On August 19, 2021, the PD-1 inhibitor nivolumab was approved for adjuvant treatment of patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical resection.1
This is the first approval by the U.S. Food and Drug Administration for adjuvant treatment of patients with high-risk urothelial carcinoma. The findings on which this approval is based also support the conversion to regular approval of the 2017 accelerated approval of nivolumab for advanced or metastatic urothelial carcinoma.
Supporting Efficacy Data
Approval was supported by findings from the phase III double-blind CheckMate 274 trial (ClinicalTrials.gov identifier NCT02632409). In this study, 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 were randomly assigned to receive nivolumab at 240 mg (n = 353) or placebo (n = 356) every 2 weeks until recurrence, unacceptable toxicity, or for up to 1 year.
At a prespecified interim analysis, investigator-assessed 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 in the intent-to-treat population (hazard ratio [HR] = 0.70, 95% CI = 0.57–0.86, P = .0008) and not reached (95% CI = 21.2 months to not estimable) vs 8.4 months (95% CI = 5.6–21.2 months) among 140 vs 142 patients with PD-L1 tumor expression ≥ 1% (HR = 0.55, 95% CI = 0.39–0.77, P = .0005). In exploratory subgroup analyses, hazard ratios were 0.83 (95% CI = 0.64–1.08) in the PD-L1–negative population and 1.15 (95% CI = 0.74–1.80) among 149 patients with upper tract urothelial carcinoma.
How It Is Used
The recommended nivolumab dosage for this indication is 240 mg every 2 weeks or 480 mg every 4 weeks until disease recurrence, unacceptable toxicity, or for up to 1 year.
No dose reductions are recommended. Prescribing information provides instructions on dosage modifications for immune-mediated adverse reactions and infusion-related reactions.
In CheckMate 274, the most common adverse events of any grade in the nivolumab group (≥ 20%) were rash (36%), fatigue (36%), diarrhea (30%), pruritus (30%), musculoskeletal pain (28%), and urinary tract infection (22%). The most common grade 3 or 4 adverse events included urinary tract infection (6%), hepatitis (4%), and diarrhea (2.8%). The most common grade 3 or 4 laboratory abnormalities were increased lipase (12%), increased amylase (8%), and hyperkalemia (5%).
Serious adverse events occurred in 30% of patients, most commonly (≥ 2%) urinary tract infection. Treatment was discontinued due to adverse events in 18%. Fatal adverse events occurred in 1% of patients, including pneumonitis (0.6%).
Nivolumab has warnings/precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryofetal toxicity.
1. Opdivo (nivolumab) injection prescribing information, Bristol Myers Squibb Company, August 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s097lbl.pdf. Accessed September 7, 2021.