Nivolumab Received FDA Approval as Postoperative Preventive Treatment for Bladder Cancer

On August 19, 2021, the FDA approved, regardless of prior neoadjuvant chemotherapy, lymph node involvement or PD-L1 status, treatment after radical surgery for patients at high risk of recurrence (relapse) of urothelial carcinoma (bladder and urinary tract cancer): adjuvant (preventive) treatment with nivolumab (Opdivo), a form of immunotherapy.

This approval is an important milestone for patients who have undergone major surgery to remove the bladder or part of the urinary tract and need additional treatment approaches that can help reduce their risk of urothelial carcinoma recurrence.

In the checkpoint inhibitor class, nivolumab is a next-generation immunotherapy found to be highly effective as adjuvant treatment in patients who had undergone surgery for muscle-invasive urothelial carcinoma; at the 2021 Genitourinary Cancers Symposium, the CheckMate 274 study announced this finding. The study drew attention as one of the most important developments in oncology in the last 5 years.

• The most important result of the study was median disease-free survival: with immunotherapy, 20.8 months (95% CI: 16.5 - 27.6) versus placebo, 10.8 months (95% CI: 8.3 - 13.9).
• Compared with placebo, nivolumab produced a 30% reduction in the risk of disease recurrence or death (HR, 0.70; 95% CI: 0.57 - 0.86; P = .0008).

In patients whose tumors had PD-L1 positivity of 1% or higher, median disease-free survival with nivolumab had not yet been reached (95% CI: 21.2 - not evaluable). In this group, median disease-free survival with placebo was 8.4 months (95% CI: 5.6 - 21.2). In this subgroup, immunotherapy produced a 45% reduction in the risk of disease recurrence or death (HR, 0.55; 95% CI, 0.39 - 0.77; P = .0005).

The CheckMate-274 data provide evidence regarding disease progression during or after platinum-containing chemotherapy, or disease progression within 1 year, in locally advanced or metastatic urothelial carcinoma patients, for nivolumab's 2017 accelerated FDA approval. They serve as confirmatory evidence for that use. Findings from the current study support converting accelerated approval to regular approval in this setting.

Study Details

The multicenter, double-blind, placebo-controlled CheckMate-274 study enrolled patients with ypT2-ypT4a or yPN-positive muscle-invasive urothelial carcinoma (MIUC) who had received neoadjuvant sisplatin chemotherapy. Patients with pT3-pT4a or pN-positive muscle-invasive urothelial cancer who had not received prior neoadjuvant sisplatin chemotherapy and were ineligible for, or unwilling to receive, adjuvant sisplatin chemotherapy were also allowed to participate.

Patients also had to have undergone radical surgery within the last 120 days and have disease-free status within 4 weeks after the first dose of the study drug.

Participants were randomized 1:1 to receive 240 mg nivolumab every 2 weeks (353 patients) or IV placebo every 2 weeks (356 patients). They received adjuvant treatment for up to 1 year.

Patients were stratified by PD-L1 expression (<1% versus ≥1%), prior neoadjuvant sisplatin-based chemotherapy (yes or no), and pathological nodal status.

The primary endpoints were investigator-assessed disease-free survival in all patients and disease-free survival in all patients with PD-L1 expression of 1% or higher. Secondary endpoints were non-urothelial recurrence-free survival, disease-specific survival and overall survival. Exploratory endpoints included distant metastasis-free survival, safety and health-related quality of life.

The 2021 Genitourinary Cancers Symposium reported that the mean age of participants across the arms was 65.6, 76.1% were male, 48.1% were from Europe and 62.8% had ECOG performance status 0. At initial diagnosis, the tumor originated in the bladder in 78.9% of patients, with upper urinary tract disease in the remainder. PD-L1 expression was 1% or higher in 39.8% of patients. In addition, 43.4% had received prior neoadjuvant sisplatin chemotherapy.

Adverse events from any cause occurred in 98.9% of the nivolumab arm and 95.4% of the placebo arm; grade 3 or higher adverse events occurred in 42.7% and 36.8%, respectively. In the immunotherapy arm, 12.8% stopped the drug because of treatment-related toxicities, whereas 2% receiving placebo stopped because of adverse events.

The most common grade 3 or higher treatment-related adverse events reported with nivolumab included diarrhea (0.9%), colitis (0.9%) and pneumonitis (0.9%). In the placebo arm, the most common adverse events were colitis (0.6%), diarrhea (0.3%), increased gamma-glutamyltransferase (0.3%) and hepatitis (0.3%).