Developers Submit BLAs for Enfortumab Vedotin for 2 Urothelial Carcinoma Indications

The submission of 2 Biologic License Applications (BLAs) for enfortumab vedotin-ejfv (Padcev) have been made to the FDA for consideration as treatment of patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1/L1 inhibitor and who are ineligible for cisplatin. The first application seeks to change the prior accelerated approval for the agent to a regular approval, Seagen Inc., and Astellas Pharma Inc. announced, in a press release, and the second would be for an expansion of the current label.¹

“The FDA’s review of our applications under Real-Time Oncology Review supports our efforts to expand Padcev’s availability as a treatment option for more patients as quickly as possible,” said Andrew Krivoshik, MD, PhD, senior vice president, and Oncology Therapeutic Area head, Astellas, Inc, in a statement. “Locally advanced or metastatic urothelial cancer is an aggressive disease with limited treatment options.”

Submission of the BLAs comes on the heels of satisfactory data presented during the recent American Society of Clinical Oncology (ASCO) 2021 Genitourinary Cancers Symposium. The request for a full, regular approval is supported by findings from the phase 3 confirmatory EV-301 trial (NCT03474107), and the second BLA is supported by findings from cohort 2 of the phase 2 EV-201 clinical trial (NCT03219333), which seeks to support an expanded label for the treatment of patients with locally advanced or metastatic urothelial cancer who were previously treated with a PD-1/L1 inhibitor and who are ineligible for cisplatin.

The EV-301 open-label, randomized, confirmatory trial demonstrated that enfortumab vedotin has superior efficacy to chemotherapy in patients with advanced urothelial carcinoma who had previously received platinum-based chemotherapy and PD-1/L1 inhibition. In 608 patients who randomized 1:1 to received either enfortumab vedotin (n = 301) or chemotherapy (n = 307). The patients were primarily assessed for overall survival (OS). The secondary outcomes of the study were investigator-assessed progression-free survival (PFS), objective response rate (ORR,. disease control rate (DCR), and safety.^2,3

The median OS observed 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). OS was also assessed in a subgroup analysis, which showed that enfortumab vedotin was more favorable in all groups except female patients (HR, 1.17). Treatment with enfortumab vedotin in the study also led to a median PFS of 5.55 months (95% CI, 5.32-5.82) versus 3.71 months (95% CI, 3.52-3.94) with chemotherapy (HR, 0.62; 95% CI, 0.51-0.75; P < .00001).

Response data from EV-301 showed an ORR of 40.6% (95% CI, 34.9%-46.5%) with enfortumab vedotin, which was inclusive of complete responses (CRs) in 4.9%. The DCR was 71.9% (95% CI, 66.3%-77.0%) in the enfortumab vedotin arm. In comparison, the ORR observed with chemotherapy was 7.9% (95% CI, 13.7%-22.8%) with CRs in 2.7%. The DCR in the chemotherapy arm was 53.4% (95% CI, 47.5%-59.2%; P < .001).

Safety was evaluated by the incidence of treatment-related adverse events (TRAEs). The emergence of TRAEs was similar between the 2 treatment arms at 94% in the enfortumab vedotin arm and 92% in the chemotherapy arm. Grade ≥3 TRAEs occurred in 51% of the experimental arm versus 50% of the control arm. Finally, serious TRAEs were seen in 23% of both the enfortumab vedotin and chemotherapy arms and led to treatment discontinuation in 14% and 11%, respectively.

Overall, findings from EV-301 support the use of enfortumab vedotin over chemotherapy in patients with previously treated advanced urothelial carcinoma.

Regarding the second prospective indication for enfortumab vedotin, EV-201 is a single-arm, open-label, multicenter study evaluating its use in patients with locally advanced or metastatic urothelial cancer who previously received immune checkpoint inhibitor therapy. In cohort 2 of the study, the patients enrolled were ineligible for cisplatin-containing chemotherapy and had no prior exposure to platinum-containing chemotherapy in the locally advanced or metastatic setting. The cohort was made up of 89 patients who were given 1.25 mg/kg enfortumab vedotin intravenously on days 1, 8, and 15 of each 28-day cycle.⁴

The primary end point of the study was centrally confirmed ORR. The study also looked at duration of response (DOR), PFS, OS, safety, and tolerability as secondary end points.

Enfortumab vedotin achieved a confirmed ORR was 52% (n = 89; 95% CI, 40.8%-62.4%) in the study. In addition, the CR rate was 20%. The median DOR was 10.9 months (95% CI, 5.78-not reached).

In terms of survival, treatment with enfortumab vedotin in the cisplatin-ineligible population led to a median PFS of 5.8 months (95% CI, 5.03-8.28) and a median OS of 14.7 months (95% CI, 10.51-18.20).

TRAEs of any grade occurred in 97% of patients, and grade ≥3 TRAEs occurred in 55% of patients. Treatment discontinuation was seen in 16% of patients. Four patients in the study died as a result of acute kidney injury, metabolic acidosis, multiple organ dysfunction syndrome, and pneumonitis.

The findings from EV-201 support further research around the use of enfortumab vedotin in multiple settings of urothelial carcinoma. Additionally, the presenter of the EV-201 data, Arjun V. Balar, MD, stated that the data may support a new standard of care for cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma.

“Advanced bladder cancer patients urgently need more treatment options,” said Roger Dansey, MD, chief medical officer, Seagen, Inc, in a statement.¹ “Based on recently presented clinical trial results, Padcev could address a significant unmet need for more patients with advanced urothelial cancer after initial immunotherapy treatment.”

Enfortumab vedotin is a first-in-class antibody-drug conjugate directed against Nectin-4. The agent was previously granted accelerated approval by the FDA for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1/L1 inhibitor and either adjuvant or neoadjuvant platinum-containing chemotherapy in a locally advanced or metastatic urothelial cancer setting. The accelerated approval was based on earlier findings from a cohort of the EV-201 trial.

_References:

_{1. Seagen and Astellas announce submission of two supplemental Biologics License Applications to the U.S. FDA for Padcev® (enfortumab vedotin-ejfv) in locally advanced or metastatic urothelial cancer. News release. February 18, 2021. Accessed February 18, 2021. https://bit.ly/3ulz3ua}

_{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. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. Published online February 12, 2021. N Engl J Med. doi:10.1056/NEJMoa2035807}

_{4. 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}