On August 19, the U.S. Food and Drug Administration (FDA) approved the anti–PD-1 therapy nivolumab (Opdivo) for the adjuvant treatment of patients with urothelial carcinoma who are at high risk of disease recurrence after undergoing radical resection. This is the first FDA approval for adjuvant treatment of patients with high-risk urothelial carcinoma. The data supporting this approval also supported the conversion of nivolumab’s accelerated approval for advanced/metastatic urothelial carcinoma to a regular approval.
Nivolumab was investigated in CheckMate 274, a randomized, double-blind, placebo-controlled trial in patients who were within 120 days of radical resection of urothelial carcinoma of the bladder or upper urinary tract (renal pelvis or ureter) at high risk of recurrence. Patients were randomly assigned 1:1 to receive nivolumab at 240 mg or placebo by intravenous infusion every 2 weeks until recurrence or until unacceptable toxicity, for a maximum treatment duration of 1 year.
The primary efficacy endpoint was investigator-assessed disease-free survival in the intent-to-treat (ITT) population and in patients with tumors expressing PD-L1 ≥ 1%. Disease-free survival was defined as time to first recurrence (local urothelial tract, local non–urothelial tract, or distant metastasis) or death.
At a prespecified interim analysis, a statistically significant improvement in disease-free survival was demonstrated in patients in the nivolumab arm vs placebo for both primary endpoints. In the ITT analysis, the median disease-free survival was 20.8 months (95% confidence interval [CI] = 16.5–27.6) in patients who received nivolumab compared with 10.8 months (95% CI = 8.3–13.9) in patients who received placebo (hazard ratio [HR] = 0.70, 95% CI = 0.57–0.86, P = .0008). For patients with tumors expressing PD-L1 ≥ 1%, median disease-free survival was not reached (95% CI = 21.2–not estimable) in those who received nivolumab vs 8.4 months (95% CI = 5.6–21.2) for patients who received placebo (HR = 0.55, 95% CI = 0.39–0.77, P = .0005).
In an exploratory analysis of patients with PD-L1–negative tumors (58%), the unstratified disease-free survival hazard ratio estimate was 0.83 (95% CI = 0.64–1.08). Overall survival data are immature, with 33% of deaths in the overall randomized population. In the upper tract urothelial carcinoma subpopulation, 37 deaths occurred (20 in the nivolumab arm and 17 in the placebo arm).
The most common adverse reactions reported in ≥ 20% of patients who received nivolumab in CheckMate 274 were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and urinary tract infection.
The recommended nivolumab dosage for the adjuvant treatment of urothelial carcinoma is 240 mg every 2 weeks or 480 mg every 4 weeks.