On 19 August 2021, the US Food and Drug Administration (FDA) approved nivolumab (Opdivo, Bristol-Myers Squibb Co.) for the adjuvant treatment of patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection.

This is the first FDA approval for adjuvant treatment of patients with high-risk UC. The results supporting this approval also supported the conversion of nivolumab’s accelerated approval for advanced/metastatic UC to a regular approval.

Nivolumab was investigated in CHECKMATE-274 (NCT02632409), a randomised, double-blind, placebo-controlled study in patients who were within 120 days of radical resection of UC of the bladder or upper urinary tract (renal pelvis or ureter) at high risk of recurrence. Patients were randomised (1:1) to receive nivolumab 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 (DFS) in the intent-to-treat (ITT) population and in patients with tumours expressing PD-L1 ≥1%. DFS 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 DFS was demonstrated in patients on the nivolumab arm vs. placebo for both primary endpoints. In the ITT analysis, the median DFS 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 = 0.0008). For patients with tumours expressing PD-L1 ≥1%, median DFS 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 = 0.0005).

In an exploratory analysis of patients with PD-L1-negative tumours (58%), the unstratified DFS HR estimate was 0.83 (95% CI 0.64, 1.08).

The overall survival data is immature with 33% of deaths in the overall randomised population. In the upper tract UC subpopulation, 37 deaths occurred (20 in the nivolumab arm, 17 in the placebo arm).

The most common adverse reactions reported in ≥20% of patients who received nivolumab in CHECKMATE-274 were rash, fatigue, diarrhoea, pruritus, musculoskeletal pain, and urinary tract infection.

The recommended nivolumab dosage for adjuvant treatment of UC is 240 mg every 2 weeks or 480 mg every 4 weeks.

Full prescribing information for Opdivo is available here.

This review used the Real-Time Oncology Review pilot programme, which streamlined data submission prior to the filing of the entire clinical application, as well as the Assessment Aid and the Product Quality Assessment Aid, voluntary submissions from the applicant to facilitate the FDA’s assessment.

This application was granted priority review for this indication.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact FDA’s Oncology Center of Excellence Project Facilitate.