Enfortumab vedotin plus pembrolizumab associated with improved survival in bladder cancer

1. In this phase 3 randomized controlled trial involving patients with muscle-invasive bladder cancer, perioperative enfortumab vedotin plus pembrolizumab significantly improved event-free survival, overall survival, and pathologic complete response compared with standard neoadjuvant cisplatin-gemcitabine.

2. The combination regimen was associated with a higher incidence of grade 3 or greater adverse events and treatment discontinuation.

Evidence Rating Level: 1 (Excellent) 

Study Rundown: Muscle-invasive bladder cancer is an aggressive malignancy with a substantial risk of recurrence and cancer-related mortality despite curative-intent surgery. Cisplatin-based neoadjuvant chemotherapy has long been the standard perioperative approach for eligible patients, but recurrence rates remain high, prompting investigation of novel perioperative strategies. In this international phase 3 randomized trial, investigators compared perioperative enfortumab vedotin (Padcev) plus pembrolizumab with standard neoadjuvant cisplatin-gemcitabine in patients eligible for cisplatin and radical cystectomy. The combination regimen resulted in superior event-free survival and overall survival while also producing substantially higher rates of pathologic complete response. These benefits were observed despite similar rates of definitive surgery between treatment groups, suggesting that improved outcomes reflected greater antitumor efficacy rather than differences in surgical management. Toxicity was greater with the investigational regimen, including more grade 3 or higher adverse events and more treatment discontinuations, although postoperative complication rates were generally comparable. Important limitations included the open-label design, which may have influenced aspects of clinical management despite blinded central efficacy assessment, relatively limited long-term follow-up for survival outcomes, and restricted generalizability to patients who were eligible for cisplatin-based chemotherapy and fit enough to receive prolonged perioperative systemic therapy. Additionally, the experimental arm incorporated both neoadjuvant and adjuvant treatment, making it difficult to determine the relative contribution of each phase to the observed benefit. Overall, these findings suggest perioperative enfortumab vedotin plus pembrolizumab may represent a new treatment option for cisplatin-eligible patients with muscle-invasive bladder cancer.

Click to read the study in NEJM

Relevant Reading: Neoadjuvant Chemotherapy plus Cystectomy Compared with Cystectomy Alone for Locally Advanced Bladder Cancer

In-Depth [randomized controlled trial]: This phase 3, multicenter, open-label randomized controlled trial evaluated perioperative enfortumab vedotin plus pembrolizumab against standard neoadjuvant cisplatin-gemcitabine in adults with cisplatin-eligible muscle-invasive bladder cancer who were candidates for radical cystectomy and pelvic lymph-node dissection. A total of 808 participants were randomized in a 1:1 ratio between the two groups. Patients assigned to the experimental arm received four neoadjuvant cycles of enfortumab vedotin and pembrolizumab, followed by cystectomy and additional adjuvant treatment with both agents. Patients in the control arm received four cycles of neoadjuvant cisplatin-gemcitabine followed by cystectomy. Randomization was stratified by PD-L1 combined positive score, clinical disease stage, and geographic region. The primary endpoint was event-free survival, while key secondary endpoints included overall survival and pathologic complete response. After a median follow-up of 33.6 months, an event or death had occurred in 21.5% of patients receiving enfortumab vedotin–pembrolizumab and 36.2% of those receiving cisplatin-gemcitabine. Estimated event-free survival at 24 months was 79.4% versus 66.2%, respectively, corresponding to a hazard ratio of 0.53 (95% confidence interval [CI], 0.41 to 0.70; p<0.001). Estimated overall survival at 24 months was 86.9% in the experimental group versus 81.3% in the control group, with a hazard ratio for death of 0.65 (95% CI, 0.48 to 0.89; p=0.006). Pathologic complete response occurred in 55.8% and 32.5% of patients, respectively (p<0.001), while pathologic downstaging below pT2N0 occurred in 63.7% versus 45.2%. Grade 3 or higher adverse events of any cause occurred in 75.7% of patients receiving enfortumab vedotin–pembrolizumab and 67.2% receiving cisplatin-gemcitabine. Drug-related treatment discontinuation was more frequent with the experimental regimen, at 35.2% versus 11.1%. Overall, perioperative enfortumab vedotin–pembrolizumab had greater toxicity but produced clinically meaningful improvements in disease control, survival, and pathologic response. 

Image: PD

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