FDA Approval Sought for Enfortumab Vedotin in Locally Advanced or Metastatic Urothelial Cancer

Andrew Krivoshik, MD, PhD

Two supplemental biologics license applications have been submitted to the FDA for enfortumab vedotin-ejfv to convert the agent’s accelerated approval into a regular one and to expand the current label to include patients with locally advanced or metastatic urothelial cancer who had received prior treatment with a PD-1/PD-L1 inhibitor and are not eligible for cisplatin.¹

The first application is based on data from the phase 3 EV-301 trial (NCT033474107), in which the antibody-drug conjugate (ADC) demonstrated superior efficacy and a survival advantage over chemotherapy in this patient population. The median overall survival (OS) with enfortumab vedotin was 12.88 months (95% CI, 10.58-15.21) versus 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 the second cohort of the phase 2 EV-201 trial (NCT032193333), where the ADC was found to elicit the highest response rates observed for any regimen examined in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who previously received PD-1/PD-L1 inhibitors.³ The confirmed objective response rate (ORR) achieved with enfortumab vedotin was 52% (95% CI, 40.8%-62.4%)

“The FDA’s review of our applications under Real-Time Oncology Review supports our efforts to expand [enfortumab vedotin]’s availability as a treatment option for more patients as quickly as possible,” Andrew Krivoshik, MD, PhD, senior vice president and oncology therapeutic head of Astellas, stated in a press release. “Locally advanced or metastatic urothelial cancer is an aggressive disease with limited therapeutic options.”

In December 2019, the FDA granted an accelerated approval to enfortumab vedotin 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 decision was based on data from the first cohort of EV-201, where enfortumab vedotin was shown to elicit an ORR of 44%; this included a 12% complete response (CR) rate and a 32% partial response rate.⁴

The open-label, confirmatory EV-301 trial compared enfortumab vedotin with chemotherapy in 608 adult patients with locally advanced or metastatic urothelial cancer who received prior platinum-based chemotherapy and a PD-1/PD-L1 inhibitor; patients had to have an ECOG performance status of 0 or 1.

Participants were randomized 1:1 to receive either the ADC (n = 301) at 1.25 mg/kg on days 1, 8, and 15 of every 28-day treatment cycle or chemotherapy (n = 307) comprised of docetaxel at 75 mg/m2, paclitaxel at 175 mg/m2, or vinflunine at 320 mg/m2, each administered on day 1 of every 21-day cycle. Stratification variables included performance status (0 or 1), region of the world, and liver metastasis (present or absent).

The primary end point of the study was OS, while secondary end points comprised investigator-assessed progression-free survival (PFS), ORR, and disease control rate (DCR) per RECIST v1.1 criteria. Investigators also evaluated the safety of the agent in this population.

Baseline characteristics were noted to be well balanced between the study arms. Additional data from subgroup analyses presented during the 2021 Genitourinary Cancers Symposium showed that OS favored the ADC arm for all groups except women (HR, 1.17), although some of the subgroups were too small to draw conclusions.

The median PFS in the investigative arm was 5.55 months (95% CI, 5.32-5.82) compared with 3.71 months (95% CI, 3.52-3.94) in the control arm (HR, 0.62; 95% CI, 0.51-0.75; P <.00001). Moreover, enfortumab vedotin elicited an ORR of 40.6% (95% CI, 34.9%-46.5%), which comprised a 4.9% CR rate. Those who received chemotherapy experienced an ORR of 17.9% (95% CI, 13.7%-22.8%), with a CR rate of 2.7%. The DCR rates in the investigative and control arms were 71.9% (95%, 66.3%-77.0%) and 53.4% (95% CI, 47.5%-59.2%), respectively (P < .001).

The rates of treatment-related toxicities between the arms proved to be comparable. Any-grade treatment-related adverse effects (TRAEs) were reported in 94% of those who received the ADC versus 92% of those given chemotherapy; rates of grade 3 or higher TRAEs were experienced by 51% and 50% of patients, respectively. Twenty-three percent of patients on each arm experienced serious toxicities. TRAEs resulted in treatment discontinuation in 14% and 11% of patients on the investigative and control arms, respectively.

In the phase 2 EV-201 trial, investigators examined enfortumab in patients with locally advanced or metastatic urothelial cancer who had previously received immunotherapy but were not candidates to receive cisplatin.

A total of 89 patients were enrolled to cohort 2 of the trial and they were given the ADC at a dose of 1.25 mg/kg on days 1, 8, and 15 of each 28-day treatment cycle. If patients had ongoing or sensory motor neuropathy that was grade 2 in severity or higher, had active central nervous system metastases, or uncontrolled diabetes mellitus, they were excluded.

The primary end point of the trial was centrally confirmed ORR, while secondary end points included duration of response (DOR), PFS, and OS, as well as safety and tolerability.

Patients in the cohort had a median age of 75 years, 74% were male, 15% were obese, 67% had a moderate decrease in kidney function, and 43% had a tumor in the upper tract. Seventy-nine percent of patients had visceral disease and 24% had liver involvement. Moreover, levels of Nectin-4 overexpression were noted to be very high in this poor-prognosis population.

Results presented during the 2021 Genitourinary Cancers Symposium showed that responses to the ADC were observed across all subgroups evaluated, including those with primary tumor sites in the upper tract (ORR = 61%), those with liver metastasis (48%), and those who were not responsive to previous immunotherapy (48%).

Additionally, the median time to response was 1.81 months with enfortumab vedotin and some participants experienced durable responses that persisted beyond 1 year or longer. The median DOR was 10.9 months (95% CI, 5.78–not reached) in this population.

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

Any-grade TRAEs were observed in 97% of patients, with 55% of them experiencing effects that were grade 3 in severity or higher. Sixteen percent of patients reported toxicities that led to treatment discontinuation. The most frequently reported toxicity was peripheral sensory neuropathy (4%).

References

1. Seagen and Astellas announce submission of two supplemental biologics license applications to the US FDA for PADCEV (enfortumab vedotin-ejfv) in locally advanced or metastatic urothelial cancer. News release. Seagen Inc. February 18, 2021. Accessed February 18, 2021. http://bit.ly/3awPvQn.

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