline characteristics of the patients enrolled to the treatment arms was well balanced and data from subgroup analyses presented during the 2021 Genitourinary Cancers Symposium indicated that OS favored enfortumab vedotin for all groups with the exception of women (HR, 1.17); however, some of the subgroups analyzed were too small to draw any conclusions.

Enfortumab vedotin resulted in a median PFS of 5.55 months (95% CI, 5.32-5.82) vs 3.71 months (95% CI, 3.52-3.94) with chemotherapy (HR, 0.62; 95% CI, 0.51-0.75; P <.00001). The ADC also was shown to induce an ORR of 40.6% (95% CI, 34.9%-46.5%) vs 17.9% (95% CI, 13.7%-22.8%) with chemotherapy. The DCR rate in the enfortumab vedotin arm was 71.9% (95% CI, 66.3%-77.0%) vs 53.4% (95% CI, 47.5%-59.2%) in the chemotherapy arm (P <.001).

In terms of toxicity, any-grade treatment-related toxicities were experienced by 94.0% of those who received enfortumab vedotin vs 92.0% of those given chemotherapy. Rates of treatment-related adverse effects (TRAEs) that were grade 3 or higher in severity were reported in 51.0% and 50.0% of the patients in the investigative and control arms, respectively. Moreover, 23.0% of patients were observed to have serious toxicities with treatment. Fourteen patients on the enfortumab vedotin arm discontinued treatment due to TRAEs vs 11.0% of those on the chemotherapy arm.

In the EV-201 trial, enfortumab vedotin was evaluated in patients with locally advanced or metastatic urothelial cancer who had prior immunotherapy but were not eligible for cisplatin. 

Eighty-nine patients were enrolled to cohort 2 of the trial. Participants were administered enfortumab vedotin at a dose of 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle. Patients who had grade 2 ongoing or sensory motor neuropathy, active central nervous system metastases, or uncontrolled diabetes mellitus, were excluded. The primary end point of the trial was centrally confirmed ORR and secondary end points comprised duration of response (DOR), PFS, OD, and safety.

Patients enrolled to cohort 2 of the trial had a median age of 75 years and the majority (74.0%) were male. Fifteen percent of the patients were obese, 67.0% had a moderate decrease in kidney function, and 43.0% had a tumor in the upper tract. Moreover, 79.0% of patients had visceral disease and 24% had liver involvement. Notably, levels of Nection-4 overexpression were observed to be very high in the poor-prognosis patient population.

The ADC was found to elicit responses in all patient subgroups evaluated, even though with primary tumor sites in the upper tract (ORR = 61.0%), those with liver metastasis (48.0%), and those who did not respond to prior immunotherapy (48.0%).

The median time to response with enfortumab vedotin was 1.81 months. Notably, some patients had responses to the agent that lasted for 1 year or longer. Moreover, the median DOR was 10.9 months (95% CI, 5.78–not reached) in these patients.

At a median follow-up of 13.4 months, the median PFS with enfortumab vedotin was 5.8 months (95% CI, 5.03-8.28) and the median OS was 14.7 months (95% CI, 10.51-18.20).

Regarding safety, TRAEs occurred in 97.0% of patients and 55% of them had events that were grade 3 or higher. Moreover, 16.0% of patients who received the ADC had AEs that led to discontinuation. The most common toxicity reported with the agent was peripheral sensory neuropathy (4.0%).

“These FDA filings, along with regulatory submissions outside of the United States under our collaboration with Astellas, are important steps in our shared goal of bringing [enfortumab vedotin] to more patients with advanced urothelial cancer,” Roger Dansey, MD, chief medical officer of Seagen, added in the release.

Under Project Orbis, health authorities in Australia and Canada are examining data from EV-301 and EV-201 for initial registrations. In March 2021, the European Medicines Agency accepted a marketing authorization application for enfortumab vedotin in this indication. Regulatory submissions for the agent were also made in Japan. 

References

1. Seagen and Astellas announce US FDA acceptance of two supplemental biologics license applications for PADCEV (enfortumab vedotin-ejfv) in locally advanced or metastatic urothelial cancer. News release. Seagen Inc and Astellas Pharma Inc. April 19, 2021. Accessed April 19, 2021. https://bit.ly/3n4sCZ1
2. Powles T, Rosenberg JE, Sonpavde G, et al. Primary results of EV-301: A phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma. J Clin Oncol. 2021;39(suppl 6):393. doi:10.1200/JCO.2021.39.6_suppl.393
3. Balar AV, McGregor BA, Rosenberg JE, et al. EV-201 Cohort 2: Enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors. J Clin Oncol. 2021;39(suppl 6).394. doi:10.1200/JCO.2021.39.6_suppl.394
4. 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