In patients with metastatic urothelial cancer (mUC) that has been heavily treated, enfortumab vedotin had a favorable tolerability profile, significant antitumor activity, and a 41% response rate, according to results from a phase 1 study presented at the annual meeting of the American Society of Clinical Oncology.
“The prognosis for patients with metastatic urothelial cancer is grim, so to be able to advance care in any way is huge,” said Daniel P. Petrylak, MD, professor of medicine (medical oncology) and of urology, Yale Cancer Center, New Haven, CT. “I am hopeful that our initial results will lead to further research and eventually improved treatment options for these patients.”
Nectin-4 is a cell adhesion molecule expressed by many solid tumors and, specifically, in metastatic urothelial cancers. Previous studies have identified it as a viable antibody-drug conjugate (ADC) target. Enfortumab vedotin is an investigational ADC that consists of an anti-Nectin-4 monoclonal antibody attached to monomethyl auristatin E, a microtubule-disrupting agent.
Researchers undertook this phase 1 study, and included 68 patients (median age: 67 years; 46 male) with solid tumors, including those with mUC, who had been previously treated with one or more previous chemotherapy regimens. All patients received varying doses of IV enfortumab vedotin once weekly for 3 of 4 weeks (0.5, 0.75, 1, and 1.25 mg/kg).
Using immunohistochemistry on archived tumor specimens, researchers assessed Nectin-4 expression, and quantified it via histochemical score (H-score). The primary endpoint of the study was tolerability, and the secondary endpoint, antitumor activity as determined every 8 weeks, according to RECIST v1.1 criteria.
In all, 62% of patients had received two or more previous chemotherapies in the metastatic setting, while 40% had undergone prior immune checkpoint inhibitor (CPI) therapy. Researchers found that Nectin-4 expression was prevalent and high among these patients, with a median H-score of 280.
In all, 85% of patients reported treatment-related adverse events (TRAEs), with diarrhea, fatigue, nausea, and pruritis reported in 25% or more of patients. Most were of grade 2 or less in severity, but 28% of patients did experience a TRAE of grade 3 or higher. The most common of these TRAEs, which occurred in 5 or more patients, included urinary tract infection (10%) and hypophosphatemia (9%). No treatment-related deaths occurred.
Among the 60 patients who underwent one or more post-baseline assessments, antitumor activity was seen across doses, and overall response rate (ORR) was 40% (95% CI: 27.6-53.5). In the 24 patients with prior exposure to CPI, ORR was 46% (95% CI: 25.6-67.2), and in 16 patients with liver metastasis, 44% (95% CI: 19.8-70.1).
At doses that were ≥ 1 mg/kg, complete responses were seen in three patients. Median treatment duration was 26 weeks, median duration of response 18 weeks, and median progression-free survival 17 weeks.