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CHICAGO -- Patients with locally advanced or metastatic urothelial cancer that was unresponsive to previous treatment achieved responses with enfortumab vedotin (EV), a researcher said here.

In a phase II EV-201 trial, 44% of patients had responses with the antibody-drug conjugate targeting Nectin-4, including 12% of patients who reached a complete response (CR) to treatment, according to Daniel Petrylak, MD, of the Yale Cancer Center in New Haven, Connecticut.

In addition, the median overall survival (OS) was 11.7 months (95% CI 9.1-not reached), median progression-free survival (PFS) was 5.8 months (95% CI 4.9-7.5), and median duration of response (DOR) was 7.6 months, he said in a presentation at the American Society of Clinical Oncology (ASCO) annual meeting.

"There is a high unmet need for patients with advanced and metastatic urothelial carcinoma," Petrylak said. "Enfortumab vedotin is the first novel therapeutic agent to demonstrate substantial clinical activity in patients who progressed after platinum chemotherapy or a PD-1 or PD-L1 inhibitor."

"This drug directly delivers the chemotherapy to the cancer cell," Petrylak told 番茄社区app. "This was a very well tolerated treatment with a low rate of discontinuation."

Results from the demonstrated an objective response rate (ORR) of 41% (95% CI, 29.3%-53.2%), including three (4%) CRs and 26 (37%) partial responses. As a result, in March 2018, the FDA granted a designation to EV for patients with locally advanced or metastatic urothelial cancer that has progressed during, or following, checkpoint inhibitor therapy.

ASCO expert Robert Dreicer, MD, of the University of Virginia Cancer Center in Charlottesville, noted that "Urothelial cancer is a very common disease, and there have been very limited therapeutics for treatment for it for decades. New therapies are badly needed ... I look at this data as showing the drug is effective and ready for approval. I would support accelerated approval for this agent, and I hope the FDA shares that opinion."

The trial enrolled patients (median age 69) who had progressed following treatment with platinum chemotherapy and a PD-1 or PD-L1 immune checkpoint inhibitor. Patients were split into two groups: group 1 had been previously treated with both chemotherapy and immunotherapy (n=128) while group 2 did not receive platinum chemotherapy and were ineligible for cisplatin. Of those patients, 125 received EV (1.25 mg/kg), given intravenously on days 1, 8, and 15 of each 28-day cycle.

The median number of previous systemic treatments was three. Most of the patients had visceral metastatic sites, and 40% had metastases to the liver, Petrylak reported. Combined positive scores of PD-L1 expression were <10 in 65% of the patients and ≥10 in 35%.

The primary endpoint was ORR per RECIST 1.1 by blinded independent central review, while secondary endpoints included DOR, PFS, OS, and safety/tolerability. Petrylak reported on results from group 1.

He reported that, as of January 2019, 28% had stable disease and 18% had progressive disease. Responses were seen across all subgroups, regardless of response to prior PD-1/L1 inhibitors or presence of liver metastases (ORR 38%, 95% CI 24.7%-52.8%). The median time to response was 1.8 months, with 44% of responses ongoing.

The most common treatment-related adverse events (AEs) of any grade were fatigue (50%), alopecia (49%), and decreased appetite (44%). Treatment-related AEs of interest included:

• Any case of rash: 48% all grade; 12% grade ≥3
• Any peripheral neuropathy: 50%; 3%
• Any hyperglycemia: 11%; 6%

"We aren't sure yet why diabetes is one of the adverse events," Petrylak said. "We are not sure of the mechanism of action. It could be that all these patients had prior checkpoint inhibitor therapy, and we know that patients develop diabetes on checkpoint inhibitors. But we can manage these adverse events."

Treatment discontinuation occurred in 12% of patients, most due to treatment-related peripheral neuropathy. One death was reported as treatment related (interstitial lung disease), but was confounded by a suspected pulmonary infection, he stated.

Petrylak noted that phase III trials comparing EV with standard chemotherapy, and in combination with checkpoint inhibitors are in the works in urothelial cancer, as well as in lung, breast, head and neck, and gastric cancers.

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