Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma

Abstract

Background: The role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery is not clear.

Methods: In a phase 3, multicenter, double-blind, randomized, controlled trial, we assigned patients with muscle-invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed. The primary end points were disease-free survival among all the patients (intention-to-treat population) and among patients with a tumor programmed death ligand 1 (PD-L1) expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary end point.

Results: A total of 353 patients were assigned to receive nivolumab and 356 to receive placebo. The median disease-free survival in the intention-to-treat population was 20.8 months (95% confidence interval [CI], 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo (hazard ratio for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 74.5% and 55.7%, respectively (hazard ratio, 0.55; 98.72% CI, 0.35 to 0.85; P<0.001). The median survival free from recurrence outside the urothelial tract in the intention-to-treat population was 22.9 months (95% CI, 19.2 to 33.4) with nivolumab and 13.7 months (95% CI, 8.4 to 20.3) with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77.0% with nivolumab and 62.7% with placebo (hazard ratio for recurrence outside the urothelial tract or death, 0.72; 95% CI, 0.59 to 0.89). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 75.3% and 56.7%, respectively (hazard ratio, 0.55; 95% CI, 0.39 to 0.79). Treatment-related adverse events of grade 3 or higher occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. Two treatment-related deaths due to pneumonitis were noted in the nivolumab group.

Conclusions: In this trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population and among patients with a PD-L1 expression level of 1% or more. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 274 ClinicalTrials.gov number, NCT02632409.).

Figure 1.. Disease-free Survival.

Symbols represent patients with censored data. The percentage of patients who were alive and disease-free at 12 months may be unstable owing to censoring of data. PD-L1 denotes programmed death ligand 1.

Figure 2.. Disease-free Survival According to Subgroups in the Intention-to-Treat Population.

The hazard ratio was not computed for categories with fewer than 10 patients per trial group (denoted by NA [not applicable]). Confidence intervals are not adjusted for multiplicity. Arrows indicate that the limits of the confidence interval are not shown. Race or ethnic group was reported by the patient. Eastern Cooperative Oncology Group (ECOG) performance-status scores range from 0 to 5, with higher scores indicating greater disability. Combined pathological tumor stage and nodal status was not a prespecified subgroup. Patients with pT2N– disease were eligible only if they received neoadjuvant cisplatin-based chemotherapy. For the combination of tumor stage and nodal status, N– includes N0 and NX, and T0 includes pTX, pT0, and pTis. Previous chemotherapy regimens that were received by patients in the trial included carboplatin, cisplatin, cisplatin–doxorubicin–methotrexate–vinblastine, cisplatin–gemcitabine, doxorubicin, epirubicin, fluorouracil, gemcitabine, investigational agent, methotrexate, paclitaxel, tuberculin, vinblastine, and vincristine.

Figure 3.. Survival Free from Recurrence Outside the Urothelial Tract.

Symbols represent patients with censored data. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 12 months may be unstable owing to censoring of data.