FDA Grants Enfortumab Vedotin Breakthrough Designation for Urothelial Carcinoma

Daniel P. Petrylak, MD

The FDA has granted enfortumab vedotin a breakthrough therapy designation for patients with locally advanced or metastatic urothelial cancer who previously received immune checkpoint therapy, according to Seattle Genetics and Astellas, the manufacturers of the antibody-drug conjugate (ADC).

The breakthrough therapy designation, which will expedite the development and review of the ADC, was granted based on interim results from a phase I dose-escalation/dose-expansion trial evaluating enfortumab vedotin monotherapy in patients with metastatic urothelial carcinoma and other solid tumors. Data from the study’s metastatic urothelial carcinoma cohort showed that the ADC had a 41% overall response rate (ORR) among 71 evaluable patients. The ORR at the recommended phase II dose (RP2D) was 53%.

“The FDA breakthrough therapy designation underscores the potential of enfortumab vedotin as a meaningful treatment for patients with locally advanced or metastatic urothelial cancer. Further, it supports our rapid development plans for this ADC, including the ongoing pivotal study in this patient population,” Robert Lechleider, MD, senior vice president, Clinical Development at Seattle Genetics, said in a statement. “We are working closely with our partner and the FDA to bring this potential new treatment to patients as quickly as possible.”

Enfortumab vedotin consists of an anti—Nectin-4 monoclonal antibody attached to the microtubule-disrupting agent MMAE using proprietary linker technology from Seattle Genetics. The phase I study including previously treated patients who received enfortumab vedotin IV at 1 of 4 dose levels (0.5, 0.75, 1, or 1.25 mg/kg) 3 out of 4 weeks until there was no further clinical benefit.

At the data cutoff of April 28, 2017, 81 patients had received enfortumab vedotin at study sites in the United States in Canada, including 21 in dose-escalation cohorts and 60 in dose-expansion cohorts.

The median patient age was 67 years (range, 41-84), 70% of patients were male. Ninety-five percent of patients had prior platinum-based therapy, 46% had received a checkpoint inhibitor, and 43% had prior taxable treatment. Ninety-seven percent of patients showed nectin-4 expression.

Among 71 evaluable patients across the entire cohort, the ORR was 41% (95% CI, 29.3-53.2), including 3 (4%) complete responses (CRs) and 26 (37%) partial responses (PRs).

Among 30 evaluable patients treated at the RP2D, the ORR was 53% (95% CI, 34.3-71.7), including 1 (3%) CR and 15 (50%) PRs. Six patients had stable disease and 6 had progressive disease. Among patients who had previously received a checkpoint inhibitor who were treated at the RP2D (n = 17), the ORR was 47% (n = 8), consisting of all PRs. Five patients had stable disease.

“These results warrant further development of enfortumab vedotin as monotherapy and in combination with other therapies for patients with metastatic urothelial carcinoma,” Daniel P. Petrylak, MD, professor of Medicine and Urology, Yale Cancer Center, said when presenting the data at the 2017 ASCO Annual Meeting.

Twenty-one (26%) patients were still receiving treatment at the cutoff, with 60 (74%) having discontinued. The median time on treatment was 15.1 weeks (range, 1.1-64.6). The reasons for treatment discontinuation included radiographic disease progression (46%), disease progression shown through clinical symptoms (6%), adverse events (AEs; 12%), withdrawal of subject consent (5%), investigator decision (4%), and other (1%).

Among 38 patients receiving the RP2D, the most common all-grade AEs were nausea (37%), pruritus (32%), fatigue (32%), diarrhea (32%), alopecia (32%), decreased appetite (29%), and dysgeusia (21%).

Grade ≥3 AEs in the RP2D cohort included urinary tract infection (8%), hypophosphatemia (3%), hyponatremia (5%), anemia (8%), and hyperuricemia (5%). Across all treatment doses, there were 3 patient deaths (cardiac arrest, small intestinal perforation and sepsis, and acute renal failure), none of which was considered to be related to enfortumab vedotin.

The ongoing, pivotal phase II EV-201 trial (NCT03219333) is exploring enfortumab vedotin in this setting, and the phase I EV-103 trial (NCT03288545) is exploring the ADC in combination with either pembrolizumab (Keytruda) or atezolizumab (Tecentriq).

Petrylak DP, Perez RP, Zhang J, et al. A phase i study of enfortumab vedotin: updated analysis of patients with metastatic urothelial cancer. J Clin Oncol 35, 2017 (suppl; abstr 106).