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

FDA Approves Nivolumab for Adjuvant Treatment of Urothelial Carcinoma

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

Nivolumab was investigated in a randomized, double-blind, placebo-controlled trial (CHECKMATE-274; NCT02632409) of patients who were within 120 days of radical resection of UC of the bladder or upper urinary tract (renal pelvis or ureter) and at high risk for recurrence. Patients were randomized 1:1 to receive nivolumab 240 mg or placebo via IV infusion every two weeks for a maximum of one year or until they experienced disease recurrence or unacceptable toxicity.

The primary efficacy endpoint was investigator-assessed, disease-free survival (DFS) in the intent-to-treat (ITT) population and in patients with tumors expressing PD-L1 ≥ 1%. DFS was defined as time to first recurrence in the local urothelial and nonurothelial tracts, distant metastasis, or death. During a prespecified interim analysis, patients in the nivolumab arm versus placebo had a statistically significant improvement in DFS for both primary endpoints. In the ITT analysis, median DFS was 20.8 months (95% CI = 16.5, 27.6) in patients who received nivolumab compared to 10.8 months (95% CI = 8.3, 13.9) in patients who received placebo (hazard ratio = 0.70; 95% CI = 0.57, 0.86; p = 0.0008). For patients with tumors expressing PD-L1 ≥ 1%, median DFS was not reached (95% CI = 21.2, not estimable) in those who received nivolumab versus 8.4 months (95% CI = 5.6, 21.2) for patients who received placebo (hazard ratio = 0.55; 95% CI = 0.39, 0.77; p = 0.0005).

In an exploratory analysis of patients with PD-L1-negative tumors (58%), the unstratified DFS hazard ratio estimate was 0.83 (95% CI = 0.64, 1.08). Overall survival data is immature, with 33% of deaths in the overall randomized population. In the upper tract urothelial cancer subpopulation, 37 deaths occurred: 20 in the nivolumab arm and 17 in the placebo arm.

The most common adverse reactions (≥ 20%) reported for nivolumab in the trial were rash, fatigue, diarrhea, 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.

View the full prescribing information for nivolumab.

The review used the Real-Time Oncology Review pilot program, 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 FDA’s assessment.

FDA granted the application priority review for the indication. A description of FDA expedited programs is in the Guidance for IndustryꟷExpedited Programs for Serious ConditionsꟷDrugs and Biologics.

Healthcare professionals should report all serious adverse events they suspect to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.