Enfortumab Vedotin Combo Produces Enduring Responses in Urothelial Cancer

"These results…add to the previously reported results from [the dose escalation cohort] of this study and indicate that [enfortumab vedotin plus pembrolizumab] may represent a new [first-line] treatment option for a patient population with high unmet need," according to the authors of the phase 1b/2 EV-103 study (NCT03288545).

Enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) demonstrated durable responses in the treatment of patients with locally advanced or metastatic urothelial cancer, according to findings from the phase 1b/2 EV-103 study (NCT03288545).

The confirmed overall response rate (ORR) was 64.5% (95% CI, 52.7%-75.1%) among patients receiving enfortumab vedotin plus pembrolizumab, which included a complete response (CR) rate of 10.5% and a partial response (PR) rate of 53.9%. The disease control rate (DCR) was 86.8% (95% CI, 77.1%-93.5%). Moreover, the median duration of response (DOR) was not reached (NR), and 65.4% of patients with a response had an ongoing response at 12 months.

The 6-month and 12-month progression-free survival (PFS) rates were 73.8% and 55.1% via blinded independent central review among those receiving combination therapy, respectively. The 6-month and 12-month overall survival (OS) rates were 88.2% and 80.7%, respectively, and the median OS was 22.3 months (95% CI, 19.09-NR).

The confirmed ORRs with enfortumab vedotin plus pembrolizumab among prespecified subgroups based on factors including PD-L1 expression, liver metastasis, ECOG performance status, and primary disease site of origin were comparable with findings from the overall population.

“These results…add to the previously reported results from [the dose escalation cohort] of this study and indicate that [enfortumab vedotin plus pembrolizumab] may represent a new [first-line] treatment option for a patient population with high unmet need,” the study authors wrote.

The confirmed ORR was 45.2% (95% CI, 33.5%-57.3%) among patients receiving enfortumab vedotin alone, which included a CR rate of 4.1% and a PR rate of 41.1%. Moreover, the DCR was 79.5% (95% CI, 68.4%-88.0%) in this cohort. At 12 months, the PFS and OS rates were 35.8% and 70.7%, respectively.

Between blinded independent central review and investigator evaluations, the concordance rate of best overall response was 86.7% in the combination arm and 85.5% in the monotherapy arm.

These data came from cohort K of the phase 1b-2 EV-103 study, in which investigators assessed enfortumab vedotin with or without pembrolizumab among patients with histologically documented, previously untreated locally advanced metastatic urothelial cancer. Patients were randomly assigned to receive 1.25 mg/kg of enfortumab vedotin as a single intravenous infusion on days 1 and 8 of a 3-week cycle with or without 200 mg of pembrolizumab intravenously on day 1 of the cycle.

The primary end point was confirmed ORR based on RECIST v1.1 criteria. Secondary end points included DCR, DOR, PFS, OS, and safety.

Patients with an ECOG performance status of 0 to 2 were eligible for enrollment on the trial. Patients were also required to have a hemoglobin level of at least 10 g/dL, a glomerular filtration rate of at least 50 mL per minute, and no New York Heart Association class III heart failure.

Overall, 76 patients received enfortumab vedotin plus pembrolizumab, and 73 received enfortumab vedotin on its own. The median duration of treatment was 9.0 months (range, 0.6-26.1) in the combination arm and 5.5 months (range, 0.5-26.9) in the monotherapy arm.

In the combination and monotherapy arms, respectively, most patients were male (71.1% vs 76.7%), White (80.3% vs 75.3%), and had an ECOG performance status of 1 (43.4% vs 47.9%). Additionally, most in each arm had a primary tumor located in the lower tract (60.5% vs 69.9%), lung metastases (48.7% vs 41.1%), visceral disease (84.2% vs 82.2%), and a PD-L1 combined positive score of less than 10 (57.9% vs 52.1%).

The most frequently observed grade 3 or higher treatment-related adverse effects (TRAEs) included maculopapular rash (17.1%), fatigue (9.2%), neutropenia (9.2%), and diarrhea (6.6%) among those receiving enfortumab vedotin plus pembrolizumab. Any-grade TRAEs associated with enfortumab vedotin in the combination arm included skin reactions (67.1%), peripheral neuropathy (60.5%), ocular events (26.3%), hyperglycemia (14.5%), and infusion-related reactions (3.9%).

TRAEs leading to death occurred in 3.9% of patients in the combination arm and 2.7% of those in the monotherapy arm. Additionally, TRAEs leading to the discontinuation of either enfortumab vedotin or pembrolizumab occurred among 47.4% and 19.2% of patients receiving enfortumab vedotin alone.

Reference

O’Donnell PH, Milowsky MI, Petrylak DP, et al. Enfortumab vedotin with or without pembrolizumab in cisplatin-ineligible patients with previously untreated locally advanced or metastatic urothelial cancer. J Clin Oncol. Published online June 27, 2023. doi:10.1200/JCO.22.02887