In the CheckMate 274 study, median disease-free survival (DFS) was significantly longer with adjuvant nivolumab than with placebo among patients with high-risk muscle-invasive urothelial carcinoma after radical surgery with curative intent. The study data show a significant and clinically meaningful benefit of adjuvant nivolumab, both in the intention-to-treat (ITT) population and in patients with a PD-L1 expression level of 1% or more. Adjuvant nivolumab was associated with the expected side effects. The findings are published by Dr. Dean F. Bajorin of the Department of Medicine, Memorial Sloan Kettering Cancer Center in New York, NY, US and colleagues in 3rd June 2021 issue of The New England Journal of Medicine.
The authors wrote in the study background that radical surgery involving cystectomy for tumours arising in the bladder or nephroureterectomy for tumours arising in the upper urinary tract is the standard of care for patients with muscle-invasive urothelial carcinoma. Although radical surgery is performed with curative intent, more than 50% of patients with pathological evidence of cancer invading through the muscularis propria or involving the regional lymph nodes will have metastatic recurrence.
There is no consensus regarding routine adjuvant cisplatin-based chemotherapy and some patients with urothelial carcinoma are ineligible for or decline neoadjuvant cisplatin-based chemotherapy. Despite a high risk of metastatic recurrence, no standard adjuvant systemic therapies have been shown to improve outcomes in patients with pathological evidence of residual disease after neoadjuvant cisplatin-based chemotherapy.
The phase III, multicentre, double-blind, randomised CheckMate 274 study was performed to evaluate the efficacy and safety of adjuvant nivolumab, as compared with placebo, in patients with muscle-invasive urothelial carcinoma after radical surgery. Patients received in a 1:1 ratio either nivolumab or placebo every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy before study entry was allowed. The primary endpoints were DFS in ITT population and among patients with a tumour PD-L1 expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary endpoint.
In total, 353 patients were assigned to receive nivolumab and 356 to receive placebo. The median DFS in the ITT 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 [HR] 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 (HR 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 ITT 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 (HR 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% (HR 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 in 7.2% of the placebo group. Two treatment-related deaths due to pneumonitis were noted in the nivolumab group.
The authors concluded that in this study involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, DFS was longer with adjuvant nivolumab than with placebo in the ITT population and among patients with a PD-L1 expression level of 1% or more. The study investigators plan further follow-up to assess overall survival.
The study was funded by Bristol Myers Squibb and Ono Pharmaceutical. The authors thanked the staff of Dako, an Agilent Technologies company, for collaborative development of the PD-L1 IHC 28-8 pharmDx assay.
Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med 2021;384:2102-2114. DOI: 10.1056/NEJMoa2034442.