As reported in The New England Journal of Medicine by Dean F. Bajorin, MD, of the Department of Medicine, Memorial Sloan Kettering Cancer Center, 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 and among those with tumor PD-L1 expression ≥ 1%.¹

Dean F. Bajorin, MD

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 or until disease recurrence or discontinuation from the trial. Neoadjuvant cisplatin-based chemotherapy prior to trial entry was permitted. Randomization was stratified by PD-L1 expression level (≥ 1% vs < 1% or indeterminate), pathologic nodal status (N+ vs N0 or NX with < 10 nodes removed vs N0 with ≥ 10 nodes removed), and use vs no use of neoadjuvant cisplatin-based chemotherapy.

High risk of recurrence was defined as a pathologic stage of pT3, pT4a, or pN+ among patients who were ineligible for or declined adjuvant cisplatin-based chemotherapy and who had not received neoadjuvant cisplatin-based chemotherapy, and a pathologic stage of ypT2 to ypT4a or ypN+ for patients who had received neoadjuvant cisplatin-based chemotherapy.

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.

For the nivolumab vs placebo groups, mean age was 65 vs 66 years (range = 30–92 years, with 56% vs 61% ≥ 65 years), 75% vs 77% were male, and 75% vs 76% were White and 23% vs 21% were Asian. Eastern Cooperative Oncology Group performance status was 0 (64% vs 62%) or 1 in all patients except for 2% vs 3% with a performance status of 2. Tumor origin was urinary bladder in 79% vs 79%, renal pelvis in 13% vs 15%, and ureter in 9% vs 7%. Pathologic nodal stage was N+ in 47% vs 47%, N0 or NX with < 10 nodes removed in 27% vs 28%, and N0 with ≥ 10 nodes removed in 26% vs 25%. PD-L1 expression was ≥ 1% in 40% vs 40%, and 43% vs 44% 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 and 12 months were 74.9% vs 60.3% and 62.8% vs 46.6% (hazard ratio [HR] = 0.70, 98.22% CI = 0.55–0.90, P < .001). In the PD-L1 ≥ 1% population, disease-free survival rates at 6 and 12 months were 74.5% vs 55.7% and 67.2% vs 45.9% (HR = 0.55, 98.72% CI = 0.35–0.85, P < .001).

In additional stratification subgroups, hazard ratios for disease-free survival were 0.82 (95% CI = 0.63–1.06) among patients with PD-L1 expression < 1% (a total of 10 patients had indeterminate or unreported status); 0.64 (95% CI = 0.48–0.85) for pathologic N+ status, 0.85 (95% CI = 0.57–1.28) for N0 or NX with < 10 nodes removed, and 0.67 (95% CI = 0.41–1.10) for N0 with ≥ 10 nodes removed; and 0.52 (95% CI = 0.38–0.71) for neoadjuvant cisplatin-based chemotherapy and 0.92 (95% CI = 0.69–1.21) for no neoadjuvant cisplatin-based chemotherapy.

Distant metastasis–free survival at 6 and 12 months was 82.5% vs 69.8% and 71.2% vs 58.6% in the intention-to-treat population (HR = 0.75, 95% CI = 0.59–0.94) and 78.7% vs 65.7% and 72.9% vs 55.9% in the PD-L1 ≥ 1% population (HR = 0.61, 95% CI = 0.42–0.90).

Median survival free from recurrence outside the urothelial tract 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 rates at 6 and 12 months of 77.0% vs 62.7% and 65.1% vs 50.4% (HR = 0.72, 95% CI = 0.59–0.89). Rates at 6 and 12 months in the PD-L1 ≥ 1% population were 75.3% vs 56.7% and 68.7% vs 46.7% (HR = 0.55, 95% CI = 0.39–0.79).

Adverse Events

Grade ≥ 3 adverse events occurred in 42.7% of the nivolumab group vs 36.8% of the placebo group. Treatment-related adverse events of any grade occurred in 77.5% vs 55.5% of patients and were grade ≥ 3 in 17.9% vs 7.2%. The most common treatment-related adverse events of any grade in the nivolumab group were pruritus (23.1% vs 11.5%), fatigue (17.4% vs 12.1%), and diarrhea (16.8% vs 10.9%). The most common treatment-related grade ≥ 3 adverse events in the nivolumab group were increased lipase (5.1% vs 2.6%) and increased amylase (3.7% vs 1.4%), with colitis and pneumonitis occurring in 0.9% each.

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.

Potential immune-mediated adverse events of any grade consisted of gastrointestinal events in 18.5% of the nivolumab group vs 11.2% of the placebo group, hepatic events in 8.3% vs 4.9%, pulmonary events in 5.4% vs 1.4%, renal events in 7.1% vs 3.4%, skin events in 40.7% vs 17.8%, and endocrine events in 19.1% vs 3.7%.

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. Dr. Bajorin has served as a consultant or advisor to Bristol Myers Squibb Foundation, Dragonfly Therapeutics, Fidia Farmaceutici S.p.A., and Merck; has received institutional research funding from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Merck, Novartis, and Seattle Genetics/Astellas; and has been reimbursed for travel, accommodations, or other expenses by Merck.

REFERENCE

1. Bajorin DF, Witjes JA, Gschwend JE, et al: Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med 384:2102-2114, 2021.