Adjuvant Nivolumab for Localized Renal Cell Carcinoma at High Risk of Recurrence After Nephrectomy: Part B of the Randomized, Placebo-Controlled, Phase III CheckMate 914 Trial

Abstract

Purpose: CheckMate 914 is a two-part, randomized phase III trial evaluating adjuvant nivolumab plus ipilimumab (part A) or adjuvant nivolumab monotherapy (part B) versus placebo in mutually exclusive populations of patients with localized renal cell carcinoma (RCC) at high risk of postnephrectomy recurrence. Part A showed no disease-free survival (DFS) benefit for adjuvant nivolumab plus ipilimumab versus placebo. We report results from part B.

Methods: Patients were randomly assigned (2:1:1) to nivolumab (240 mg once every 2 weeks for up to 12 doses), placebo, or nivolumab (240 mg once every 2 weeks for up to 12 doses) plus ipilimumab (1 mg/kg once every 6 weeks for up to four doses). The planned treatment duration was 24 weeks (approximately 5.5 months). The primary end point was DFS per blinded independent central review (BICR) for nivolumab versus placebo; safety was a secondary end point.

Results: Overall, 825 patients were randomly assigned to nivolumab (n = 411), placebo (n = 208), or nivolumab plus ipilimumab (n = 206). With a median follow-up of 27.0 months (range, 18.0-42.4), the primary end point of improved DFS per BICR with nivolumab versus placebo was not met (hazard ratio [HR], 0.87 [95% CI, 0.62 to 1.21]; P = .40); the median DFS was not reached in either arm, and 18-month DFS rates were 78.4% versus 75.4%. The HR for DFS per investigator was 0.80 (95% CI, 0.58 to 1.12; P = .19). Grade 3-4 all-cause adverse events (AEs) occurred in 17.2%, 15.0%, and 28.9% of patients with nivolumab, placebo, and nivolumab plus ipilimumab, respectively. Any-grade treatment-related AEs led to discontinuation in 9.6%, 1.0%, and 28.4%, respectively.

Conclusion: Part B of CheckMate 914 did not meet the primary end point of improved DFS for nivolumab versus placebo in patients with localized RCC at high risk of postnephrectomy recurrence.

Trial registration: ClinicalTrials.gov NCT03138512.

FIG 1.

CONSORT diagram. AE, adverse event; ITT, intention-to-treat. ^aThree patients were excluded before random assignment due to COVID-19 disease. ^bIncludes patients who withdrew consent or requested to discontinue study treatment. ^cFour patients in the nivolumab arm, two in the placebo arm, and two in the nivolumab plus ipilimumab arm discontinued treatment due to COVID-19 disease.

FIG 2.

DFS per BICR in the overall ITT population for nivolumab versus placebo. DFS was estimated in all randomly assigned patients and defined as the time from random assignment to the development of local disease recurrence, distant metastasis, or death, whichever came first. BICR, blinded independent central review; DFS, disease-free survival; HR, hazard ratio; ITT, intention-to-treat; NE, not estimable; NR, not reached.

FIG 3.

DFS per BICR in key subgroups for nivolumab versus placebo. DFS was estimated in all randomly assigned patients and defined as the time from random assignment to the development of local disease recurrence, distant metastasis, or death, whichever came first. The influence of demographic and baseline clinical characteristics on DFS among randomly assigned patients was assessed via exploratory subgroup analyses. HRs were not computed for subgroups with <11 patients per treatment arm (except for age, region, and sex). The statistical analysis plan prespecified that subgroup analyses for stratification factors (TNM staging and type of nephrectomy) would be based on case report form data. BICR, blinded independent central review; DFS, disease-free survival; HR, hazard ratio; ITT, intention-to-treat; LLN, lower limit of normal.

FIG 4.

DFS per BICR in pooled subgroups of interest with sarcomatoid features (A), PD-L1 expression ≥1% (B), or pT4, any grade (N0M0) or any pT, any grade (N1M0) staging (C). Ad hoc analyses were conducted using pooled data from parts A and B of the study to compare DFS per BICR with immunotherapy (nivolumab plus ipilimumab in part A and either nivolumab or nivolumab plus ipilimumab in part B) versus placebo (from parts A and B) in select subgroups of patients. DFS was estimated in all randomly assigned patients and defined as the time from random assignment to the development of local disease recurrence, distant metastasis, or death, whichever came first. PD-L1 testing was performed locally (Labcorp) using a validated tumor proportion score–based PD-L1 immunohistochemical assay (Dako PD-L1 IHC 28-8 pharmDx). BICR, blinded independent central review; DFS, disease-free survival; HR, hazard ratio; NE, not estimable; NR, not reached.