As reported in The New England Journal of Medicine by Dean F. Bajorin, MD, and colleagues, an interim analysis of the phase III CheckMate 274 trial has shown improved disease-free survival with adjuvant nivolumab vs placebo among all patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, as well as among those with tumor PD-L1 expression ≥ 1%.

Study Details

In the double-blind trial, 709 high-risk patients at sites in 29 countries who had undergone radical surgery were randomly assigned between April 2016 and January 2020 to receive adjuvant nivolumab at 240 mg (n = 353) or placebo (n = 356) every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy prior to trial entry was permitted. High risk of recurrence was defined as: pathologic stage of pT3, pT4a, or pN+ and patients not eligible for or declined adjuvant cisplatin-based combination chemotherapy among patients who had not received neoadjuvant cisplatin-based chemotherapy; and pathologic stage of ypT2 to ypT4a or ypN+ for patients who received neoadjuvant cisplatin.

The dual primary endpoints were investigator-assessed disease-free survival in the intention-to-treat population and in the population of patients with tumor PD-L1 expression ≥ 1%. The PD-L1 ≥ 1% population consisted of 140 patients in the nivolumab group and 142 patients in the placebo group. A total of 43.3% of patients in the nivolumab group and 43.5% in the placebo group had received neoadjuvant cisplatin-based chemotherapy.

Disease-Free Survival

Median follow-up was 20.9 months (range = 0.1–48.3 months) in the nivolumab group and 19.5 months (range = 0–50.0 months) in the placebo group, with a minimum follow-up of 5.9 months.

In the intention-to-treat population, median disease-free survival was 20.8 months (95% confidence interval [CI] = 16.5–27.6 months) in the nivolumab group vs 10.8 months (95% CI = 8.3–13.9 months) in the placebo group. Rates at 6 months were 74.9% vs 60.3% (hazard ratio [HR] = 0.70, 98.22% CI = 0.55–0.90, P < .001). In the PD-L1 ≥ 1% population, disease-free survival at 6 months was 74.5% vs 55.7% (HR = 0.55, 98.72% CI = 0.35–0.85, P < 0.001).

Median survival free from recurrence outside the urothelial tract (a secondary endpoint) was 22.9 months (95% CI = 19.2–33.4 months) with nivolumab and 13.7 months (95% CI = 8.4–20.3 months) with placebo in the intention-to-treat population, with 6-month rates of 77.0% vs 62.7% (HR = 0.72, 95% CI = 0.59–0.89). Rates at 6 months in the PD-L1 ≥ 1% population were 75.3% vs 56.7% (HR = 0.55, 95% CI = 0.39–0.79)

Adverse Events

Grade ≥ 3 adverse events occurred in 42.7% of patients in the nivolumab group vs 36.8% of the placebo group and were considered related to treatment in 17.9% vs 7.2%. The most common treatment-related grade ≥ 3 adverse events in the nivolumab group were increased lipase (5.1% vs 2.6% in placebo group) and increased amylase (3.7% vs 1.4%), with colitis and pneumonitis occurring in 0.9% each.  The most common treatment-related adverse events of any grade in the nivolumab group were pruritus (23.1%), fatigue (17.4%), and diarrhea (16.8%). Treatment-related adverse events of any grade led to discontinuation of treatment in 12.8% vs 2.0% of patients, with the most common causes in the nivolumab group being pneumonitis (1.7%), rash (1.1%), colitis (0.9%), and increased alanine aminotransferase (0.9%). Treatment-related adverse events led to death in two patients in the nivolumab group, with the cause being pneumonitis in both patients.

The investigators concluded, “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.”

Disclosure: The study was funded by Bristol Myers Squibb and Ono Pharmaceutical. For full disclosures of the study authors, visit nejm.org.