A Noteworthy Result in Bladder Cancer Treatment – Enfortumab Vedotin Plus Pembrolizumab

Metastatic (stage 4) urothelial carcinoma, cancer of the bladder and urinary tract, is treated as standard with first-line platinum-based chemotherapy. However, for patients unsuitable for platinum treatment, the alternative standard, gemcitabine plus carboplatin, may also be poorly tolerated and offer limited survival benefit. For this reason, the immune checkpoint inhibitor pembrolizumab (Keytruda) was studied in combination with the antibody–drug conjugate enfortumab vedotin (Padcev) to determine whether the combination could be an alternative for platinum-ineligible patients with locally advanced or metastatic urothelial carcinoma, in the EV-103 clinical trial . Early results of the study were presented at the 2020 Genitourinary (GU) Cancers Symposiumby Dr. Jonathan E. Rosenberg .

EV-103 Study Design and Results

• As of October 2019, platinum-ineligible patients with locally advanced or metastatic urothelial carcinoma, totaling 45 patients (median age = 69 years), received 1.25 mg/kg enfortumab vedotin (days 1 and 8) plus pembrolizumab (day 1).
• The study's primary endpoint was safety / tolerability.
• Patients received a median of 9 cycles of enfortumab vedotin + pembrolizumab.
• The objective response rate with enfortumab vedotin + pembrolizumab was %73, with %15.6 complete responses. The disease control rate was %93.3.
• The most common treatment adverse effect (% 58) was fatigue (% 11 at least grade 3), followed by alopecia (% 53) and peripheral sensory neuropathy (% 53; %4 at least grade 3).
• One patient died from an adverse event reported as treatment-related (multiple organ failure).
• Progression-free survival was 12.3 months, and at 1 year overall survival was % 81.6.
• Median response duration had not been reached because more than half of patients continued responding. Of 33 responders, 18 (% 55) had ongoing responses, and beyond 10 months there were 11 responses.

Conclusion

For first-line cisplatin-ineligible patients with metastatic urothelial carcinoma, enfortumab vedotin + pembrolizumab demonstrates promising activity and durability with a manageable safety profile.

• Enfortumab vedotin-ejfv received FDA approval for bladder cancers FURTHER READING

What Is Enfortumab Vedotin's Mechanism of Action?

Enfortumab vedotin-ejfv is the first FDA-approved Nectin-4-targeted antibody–drug conjugate.

Enfortumab vedotin is a first-in-class antibody–drug conjugate targeting Nectin-4, a cell-surface protein highly expressed in bladder cancer cells. Preclinical data suggest that its anticancer activity results from binding to Nectin-4-expressing cells, followed by entry and release of a microtubule, cellular cytoskeleton-disrupting antitumor agent. This stops cell proliferation and triggers apoptosis, programmed cell death (see the figure above). Enfortumab vedotin has been developed through collaboration between Seattle Genetics and Astellas since 2007.