Health Canada approves KEYTRUDA and Enfortumab Vedotin for advanced urothelial cancer

Merck (NYSE: MRK), known as MSD outside the United States and Canada, has announced that Health Canada has granted approval for KEYTRUDA (pembrolizumab) in combination with enfortumab vedotin for the treatment of adult patients with unresectable locally advanced or metastatic urothelial cancer (mUC) who have not received prior systemic therapy for this condition. This decision is based on compelling results from the Phase 3 KEYNOTE-A39 trial, which demonstrated notable improvements in overall survival (OS) and progression-free survival (PFS) compared to traditional platinum-based chemotherapy.

KEYNOTE-A39 Trial: A Major Breakthrough in Cancer Treatment

The Phase 3 KEYNOTE-A39 trial, also known as EV-302, was a rigorous open-label, multicenter, randomized, active-controlled study that compared the efficacy of the combination of pembrolizumab and enfortumab vedotin (P+EV) with gemcitabine plus platinum-based chemotherapy. Conducted in collaboration with Pfizer, formerly Seagen, and Astellas, the trial revealed a 53% reduction in the risk of death with the P+EV regimen (HR=0.47 [95% CI, 0.38-0.58]; p<0.0001) compared to the chemotherapy group. The median OS for the P+EV combination was 31.5 months, compared to 16.1 months for the standard chemotherapy arm.

In addition to improved overall survival, the combination therapy also showed statistically significant enhancements in progression-free survival and objective response rate (ORR), indicating a higher rate of tumor shrinkage and disease control among patients treated with P+EV. This improvement underscores the potential of combining immunotherapy with targeted therapies to provide more effective treatment options for advanced bladder cancer.

Expert Opinions and Clinical Impact

Dr. Srikala Sridhar, Professor in the Department of Medicine at the University of Toronto and a Genitourinary Medical Oncologist at the Princess Margaret Cancer Centre, highlighted the significance of this approval, stating, “Bladder cancer remains a critical cause of cancer-related mortality. The approval of this new combination therapy represents a significant advancement, providing patients with more effective treatment options and potentially extending survival.”

André Galarneau, PhD, Executive Director & Vice President, Oncology Business Unit at Merck Canada, commented on the impact of this approval: “This new combination therapy offers an important alternative for individuals with advanced bladder cancer. It reinforces our commitment to advancing cancer care in Canada and expanding the range of treatment options available to patients.”

Michelle Colero, Executive Director of Bladder Cancer Canada, also praised the development, noting, “Bladder cancer affects over 12,000 Canadians each year. This new approval broadens the range of available therapies, allowing for more personalized treatment plans that can improve outcomes for patients with advanced disease.”

Trial Details and Safety Profile

The KEYNOTE-A39 trial involved 865 patients with unresectable locally advanced or metastatic urothelial cancer who had not previously received systemic therapy. The primary efficacy endpoints were overall survival and progression-free survival, with additional measures including objective response rate assessed by blinded independent central review according to RECIST v1.1.

The safety profile of the P+EV combination was consistent with previous studies, with common adverse events including fatigue, pruritus, rash, decreased appetite, and hypothyroidism reported in at least 10% of patients. For detailed safety information, the KEYTRUDA product monograph should be consulted.

Urothelial Cancer: A Persistent Challenge

Urothelial cancer, which accounts for 90% of all bladder cancers, originates in the urothelial cells lining the bladder and can affect other parts of the urinary tract, including the renal pelvis, ureters, and urethra. In Canada, bladder cancer is the fifth most common cancer and the ninth leading cause of cancer-related deaths, with approximately 12,300 new cases diagnosed annually. The risk of bladder cancer increases with age, predominantly affecting individuals over 65 years, with a higher prevalence in Caucasian men.

Collaborative Efforts in Cancer Research

The clinical collaboration between Seagen (acquired by Pfizer in December 2023), Astellas, and Merck aimed to evaluate the efficacy of combining enfortumab vedotin with KEYTRUDA for treating metastatic urothelial cancer. This partnership reflects a broader trend in oncology towards integrating different therapeutic modalities to enhance treatment outcomes.

About KEYTRUDA

KEYTRUDA is an anti-PD-1 therapy designed to boost the immune system’s ability to recognize and combat tumor cells. It works by blocking the interaction between PD-1 and its ligands PD-L1 and PD-L2, thereby activating T lymphocytes to target both tumor and healthy cells. Since its initial approval in Canada in 2015, KEYTRUDA has been indicated for a range of cancers, including advanced bladder cancer, renal cell carcinoma, non-small cell lung carcinoma, and several others.