CheckMate 274: Adjuvant nivolumab ups DFS in high-risk MIUC

Treatment with the PD-1 immune checkpoint inhibitor nivolumab after radical surgery significantly extends disease-free survival (DFS) compared with placebo in patients with muscle-invasive urothelial carcinoma (MIUC) at high risk of recurrence, regardless of their PD-L1 status, according to the CheckMate 274 study presented at the 2021 ASCO GUCS. 

Currently, the standard of care for MIUC is neoadjuvant cisplatin-based chemotherapy followed by radical surgery by removing the bladder. However, some patients are reluctant to undergo chemotherapy or ineligible for cisplatin due to poor kidney function, pointed out lead author Dr Dean Bajorin of Memorial Sloan Kettering Cancer Center in New York, New York, US.

“Even with the current standard of care — surgery with or without presurgery chemotherapy — MIUC has a high risk of recurring. These new findings show that treating patients at highest risk of recurrence with an immunotherapy after surgery can help extend the time until the disease returns,” said Dr Robert Dreicer, ASCO expert in genitourinary cancers.

The phase III, double-blind, multicentre study randomized 709 patients (mean age 65 years) with high-risk MIUC (involving bladder, renal pelvis, or ureter) in a 1:1 ratio to receive intravenous (IV) nivolumab 240 mg Q2W or IV placebo for up to 1 year of adjuvant therapy, following a recent radical surgery. Patients had either received prior neoadjuvant cisplatin chemotherapy or had not undergone prior neoadjuvant cisplatin or were ineligible/ refused cisplatin-based chemotherapy.

After a median follow-up of around 20 months, the primary endpoint of DFS was almost doubled in nivolumab-treated patients compared with those on placebo (median, 21.0 vs 10.9 months; hazard ratio [HR], 0.70; p<0.001). [ASCO GUCS 2021, abstract 391]

Among a subset of patients with PD-L1 levels ≥1 percent (PD-L1-positive), the improvement in DFS with nivolumab was even more pronounced (median, not reached vs 10.8 months; HR, 0.53; p<0.001).

“Nivolumab is the first immune therapy to be used in the adjuvant setting that provides a statistically significant and clinically meaningful improvement in DFS for patients with high-risk MIUC after radical surgery with curative intent, irrespective of PD-L1 status,” said Bajorin.

Moreover, the secondary outcome of non–urothelial tract recurrence-free survival (NUTRFS) was also prolonged in the nivolumab arm vs the placebo arm (median, 24.6 vs 13.7 months; HR, 0.72; 95 percent confidence interval [CI], 0.58–0.89) in the intention-to-treat population. Again, the NUTRFS benefit was even greater in the PD-L1-positive (median, not reached vs 10.9 months; HR, 0.54; 95 percent CI, 0.38-0.77).

The exploratory outcome of distant metastasis-free survival (DMFS) was similarly longer with nivolumab vs placebo in both the in both the intention-to-treat population (median, 35.0 vs 29.0 months; HR, 0.74, 95 percent CI, 0.58–0.93) and the PD-L1 positive subgroup (median, not reached vs 21.2 months; HR, 0.60, 95 percent CI, 0.41–0.88).

“The safety and tolerability of nivolumab was consistent with previous reports in other tumour types, including in patients with metastatic UC,” Bajorin reported.  

Treatment-related adverse effects (TRAEs) of grade 3–4 occurred in 17.9 percent of patients in the nivolumab arm compared with 7.2 percent in the placebo arm — with colitis, diarrhoea, and pneumonitis being most common in the nivolumab arm; while colitis, diarrhoea, hepatitis, and elevated gamma-glutamyl transferase levels most frequently reported in the placebo arm.

“No deterioration in HRq=QoL, as measured by change in EORTC QLQ-C30 global health status score, was observed with nivolumab vs placebo,” Bajorin noted.

“These results support nivolumab monotherapy as a new standard of care in the adjuvant setting for patients with high-risk MIUC after radical surgery regardless of PD-L1 status and prior neoadjuvant chemotherapy,” he stated.