As reported in The Lancet by Robert J. Motzer, MD, and colleagues, part A of the phase III CheckMate 914 trial has shown no improvement in disease-free survival with adjuvant nivolumab/ipilimumab vs placebo in resected localized clear cell renal cell carcinoma.

Part B of the trial is evaluating nivolumab monotherapy vs placebo in this setting.

Robert J. Motzer, MD

Study Details

The double-blind trial included 816 patients at high risk of recurrence after radical or partial nephrectomy from sites in 20 countries. They were randomly assigned between August 2017 and March 2021 to receive nivolumab at 240 mg every 2 weeks for 12 doses plus ipilimumab at 1 mg/kg every 6 weeks for 4 doses (n = 405) or placebo (n = 411). The expected treatment period was 24 weeks; treatment could be continued for 36 weeks to allow for treatment delays. The primary endpoint was disease-free survival according to masked independent central review in the intent-to-treat population.

Disease-Free Survival

Median follow-up was 37.0 months (interquartile range = 31.3–43.7 months). Disease-free survival events had occurred in 110 patients in the nivolumab/ipilimumab group and in 118 in the placebo group. Median disease-free survival was not reached in the nivolumab/ipilimumab group vs 50.7 months (95% confidence interval [CI] = 48.1 months to not estimable) in the placebo group (hazard ratio = 0.92, 95% CI = 0.71–1.19, P = .53). Rates at 24 months were 76% (95% CI = 72%–81%) vs 74% (95% CI = 69%–78%).

Subsequent systemic therapy was received by 57 patients (14%) in the nivolumab/ipilimumab group (most commonly a VEGF-targeted agent, in 55) and 77 patients (19%) in the placebo group (most commonly a PD-1 or PD-L1 inhibitor, in 53). The number of events required for the planned overall survival interim analysis was not reached at time of data cutoff; 61 deaths had occurred: 33 in the nivolumab/ipilimumab group and 28 in the placebo group.

Adverse Events

Grade ≥ 3 adverse events occurred in 38% of patients in the nivolumab/ipilimumab group vs 10% in the placebo group. Adverse events led to discontinuation of treatment in 32% vs 2% of patients. The most common grade 3 or 4 immune-mediated adverse events in the nivolumab/ipilimumab group were diarrhea/colitis (5%), adrenal insufficiency (3%), hypophysitis (3%), and hepatitis (3%).  Treatment-related adverse events led to death in four patients (1%) in the nivolumab/ipilimumab group, with causes consisting of immunotherapy-induced diarrhea/colitis; aortic dissection; ischemic cerebral infarction or pulmonary embolism; and drug-induced myocarditis. No treatment-related deaths occurred in the placebo group.

The investigators concluded, “Adjuvant therapy with nivolumab plus ipilimumab did not improve disease-free survival vs placebo in patients with localized renal cell carcinoma at high risk of recurrence after nephrectomy. Our study results do not support this regimen for the adjuvant treatment of renal cell carcinoma.”

Dr. Motzer, of the Department of Medicine, Memorial Sloan Kettering Cancer Center, is the corresponding author for The Lancet article.

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