Laura Bukavina, MD, MPH, MSc, outlines key considerations in wake of KEYNOTE-B15 data

In a video discussing results from the phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124), Laura Bukavina, MD, MPH, MSc, highlighted the potential practice-changing impact of perioperative enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) for muscle-invasive bladder cancer (MIBC).

The study demonstrated significant improvements in event-free survival, overall survival, and pathologic complete response compared with cisplatin-based chemotherapy, representing the first regimen in nearly 25 years to outperform the long-standing standard for cisplatin-eligible patients.

Despite these encouraging outcomes, Bukavina emphasized that clinicians still lack clear biomarkers or clinical characteristics identifying which patient subgroups benefit most. Although the regimen appears poised to become a new standard across both cisplatin-eligible and ineligible populations, patient selection remains heavily influenced by tolerability. Ideal candidates are patients with good functional status who can withstand prolonged systemic therapy, which may extend to approximately 12 months when perioperative and adjuvant treatments are combined. High rates of grade 3 toxicities and treatment discontinuation underscore the importance of assessing frailty, particularly because many patients with bladder cancer are older and medically complex.

Counseling patients about treatment options presents additional challenges. Bukavina noted that urologists often focus on ensuring patients can complete systemic therapy while remaining surgical candidates. A key decision point arises when toxicity becomes significant, requiring clinicians to weigh continuing therapy against proceeding directly to cystectomy. She also stressed the need to discuss long-term risks unique to immunotherapy, as immune-related adverse events may persist months or even years after treatment—unlike chemotherapy toxicities, which are typically transient.

As immunotherapy and antibody-drug conjugates move earlier in treatment, questions about sequencing therapies are emerging. For patients who progress during perioperative therapy and become unresectable or metastatic, clinicians currently often transition to cisplatin-based chemotherapy, though evidence guiding post-immuno-ADC management remains limited. Bukavina described this evolving space as a “Wild West,” with treatment decisions increasingly driven by tumor biology, molecular testing, and clinical trial availability.