Adjuvant Nivolumab in High-Risk Muscle-Invasive Urothelial Carcinoma: Expanded Efficacy From CheckMate 274

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.CheckMate 274 is a phase III, randomized, double-blind trial of adjuvant nivolumab versus placebo for muscle-invasive urothelial carcinoma (MIUC) at high risk of recurrence after radical resection. The primary end points of disease-free survival (DFS) in intent-to-treat (ITT) and tumor PD-L1 expression ≥1% populations were met. We report results at an extended median follow-up of 36.1 months in the ITT population. In addition, we report interim overall survival (OS) data for the first time and an exploratory analysis among patients with bladder primary tumors (muscle-invasive bladder cancer [MIBC]). Consistent DFS benefit with nivolumab versus placebo was observed in both the ITT (hazard ratio [HR], 0.71 [95% CI, 0.58 to 0.86]) and PD-L1 ≥1% (HR, 0.52 [95% CI, 0.37 to 0.72]) patients. The HR for OS with nivolumab versus placebo was 0.76 (95% CI, 0.61 to 0.96) in the ITT population and 0.56 (95% CI, 0.36 to 0.86) in the PD-L1 ≥1 population. Continuous benefit in nonurothelial tract recurrence-free survival and distant metastasis-free survival was also observed in both patient populations. The exploratory analysis of patients with MIBC also showed continued efficacy benefits, irrespective of PD-L1 status. No new safety signals were reported. Overall, these results further support adjuvant nivolumab as a standard of care for high-risk MIUC after radical resection.

Trial registration: ClinicalTrials.gov NCT02632409.

FIG 1.

(A) Disease-free survival. (B) Overall survival. (C) Nonurothelial tract recurrence-free survival. (D) Distant metastasis-free survival. (E) Second progression-free survival. Kaplan-Meier estimates of efficacy outcomes in ITT patients. Marks indicate censored observations. ^aSubsequent systemic therapies categorized as adjuvant (n = 6) were not considered in PFS2 derivation. DFS, disease-free survival (the time between the date of random assignment and the date of first recurrence [local urothelial tract, local nonurothelial tract [in pelvic soft tissue or involving pelvic nodes below the aortic bifurcation, or distant] or death [of any cause], whichever occurred first); DMFS, distant metastasis-free survival (the time between the date of random assignment and the date of first distant recurrence [non-local] or date of death [whatever the cause], whichever occurred first); HR, hazard ratio; ITT, intent-to-treat; NE, not estimable; NUTRFS, nonurothelial tract recurrence-free survival (the time between the date of random assignment and the date of first local nonurothelial tract or distant recurrence or death [of any cause], whichever occurred first); OS, overall survival (time between the date of random assignment and the date of death [of any cause]); PFS2, second progression-free survival (time from random assignment to disease progression after subsequent next-line systemic anticancer therapy, start of second subsequent next-line systemic anticancer therapy, or death from any cause, whichever occurred first).

FIG 2.

(A) Disease-free survival. (B) Overall survival. (C) Nonurothelial tract recurrence-free survival. (D) Distant metastasis-free survival. (E) Second progression-free survival. Kaplan-Meier estimates of efficacy outcomes in patients with tumor PD-L1 expression ≥1%. Marks indicate censored observations. ^aSubsequent systemic therapies categorized as adjuvant (n = 2) were not considered in PFS2 derivation. DFS, disease-free survival (the time between the date of randomization and the date of first recurrence [local urothelial tract, local nonurothelial tract (in pelvic soft tissue or involving pelvic nodes below the aortic bifurcation), or distant] or death [of any cause], whichever occurred first); DMFS, distant metastasis-free survival (the time between the date of random assignment and the date of first distant recurrence [nonlocal] or date of death [whatever the cause], whichever occurred first); HR, hazard ratio; NR, not reached; NUTRFS, nonurothelial tract recurrence-free survival (the time between the date of random assignment and the date of first local nonurothelial tract or distant recurrence or death [of any cause], whichever occurred first); OS, overall survival (time between the date of random assignment and the date of death [of any cause]); PFS2, second progression-free survival (time from random assignment to disease progression after subsequent next-line systemic anticancer therapy, start of second subsequent next-line systemic anticancer therapy, or death from any cause, whichever occurred first).