Background
The role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery is not clear.
Methods
In a phase 3, multicenter, double-blind, randomized, controlled trial, we assigned patients with muscle invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed. The primary end points were disease-free survival among all the patients (intention-to-treat population) and among patients with a tumor programmed death ligand 1 (PD-L1) expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary end point.
Results
A total of 353 patients were assigned to receive nivolumab and 356 to receive placebo. The median disease-free survival in the intention-to-treat population was 20.8 months (95% confidence interval [CI], 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo (hazard ratio for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 74.5% and 55.7%, respectively (hazard ratio, 0.55; 98.72% CI, 0.35 to 0.85; P<0.001). The median survival free from recurrence outside the urothelial tract in the intention-to-treat population was 22.9 months (95% CI, 19.2 to 33.4) with nivolumab and 13.7 months (95% CI, 8.4 to 20.3) with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77.0% with nivolumab and 62.7% with placebo (hazard ratio for recurrence outside the urothelial tract or death, 0.72; 95% CI, 0.59 to 0.89). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 75.3% and 56.7%, respectively (hazard ratio, 0.55; 95% CI, 0.39 to 0.79). Treatment-related adverse events of grade 3 or higher occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. Two treatment-related deaths due to pneumonitis and one treatment-related death due to bowel perforation were noted in the nivolumab group.
Conclusions
In this trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population and among patients with a PD-L1 expression level of 1% or more. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 274 ClinicalTrials.gov number, NCT02632409.)
Expert’s comments
By Dr. Marco Moschini
In this phase 3, multicenter, double-blind, randomized, controlled trial, patients with muscle invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year. A total of 353 patients were assigned in the nivolumab and 356 in the placebo groups, respectively. All patients had a radical surgery (with negative surgical margins) within 120 days before randomization, with or without neoadjuvant cisplatin-based chemotherapy. Both bladder (radical cystectomy) and upper urinary tract tumor (treated with radical nephroureterectomy) with pa pathological stage of pT3, pT4 or pN+ and patient not eligible for or declined adjuvant cisplatin-based combination chemotherapy were enrolled. All patients were disease-free as determined by means of a complete physical examination and imaging within 4 weeks before randomization, had adequate tumor tissue for biomarker analysis and had an Eastern Cooperative Oncology Group performance-status score of 0 or 1.
The median disease-free survival in the intention-to-treat population was 20.8 months with nivolumab and 10.8 months with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo. Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 74.5% and 55.7%, respectively. Treatment-related adverse events of grade 3 or higher occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. Two treatment-related deaths due to pneumonitis and one treatment-related death due to bowel perforation were noted in the nivolumab group.
Expert’s summary
There is a paucity of adjuvant treatments for patients with locally advanced or node positive disease after radical cystectomy and radical nephroureterectomy. Adjuvant cisplatin-based chemotherapy has been the standard for many years, but these data suggests that Nivolumab might play an important role in this setting, even in those patients who received neoadjuvant cisplatin chemotherapy.