Neoadjuvant treatment with the antibody-drug conjugate enfortumab vedotin-ejfv achieved notable antitumor activity in patients with muscle-invasive bladder cancer who are ineligible for treatment with cisplatin, according to preliminary results for cohort H of the EV-103 trial reported at the 2022 ASCO Genitourinary Cancers Symposium.¹

In cohort H of the phase Ib/II trial, patients with muscle-invasive bladder cancer treated with neoadjuvant enfortumab vedotin monotherapy yielded a pathologic complete response rate of 36%, and 50% were downstaged from muscle-invasive disease. All patients enrolled in the trial underwent surgery without delay.

Daniel P. Petrylak, MD

“Enfortumab vedotin produced promising antitumor responses in patients with [muscle-invasive bladder cancer] who were cisplatin-ineligible. All were able to undergo surgery with no delay due to neoadjuvant enfortumab vedotin. This first disclosure of data supports the ongoing phase II and III programs evaluating enfortumab vedotin alone or in combination with pembrolizumab in muscle-invasive bladder cancer,” said lead study author Daniel P. Petrylak, MD, Professor of Medical Oncology and of Urology at Yale School of Medicine.

About 25% of patients with bladder cancer present with muscle-invasive disease. In cisplatin-ineligible patients with muscle-invasive bladder cancer, surgery with radical cystectomy and lymph node dissection is the standard of care. No standard neoadjuvant therapy has been shown to prolong survival in cisplatin-ineligible patients undergoing surgery for muscle-invasive bladder cancer. Dr. -Petrylak said pathologic complete response for patients who receive cisplatin-based combination chemotherapy ranges from 36% to 42%, and the 36% rate reported in cohort H is consistent with the literature in cisplatin-eligible patients.

Enfortumab vedotin is approved by the U.S. Food and Drug Administration for patients with locally advanced or metastatic urothelial carcinoma who have previously received a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy as well as for cisplatin-ineligible patients following prior therapy. The monoclonal antibody portion of the conjugate is directed at Nectin-4, “which is almost ubiquitously expressed in urothelial cancer,” Dr. Petrylak explained. The antibody is linked to monomethyl auristatin E (MMAE), a microtubule inhibitor. Once the drug is internalized into Nectin-4–expressing cells, MMAE is released by proteolytic cleavage, and the microtubule network disruption leads to cell-cycle arrest and apoptosis.

Study Details

Cohort H enrolled cisplatin-ineligible patients with clinical stage T2 to T4a muscle-invasive bladder cancer. Cancers of the upper urinary tract were excluded. All patients had at least 50% urothelial carcinoma pathology. Overall, 90% were male; the median age was 75 years; and 95.5% were current or former smokers. All patients were White. Stage T2 disease was present in 68%; T3, in 27.3%; and T4, in 4.5%. Transitional cell carcinoma was the predominant histologic type (69.2%).

Of 22 patients enrolled in the trial, 19 completed all three planned cycles of neoadjuvant enfortumab vedotin. The median duration of neoadjuvant treatment was 2.1 months. All patients underwent surgery as planned. The median time from the end of neoadjuvant therapy to surgery was 1.6 months.

The observed safety profile of neoadjuvant enfortumab vedotin monotherapy in patients with cisplatin-ineligible muscle-invasive bladder cancer is consistent with the known adverse event profile of the antibody-drug conjugate in other settings, Dr. Petrylak said. All patients experienced treatment-emergent adverse events. The overall incidence of grade 3 or higher treatment-related adverse events was low (4 patients; 18%), and no new safety signals were identified. 

DISCLOSURE: Dr. Petrylak reported financial relationships with Advanced Accelerator Applications, Amgen, Astellas Pharma, AstraZeneca, Bayer, Bellicum Pharmaceuticals, Bicycle Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Clovis Oncology, Exelixis, Gilead Sciences, Incyte, Ipsen, Janssen, Lilly, Mirati Therapeutics, Monopteros Therapeutics, Pfizer, Pharmacyclics, Regeneron, Roche, Sanofi, Seattle Genetics, TYME, and UroGen Pharma.

REFERENCE

1. Petrylak D, Flaig TW, Mar N, et al: Study EV-103 Cohort H: Antitumor activity of neoadjuvant treatment with enfortumab vedotin monotherapy in patients with muscle invasive bladder cancer who are cisplatin-ineligible. 2022 ASCO Genitourinary Cancers Symposium. Abstract 435. Presented February 18, 2022.