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Enfortumab vedotin () appeared to be effective as a neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC) who were ineligible for cisplatin-based chemotherapy, according to a small phase Ib/II study.

Results from a preliminary analysis of 22 patients showed that eight had a pathologic complete response (pCR, 36.4%, 95% CI 17.2-59.3), displaying no signs of cancer when their bladder was removed, after receiving pre-surgical treatment with the antibody drug conjugate (ADC), reported Daniel P. Petrylak, MD, of Yale University in New Haven, Connecticut.

In addition, half of patients had pathological downstaging to less than MI disease, he said in a presentation at the Genitourinary Cancers Symposium (GuCS).

Those results are "comparable to what we see with cisplatin-based chemotherapy in those patients who are cisplatin eligible," Petrylak told 番茄社区app. "So that justifies further studies of these agents [ADCs] in this clinical setting."

The in 2021 for adult patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy, or are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.

The agent received FDA accelerated approval in 2019 for patients with locally advanced or metastatic urothelial cancer who have received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.

Patients with MIBC are typically treated with a combination of cisplatin-based chemotherapy, along with radical cystectomy and pelvic node dissection (RC+PLND). However, about 30%-40% of patients are not eligible for cisplatin-based upon poor renal function, neuropathy, congestive heart failure, and , and thus don't have established neoadjuvant options prior to undergoing RC+PLND, Petrylak pointed out.

Patients in cohort H of the had a median age of 74.5. They were cisplatin-ineligible patients, with cT2-T4aN0M0 MIBC, and were eligible for RC+PLND. They had an ECOG performance status of 0-2. Patients received three cycles of neoadjuvant enfortumab vedotin on days 1 and 8 of every 3-week cycle prior to surgery.

The duration of neoadjuvant treatment was a median of 2.1 months, with time from the end of neoadjuvant to surgery of 1.8 months. All 22 patients underwent surgery, with 19 remaining on study. Three patients were off-study, all due to perioperative deaths due to acute kidney injury, cardiac arrest related to RC+PLND, and pulmonary embolism related to RC+PLND.

GuCS session moderator Todd Morgan, MD, of the University of Michigan in Ann Arbor, said the report of the three perioperative deaths "caught my eye...In a cohort of 22 patients, that's really high."

Petrylak said he agreed, and suggested this could be related to the small number of patients in the study.

"There are studies that reported a 9% rate of perioperative deaths, which is consistent with what we are seeing here," he added. "And this is an older group of patients."

He also noted that two of the three patients had residual disease, and that previous research indicates that bladder cancer treated with chemotherapy or other treatments can cause thrombogenic events. "And as we saw, there were two events that were cardiovascular in nature," Petrylak said. "It is a concern, and it is going to be monitored in phase III studies, and, of course, if there is a safety signal that is concerning the studies will be appropriately evaluated."

The most common treatment-emergent adverse events (TEAEs) were fatigue (45.5%), alopecia (36.4%), and dysgeusia (36.4%). Four patients had grade 3 study-agent-related TEAEs, but no surgeries were delayed due to enfortumab vedotin administration.

GuCS discussant Guru P. Sonpavde, MD, of the Dana Farber Cancer Institute and Harvard Medical School in Boston, said ADC development in earlier disease settings is rational, and that the pCR rate is impressive with enfortumab. "But will pCR here translate into improved long-term outcomes?" he asked. "Is this good-quality pCR or just a shallow pCR? I think this remains to be seen."

Sonpavde observed that there are ongoing phase III trials evaluating neoadjuvant therapy in MIBC, "and these data with enfortumab vedotin alone in the neoadjuvant setting nicely support a role for it in the neoadjuvant setting." He pointed out that there are now multiple phase III trials evaluating checkpoint inhibitors combined with enfortumab vedotin.

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