The treatment landscape for urothelial carcinoma is evolving, with the combination of enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) challenging the established role of platinum-doublet chemotherapy. According to Dr. Jacqueline Brown, this shift necessitates ongoing research to refine second-line treatment strategies and identify scenarios where the combination may not be suitable or accessible.
CheckMate 901 Trial: A Paradigm Shift
The phase 3 CheckMate 901 trial (NCT03036098) demonstrated a significant improvement in overall survival (OS), progression-free survival, and overall response rate with the addition of nivolumab (Opdivo) to cisplatin and gemcitabine in cisplatin-eligible patients with advanced urothelial carcinoma. This contrasts with the KEYNOTE-361 and IMvigor130 trials, which evaluated platinum-based chemotherapy plus immune checkpoint inhibition but yielded negative results. Dr. Brown noted that CheckMate 901 enrolled only cisplatin-eligible patients, potentially representing a healthier population compared to the platinum-eligible cohorts in the other trials, which included both cisplatin-eligible and -ineligible individuals.
NCCN Guidelines Update
As of May 2024, the National Comprehensive Cancer Network (NCCN) guidelines for bladder cancer favor enfortumab vedotin plus pembrolizumab for all patients, irrespective of cisplatin eligibility. While platinum-doublet chemotherapy with gemcitabine plus cisplatin followed by avelumab maintenance remains an option for cisplatin-eligible patients, it has been superseded by the enfortumab vedotin plus pembrolizumab combination. This shift has complicated second-line treatment recommendations, leaving oncologists with limited guidance due to the lack of data on optimal sequencing strategies.
Impact of Enfortumab Vedotin Plus Pembrolizumab Approval
The FDA approval of enfortumab vedotin plus pembrolizumab has led to a significant change in first-line treatment approaches. Dr. Brown suggests that cisplatin, gemcitabine, and dose-dense MVAC should be avoided in the first-line setting if a patient is eligible for enfortumab vedotin plus pembrolizumab, given the median OS of 31.5 months observed in the phase 3 EV-302 trial (NCT04223856). However, she acknowledges that certain patient characteristics, such as severe peripheral neuropathy, may pose challenges to using this combination.
Accessibility and Cost Considerations
Despite its clinical benefits, the high cost of enfortumab vedotin plus pembrolizumab, approximately $45,000 per 3-week cycle, raises concerns about accessibility. Dr. Brown emphasizes that this combination may not be available to underinsured or uninsured patients, as well as those in regions with limited access to advanced therapies. Consequently, cisplatin and gemcitabine remain essential tools in the treatment of bladder cancer due to their affordability.
