Top Line: Is there an effective adjunct systemic therapy regimen for cisplatin-ineligible patients choosing definitive surgery for muscle-invasive bladder cancer (MIBC)?
The Study: In the international phase 3 trial KEYNOTE-905 344 patients planned for cystectomy for cT2–T4aN-1M0 MIBC who were ineligible for or declined cisplatin were randomized to +/- perioperative enfortumab vedotin (an antibody-drug conjugate targeting nectin-4) + pembrolizumab. Importantly, >75% of patients had ≥T3 disease and >80% were ≥65 years old, reflecting real-world demographics. Peri-op therapy was delivered for 3 neoadjuvant cycles and 6 adjuvant cycles plus another 8 infusions of pembro. Adjuvant immune checkpoint inhibition was allowed in the control arm and was received by 17%. At two years, peri-op enfortumab vedotin + pembro significantly improved event-free (75% vs 39%, HR 0.40) and overall (80% v 63%, HR 0.50) survival. Pathologic complete response was an eyebrow-raising 57% among the intention-to-treat cohort (and 65% among those proceeding to cystectomy) following neoadjuvant enfortumab vedotin + pembro versus 9% with surgery alone. Surgery rates and delays were similar between arms. The most common drug-related events were skin reactions and neuropathy. Now, the question every patient is asking: is there a commonsense approach to bladder preservation and de-escalation of prolonged therapy when 4 of 7 patients have no residual disease following only 3 cycles of enfortumab vedotin + pembro..?
TBL: The addition of enfortumab vedotin + pembro to cystectomy for cisplatin-ineligible MIBC dramatically improves disease control and survival. | Vulsteke, N Engl J Med 2026
The Study: In the international phase 3 trial KEYNOTE-905 344 patients planned for cystectomy for cT2–T4aN-1M0 MIBC who were ineligible for or declined cisplatin were randomized to +/- perioperative enfortumab vedotin (an antibody-drug conjugate targeting nectin-4) + pembrolizumab. Importantly, >75% of patients had ≥T3 disease and >80% were ≥65 years old, reflecting real-world demographics. Peri-op therapy was delivered for 3 neoadjuvant cycles and 6 adjuvant cycles plus another 8 infusions of pembro. Adjuvant immune checkpoint inhibition was allowed in the control arm and was received by 17%. At two years, peri-op enfortumab vedotin + pembro significantly improved event-free (75% vs 39%, HR 0.40) and overall (80% v 63%, HR 0.50) survival. Pathologic complete response was an eyebrow-raising 57% among the intention-to-treat cohort (and 65% among those proceeding to cystectomy) following neoadjuvant enfortumab vedotin + pembro versus 9% with surgery alone. Surgery rates and delays were similar between arms. The most common drug-related events were skin reactions and neuropathy. Now, the question every patient is asking: is there a commonsense approach to bladder preservation and de-escalation of prolonged therapy when 4 of 7 patients have no residual disease following only 3 cycles of enfortumab vedotin + pembro..?
TBL: The addition of enfortumab vedotin + pembro to cystectomy for cisplatin-ineligible MIBC dramatically improves disease control and survival. | Vulsteke, N Engl J Med 2026