EV plus pembrolizumab approved in Canada for urothelial carcinoma

Health Canada has approved the combination of enfortumab vedotin (EV; Padcev) plus pembrolizumab (Keytruda) for the treatment of adult patients with unresectable locally advanced or metastatic urothelial carcinoma (la/mUC) who had not previously received systemic therapy for UC, Pfizer and Merck announced in separate news releases.^1,2

EV plus pembrolizumab was approved in the US for patients with la/mUC in December 2023.

“Bladder cancer is an important cause of cancer-related death. The approval of this new combination of an immunotherapy and an antibody drug conjugate represents a significant step forward for patients with advanced bladder cancer,” said Srikala Sridhar, MD, a professor in the department of medicine at the University of Toronto and a genitourinary medical oncologist at the Princess Margaret Cancer Centre in Canada.¹ “The availability of this new treatment means more options to help patients affected by this disease.”

The approval is supported by findings from the phase 3 EV-302 trial (KEYNOTE-A39; NCT04223856), in which the combination of EV plus pembrolizumab significantly extended overall survival (OS) and progression-free survival (PFS) vs platinum-based chemotherapy (gemcitabine plus cisplatin or carboplatin) in patients with previously untreated la/mUC.³

Specifically, at a median follow-up of 17.2 months, treatment with EV plus pembrolizumab reduced the rate of death by 53% vs chemotherapy. Patients in the combination arm demonstrated a median OS of 31.5 months compared with 16.1 months among patients treated with chemotherapy (HR, 0.47; 95% CI, 0.38 to 0.58; P < .001). Additionally, the median PFS was 12.5 months with EV/pembrolizumab vs 6.3 months with chemotherapy, translating to a 55% reduction in the rate of disease progression or death (HR, 0.45; 95% CI, 0.38 to 0.54; P < .001).

The combination of EV plus pembrolizumab also demonstrated significant improvements on the trial’s secondary end points of objective response rate (ORR), duration of response (DOR), and time to pain progression. In the combination arm, the confirmed ORR by blinded independent central review was 67.7% (95% CI, 63.1%-72.1%), vs 44.4% (95% CI, 39.7%-49.2%) in the chemotherapy arm (P < .00001). At the time of data analysis, the median DOR had not yet been reached in the combination arm; in the chemotherapy arm, the median DOR was 7 months. The median time to pain progression was 14.2 months in the EV/pembrolizumab arm vs 10 months in the chemotherapy arm (HR, 0.92; 95% CI, 0.72 to 1.17; P = .48).

The safety profile for the combination was consistent with previously reported safety findings from the phase 1/2 EV-103 trial (NCT03288545). In EV-302, treatment-related adverse events of grade 3 or higher were experienced by 55.9% of patients in the combination arm and 69.5% of those in the chemotherapy arm.

In total, the global, open-label phase 3 EV-302 trial enrolled 886 adult patients with previously untreated la/mUC. Patients were eligible for enrollment in the trial regardless of eligibility for cisplatin-based chemotherapy or PD-L1 status. Those included in the trial were randomly assigned 1:1 to receive EV (at a dose of 1.25 mg/kg of body weight intravenously on days 1 and 8) plus pembrolizumab (at a dose of 200 mg intravenously on day 1) (n = 442) or to chemotherapy (n = 444) with gemcitabine and either cisplatin or carboplatin, based on cisplatin eligibility. Patients in the EV/pembrolizumab cohort received a median of 12 cycles (range, 1-46) of treatment vs 6 cycles (range, 1-6) in the chemotherapy cohort.

The dual primary end points for the trial were PFS, per blinded independent central review, and OS. Secondary outcome measures included ORR, DOR, time to pain progression, and the incidence of adverse events.

Data from EV-302 also supported the US FDA approval of EV plus pembrolizumab for patients with la/mUC in December 2023. The combination is also currently under review in the European Union, China, and Japan.

References

1. PADCEV (enfortumab vedotin) in combination with pembrolizumab approved by Health Canada to treat advanced bladder cancer. News release. Pfizer Canada ULC. August 22, 2024. Accessed August 23, 2024. https://www.pfizer.ca/en/media-centre/padcev-enfortumab-vedotin-in-combination-with-pembrolizumab-approved-by-health-canada-to-treat-advanced-bladder-cance

2. Health Canada Approves KEYTRUDA for the treatment of adult patients with unresectable locally advanced or metastatic urothelial cancer (mUC) with no prior systemic therapy for mUC, in combination with enfortumab vedotin. News release. Merck. August 22, 2024. Accessed August 23, 2024. https://www.biospace.com/health-canada-approves-keytruda-for-the-treatment-of-adult-patients-with-unresectable-locally-advanced-or-metastatic-urothelial-cancer-muc-with-no-prior-systemic-therapy-for-muc-in-combination-with-enfortumab-vedotin

3. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial carcinoma. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117