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Enfortumab Vedotin Granted FDA's Breakthrough Designation for Treatment of Urothelial Carcinoma

Jason M. Broderick
Published Online:5:18 PM, Mon March 26, 2018

Daniel P. Petrylak, MD
Enfortumab vedotin has been granted a breakthrough therapy designation by the FDA for the treatment of patients with locally advanced or metastatic urothelial cancer who previously received immune checkpoint therapy. These findings have been released by Seattle Genetics and Astellas, the manufacturers of the antibody-drug conjugate (ADC).

Based on interim results from a phase I dose-escalation/dose-expansion trial, the breakthrough therapy designation will expedite the development and review of the ADC. The trial evaluated enfortumab vedotin monotherapy in patients with metastatic urothelial carcinoma and other solid tumors.

After looking at the 71 patients enrolled in the trial, findings from the metastatic urothelial carcinoma cohort demonstrated that the ADC had a 41% overall response rate (ORR). At the recommended phase II dose (RP2D), there was an ORR of 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. We are working closely with our partner and the FDA to bring this potential new treatment to patients as quickly as possible,” Robert Lechleider, MD, senior vice president, Clinical Development at Seattle Genetics, said.

Using proprietary linker technology from Seattle Genetics, an anti–Nectin-4 monoclonal antibody is attached to the microtubule-disrupting agent MMAE in enfortumab vedotin. Previously treated patients 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 in this trial.

With a data cutoff on April 28, 2017, 81 of the patients were given enfortumab vedotin in the United States and in Canada at various study sites. This included 21 in dose-escalation cohorts and 60 in dose-expansion cohorts. 

Median patient age was 67 years (range, 41-84), while 70% of the patients were male. Additionally, 95% of patients in this trial had previously received platinum-based therapy, 46% received a checkpoint inhibitor, and 43% had prior taxable treatment. Investigators also noted that 97% of patients demonstrated nectin-4 expression. 

In the 71 evaluable patients across the cohort, there was an ORR of 41% (95% CI, 29.3-53.2).  Three patients (4%) had complete responses (CRs) while 26 (37%) had partial responses (PRs). 

In the 30 evaluable patients treated at the RP2D, ORR was 53% (95% CI, 34.3-71.7). This included 1 patient (3%) with CR and 15 (50%) who had PRs. It was also noted that 6 patients had stable disease and 6 had progressive disease. Among patients that previously received a checkpoint inhibitor and who were also treated at the RP2D (n = 17), the ORR found in the trial was 47% (n = 8), all of which had PRs. There were 5 patients found with stable disease. 

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

According to the results, 21 (26%) of the patients were still receiving treatment at the cutoff, while 60 (74%) had discontinued. The median time on treatment was 15.1 weeks (range, 1.1-64.6). The leading cause for discontinuation was 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%) were amongst other reasons for discontinuation.

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

Urinary tract infection (8%), hypophosphatemia (3%), hyponatremia (5%), anemia (8%), and hyperuricemia (5%) were found in the grade ≥3 AEs in the RP2D cohort. There were 3 patient deaths (cardiac arrest, small intestinal perforation and sepsis, and acute renal failure) across all treatment doses. None of these were found to be related to enfortumab vedotin.

The phase II EV-201 trial (NCT03219333) remains ongoing, exploring enfortumab vedotin in this setting. The phase I EV-103 trial (NCT03288545) looks at potential role and benefits of 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).

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