Adjuvant nivolumab confers survival benefit for bladder cancer

In patients with high-risk muscle-invasive urothelial carcinoma (miUC) who had undergone radical surgery, disease-free survival (DFS) was longer among those who received adjuvant nivolumab vs those on placebo, according to interim findings from the phase III CheckMate 274 trial.

Radical surgery involving cystectomy* or nephroureterectomy** is the standard of care for miUC. [Eur Urol 2017;71:462-475] “[However,] although radical surgery is performed with curative intent, >50 percent of patients with pathological evidence of cancer invading through the muscularis propria or involving the regional lymph nodes will have lethal metastatic recurrence,” said the researchers.

Adjuvant cisplatin-based chemotherapy (CT) may improve outcomes following definitive surgery in cisplatin-eligible individuals who have not received neoadjuvant CT. However, no previous adjuvant systemic therapies have been proven to improve outcomes in cisplatin-ineligible individuals or those with pathologic evidence of residual disease despite neoadjuvant cisplatin-based CT, they continued.

“[Our] trial showed a significant and clinically meaningful benefit of adjuvant systemic immunotherapy vs placebo, both in the intention-to-treat (ITT) cohort and in patients with ≥1 percent PD-L1 expression level,” they said.

A total of 709 participants (mean age 65 years, 76 percent male; n=282 with ≥1 percent PD-L1 expression level) were randomized 1:1 to receive either IV nivolumab 240 mg or placebo Q2W for up to 1 year or until recurrence or trial discontinuation. [N Engl J Med 2021;384:2102-2114]

In the ITT cohort, median DFS was twice as long with nivolumab vs placebo (20.8 vs 10.8 months). At 6 months, 75 percent of nivolumab recipients were alive and disease-free as opposed to 60 percent of those on placebo (hazard ratio [HR] for disease recurrence or death, 0.70; p<0.001).

A similar trend was seen in the subgroup of individuals with ≥1 percent PD-L1 expression level (74 percent vs 56 percent; HR, 0.55; p<0.001).

In terms of recurrence-free survival (RFS) outside the urothelial tract, median RFS was longer with nivolumab vs placebo in the ITT cohort (22.9 vs 13.7 months). More nivolumab vs placebo recipients were alive and recurrence-free at 6 months, both in the ITT cohort (77 percent vs 63 percent; HR, 0.72) and in individuals with ≥1 percent PD-L1 expression level (75 percent vs 57 percent; HR, 0.55).

There was a higher incidence of grade ≥3 treatment-related adverse events (TRAEs) with nivolumab vs placebo (18 percent vs 7 percent). The most common grade ≥3 TRAEs tied to nivolumab were elevated levels of lipase (5 percent) and amylase (4 percent).

The incidence of any-grade TRAEs leading to discontinuation was also higher with nivolumab vs placebo (13 percent vs 2 percent), the most frequent being pneumonitis (2 percent). Three treatment-related deaths (two due to pneumonitis and one due to bowel perforation) were associated with nivolumab.

Overall, the safety profile of nivolumab ties with that seen in other trials on metastatic UC and other cancers. [Lancet Oncol 2016;17:1590-1598; Lancet Oncol 2017;18:312-322; N Engl J Med 2015;373:1803-1813]

“[Taken together, our findings suggest that] nivolumab improved clinical outcomes when administered as adjuvant therapy to patients with UC at high risk for local and metastatic recurrence after surgery,” said the researchers. “These initial results … may thus affect clinical decision making in this context,” they added.

Data on other endpoints, including overall survival, shall follow to further shed light on the potential of nivolumab in this setting. Further exploration shall also ascertain subgroup findings reflecting larger effect sizes in patients with bladder UC vs those with renal pelvic and ureteral tumours, as well as in patients previously treated with neoadjuvant CT vs those who were not.