FDA Approves Adjuvant Nivolumab for High-Risk Urothelial Carcinoma


The FDA has approved nivolumab for the adjuvant treatment of patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical resection, irrespective of prior neoadjuvant chemotherapy, nodal involvement or PD-L1 status.



The FDA has approved nivolumab (Opdivo) for the adjuvant treatment of patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical resection, irrespective of prior neoadjuvant chemotherapy, nodal involvement or PD-L1 status.1

The regulatory decision is based on data from the phase 3 CheckMate-274 trial (NCT02632409), in which the immunotherapy resulted in a median disease-free survival (DFS) that was nearly double that reported in those who received placebo, at 20.8 months (95% CI, 16.5-27.6) and 10.8 months (95% CI, 8.3-13.9), respectively. Nivolumab resulted in a 30% reduction in the risk of disease recurrence or death vs placebo (HR, 0.70; 95% CI, 0.57-0.86; P = .0008).

In the patients whose tumors had a PD-L1 expression of 1% or higher, the median DFS had not yet been reached (95% CI, 21.2–not evaluable) with nivolumab vs 8.4 months (95% CI, 5.6-21.2) with placebo. In this subset, the immunotherapy resulted in a 45% reduction in the risk of disease recurrence or death (HR, 0.55; 95% CI, 0.39-0.77; P = .0005).

Data from CheckMate-274 serve as confirmatory evidence for the February 2017 accelerated approval that was granted to nivolumab for use in patients with locally advanced or metastatic urothelial carcinoma who experience disease progression during or after platinum-containing chemotherapy or who have disease progression within 1 year of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy.2 The findings from the trial support the conversion of the accelerated approval into a regular approval in this setting.

“This approval is a major milestone for patients who have undergone major surgery to remove the bladder or parts of the urinary tract and are in need of additional treatment approaches that can help reduce the risk of their urothelial carcinoma returning,” Matthew D. Galsky, MD, primary trial investigator, professor of medicine, director of Genitourinary Medical Oncology, co-director of the Center of Excellence for Bladder Cancer, and associate director for Translational Research at The Tisch Cancer Institute and the Icahn School of Medicine at Mount Sinai, stated in a press release. “Nivolumab provides a new FDA-approved treatment shown to reduce the risk of disease recurrence or death based on the safety and efficacy findings from CheckMate-274, and has the potential to become a new standard-of-care option in this setting.”

The multicenter, double-blind, placebo-controlled CheckMate-274 trial enrolled patients with ypT2-ypT4a or yPN-positive muscle-invasive urothelial carcinoma (MIUC) who had received neoadjuvant cisplatin chemotherapy.3 Patients with pT3-pT4a or pN-positive MIUC who did not receive prior neoadjuvant cisplatin chemotherapy and were not candidates for or refused adjuvant cisplatin chemotherapy, were also permitted.

Additionally, patients were required to have undergone radical surgery within the past 120 days and to have disease-free status within 4 weeks of dosing on the trial.

Study participants were randomized 1:1 to receive intravenous (IV) nivolumab at a dose of 240 mg every 2 weeks (n = 353) or IV placebo every 2 weeks (n = 356). They received adjuvant treatment for up to 1 year.

Patients were stratified based on PD-L1 expression (<1% vs ≥1%), prior neoadjuvant cisplatin-based chemotherapy (yes vs no), and pathologic nodal status (N-positive vs N0/x with <10 nodes removed vs N0 with ≥10 nodes removed).

The primary end points of the trial were investigator-assessed DFS in the intent-to-treat population and DFS in all randomized patients with a PD-L1 expression of 1% or higher. Key secondary end points comprised non–urothelial tract recurrence-free survival, disease-specific survival, and overall survival. Exploratory end points included distant metastasis-free survival, safety, and health-related quality of life (HRQoL).

At the time of the 2021 Genitourinary Cancers Symposium, study participants across the arms had a mean age of 65.6 years, 76.1% were male, 48.1% were from Europe, and 62.8% had an ECOG performance status of 0. Moreover, the tumor origin at initial diagnosis for 78.9% of patients was the urinary bladder, and the remainder had upper tract disease. By interactive voice-response system, 39.8% of patients had a PD-L1 expression of 1% or higher. Additionally, 43.4% of patients had previously received neoadjuvant cisplatin chemotherapy.

Regarding safety, any-cause adverse effects (AEs) were experienced by 98.9% of those on the nivolumab arm (n = 351) vs 95.4% of those on the placebo arm (n = 348); 42.7% vs 36.8% of patients, respectively, experienced grade 3 or higher AEs. Additionally, 77.5% and 55.5% of those on the investigative and control arms, respectively, experienced treatment-related AEs; these effects were grade 3 or higher in 17.9% and 7.2% of patients, respectively. Just under 13% (12.8%) of patients who received the immunotherapy discontinued the drug because of treatment-related toxicities vs 2.0% of those on placebo.

The most common grade 3 or higher treatment-related select AEs reported with nivolumab included diarrhea (0.9%), colitis (0.9%), and pneumonitis (0.9%). In the placebo arm, the most frequently experienced effects were colitis (0.6%), diarrhea (0.3%), gamma-glutamyltransferase increase (0.3%), and hepatitis (0.3%).


  1. US Food and Drug Administration approves Opdivo (nivolumab) for the adjuvant treatment of patients with high-risk urothelial carcinoma. News release. Bristol Myers Squibb. August 20, 2021. Accessed August 20, 2021. https://bit.ly/3mevpR8
  2. Nivolumab for treatment of urothelial carcinoma. News release. FDA. February 2, 2017. Accessed August 20, 2021. https://bit.ly/37XpYh2
  3. Bajorin DF, Witjes A, Gschwend J, et al. First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab vs placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC). J Clin Oncol. 2021;39(suppl 6):391. doi:10/1200/JCO.2021.39.6_suppl.391
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