Patients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy proceed directly to radical cystectomy with pelvic lymph-node dissection. Perioperative therapy may improve outcomes in this population.
In this phase 3, open-label trial, participants with muscle-invasive bladder cancer who were ineligible for or declined cisplatin-based chemotherapy were randomly assigned to perioperative (neoadjuvant and adjuvant) enfortumab vedotin, an antibody–drug conjugate directed at nectin-4, plus pembrolizumab and surgery (9 total cycles of enfortumab vedotin [1.25 mg per kilogram of body weight on days 1 and 8] plus 17 total cycles of pembrolizumab [200 mg on day 1 every 3 weeks], with surgery after 3 cycles) or surgery alone (control). The primary end point was event-free survival. Key secondary end points were overall survival and pathological complete response (absence of viable tumor after surgical resection). Other secondary end points included safety.
A total of 344 participants underwent randomization (170 in the enfortumab vedotin–pembrolizumab group and 174 in the control group). At data cutoff, median follow-up was 25.6 months (range, 11.8 to 53.7). Surgery was performed in 87.6% of participants in the enfortumab vedotin–pembrolizumab group and in 89.7% in the control group. At 2 years, estimated event-free survival was 74.7% in the enfortumab vedotin–pembrolizumab group and 39.4% in the control group (hazard ratio for an event or death, 0.40; 95% confidence interval [CI], 0.28 to 0.57; two-sided P<0.001); estimated overall survival was 79.7% and 63.1% (hazard ratio for death, 0.50; 95% CI, 0.33 to 0.74; two-sided P<0.001). A pathological complete response had occurred in 57.1% and 8.6% of the participants (estimated difference, 48.3 percentage points; 95% CI, 39.5 to 56.5; two-sided P<0.001). Adverse events occurred in all participants in the enfortumab vedotin–pembrolizumab group (grade ≥3, 71.3%; grade ≥3 drug-related, 45.5%) and in 64.8% in the control group (grade ≥3, 45.9%).
Perioperative enfortumab vedotin plus pembrolizumab and surgery led to significantly better event-free and overall survival outcomes and a greater percentage of participants with pathological complete response than surgery alone in a predominantly cisplatin-ineligible population with muscle-invasive bladder cancer. Safety was also assessed. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-905 ClinicalTrials.gov number, NCT03924895.)
The rise of peri-operative enfortumab vedotin plus pembrolizumab: a new area for muscle-invasive bladder cancer patients
Perioperative systemic therapy in muscle invasive bladder cancer (MIBC) is undergoing rapid evolution, driven by the emergence of enfortumab vedotin (EV) combined with pembrolizumab. Historically, cisplatin ineligible patients (nearly half of all individuals with MIBC) have proceeded directly to radical cystectomy (RC), despite poor long term outcomes and a high risk of relapse. The phase III KEYNOTE 905/EV 303 trial [1] directly addresses this longstanding therapeutic gap, evaluating perioperative EV+pembrolizumab administered in conjunction with RC in a predominantly elderly, comorbidity burdened population.
The efficacy signals are remarkable. At two years, EV+pembrolizumab nearly doubled event free survival (74.7% versus 39.4%; HR 0.40; p<0.001) and produced a significant improvement in overall survival (79.7% versus 63.1%; HR 0.50; p<0.001) relative to surgery alone. Benefits emerged early and remained durable across prespecified subgroups, including patients with locally advanced disease (i.e. T3–T4a or N1). The pathological complete response (pCR) rate is unprecedented in cisplatin ineligible MIBC (57.1% with EV+pembrolizumab versus 8.6% with surgery alone; p<0.001) and mirrors the profound activity observed with this combination in metastatic urothelial carcinoma. Pathological downstaging (66% versus 13%) further demonstrated how effectively the neoadjuvant phase shapes outcomes.
These findings align closely with the recently presented phase III KEYNOTE B15/EV 304 trial, which examined EV+pembrolizumab as neoadjuvant therapy in cisplatin-eligible patients. EV 304 similarly reported strikingly high pCR (55.8% versus 32.5%; p<0.001) and downstaging (63.7% versus 45.2%) rates compared with standard cisplatin based chemotherapy. Together, EV 303 and EV 304 outline a coherent therapeutic narrative: EV anchored perioperative therapy is emerging as a foundational strategy across the full spectrum of MIBC, independent of cisplatin eligibility.
Toxicity, however, remains a central consideration. In EV 303, grade ≥3 adverse events occurred in over 70% of patients receiving EV+pembrolizumab, driven by known toxicities such as skin reactions, neuropathy, and immune mediated events. Despite this, surgical feasibility was preserved: rates of RC, surgical delay, and perioperative adverse events were comparable between arms, suggesting that the survival benefit observed with EV+pembrolizumab was achieved without compromising definitive surgery. This supports the pragmatic integration of EV based therapy in the perioperative setting, provided that vigilant monitoring and multidisciplinary management are in place.
Taken together, KEYNOTE 905/EV 303, reinforced by the parallel KEYNOTE B15/EV 304 results, represents a major turning point in the management of MIBC. For the first time, cisplatin ineligible patients gain access to a perioperative regimen that produces deep pathological responses and meaningful survival improvements. Importantly, these results should be interpreted within the context of a perioperative multimodal approach in which definitive RC remained a key component of treatment. As EV based strategies rapidly move toward global adoption, close collaboration between urologists and oncologists will be essential to optimise patient selection, manage toxicity, and define treatment sequencing in this emerging therapeutic paradigm.
[1] Vulsteke C, Adra N, Danchaivijitr P, Sabadash M, Rodriguez-Vida A, Zhang Z, et al; KEYNOTE-905/EV-303 Investigators. Perioperative Enfortumab Vedotin and Pembrolizumab in Bladder Cancer. N Engl J Med. 2026 Apr 2;394(13):1257-1269.