Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial

Abstract

Background: Effective adjuvant therapy for patients with resected localised renal cell carcinoma represents an unmet need, with surveillance being the standard of care. We report results from part A of a phase 3, randomised trial that aimed to assess the efficacy and safety of adjuvant nivolumab plus ipilimumab versus placebo.

Methods: The double-blind, randomised, phase 3 CheckMate 914 trial enrolled patients with localised clear cell renal cell carcinoma who were at high risk of relapse after radical or partial nephrectomy between 4-12 weeks before random assignment. Part A, reported herein, was done in 145 hospitals and cancer centres across 20 countries. Patients were randomly assigned (1:1) to nivolumab (240 mg) intravenously every 2 weeks for 12 doses plus ipilimumab (1 mg/kg) intravenously every 6 weeks for four doses, or matching placebo, via an interactive response technology system. The expected treatment period was 24 weeks, and treatment could be continued until week 36, allowing for treatment delays. Randomisation was stratified by TNM stage and nephrectomy (partial vs radical). The primary endpoint was disease-free survival according to masked independent central review; safety was a secondary endpoint. Disease-free survival was analysed in all randomly assigned patients (intention-to-treat population); exposure, safety, and tolerability were analysed in all patients who received at least one dose of study drug (all-treated population). This study is registered with ClinicalTrials.gov, NCT03138512.

Findings: Between Aug 28, 2017, and March 16, 2021, 816 patients were randomly assigned to receive either adjuvant nivolumab plus ipilimumab (405 patients) or placebo (411 patients). 580 (71%) of 816 patients were male and 236 (29%) patients were female. With a median follow-up of 37·0 months (IQR 31·3-43·7), median disease-free survival was not reached in the nivolumab plus ipilimumab group and was 50·7 months (95% CI 48·1 to not estimable) in the placebo group (hazard ratio 0·92, 95% CI 0·71-1·19; p=0·53). The number of events required for the planned overall survival interim analysis was not reached at the time of the data cutoff, and only 61 events occurred (33 in the nivolumab plus ipilimumab group and 28 in the placebo group). 155 (38%) of 404 patients who received nivolumab plus ipilimumab and 42 (10%) of 407 patients who received placebo had grade 3-5 adverse events. All-cause adverse events of any grade led to discontinuation of nivolumab plus ipilimumab in 129 (32%) of 404 treated patients and of placebo in nine (2%) of 407 treated patients. Four deaths were attributed to treatment with nivolumab plus ipilimumab and no deaths were attributed to treatment with placebo.

Interpretation: Adjuvant therapy with nivolumab plus ipilimumab did not improve disease-free survival versus placebo in patients with localised renal cell carcinoma at high risk of recurrence after nephrectomy. Our study results do not support this regimen for the adjuvant treatment of renal cell carcinoma.

Funding: Bristol Myers Squibb and Ono Pharmaceutical.

Figure 1:. Trial profile for CheckMate 914 part A

*Ten patients were not randomised due to COVID-19. †Nine patients discontinued nivolumab plus ipilimumab due to COVID-19 (all nine patients discontinued due to “other” reason). ‡Eight patients discontinued placebo due to COVID-19 (one patient withdrew consent; seven patients discontinued due to “other” reason). ¶Two patients in the nivolumab plus ipilimumab arm were reported as having completed treatment by the investigators even though one patient skipped nivolumab at cycle 3 and one patient skipped nivolumab at cycle 12. §One patient in the placebo arm was reported as having completed treatment by the investigator even though the patient skipped ipilimumab-placebo at cycle 7.

Figure 2:. Kaplan-Meier estimates of disease-free survival (primary definition*) per blinded independent central review

Disease-free survival according to blinded independent central review was assessed in all randomly assigned patients. The reported p value is two-sided. Tick marks represent data censored at the last time that the patient was known to be alive and free from disease recurrence. *Subsequent therapy includes systemic anticancer therapy, tumour-directed radiotherapy, or tumour-directed surgery. Patients who died without a reported recurrence were considered to have recurred on the date of their death. The following censoring rules were applied for the primary definition of disease-free survival: 1. patients who did not recur or die were censored on the date of their last evaluable tumour assessment; 2. patients who did not have any on-study tumour assessments and did not die were censored on their date of randomisation; 3. patients who received subsequent systemic anticancer therapy, tumour-directed radiotherapy, or tumour-directed surgery before documented recurrence were censored at the date of the last tumour assessment conducted on or before the initiation of the new therapy; 4. patients who did not have a documented recurrence and received subsequent systemic anticancer therapy, tumour-directed radiotherapy, or tumour-directed surgery were censored at the date of the last tumour assessment conducted on or before the initiation of the new therapy (see supplemental methods for full censoring scheme).

Figure 3:. Disease-free survival per blinded independent central review according to key subgroups

*The influence of demographic and baseline clinical characteristics on disease-free survival among randomised patients was assessed via exploratory subgroup analyses for age, sex, race, ethnicity, region, ECOG performance status, type of nephrectomy, TNM staging, risk group, Fuhrman grade, Sarcomatoid features, time from diagnosis to randomisation, lactate dehydrogenase level, haemoglobin, corrected calcium, and alkaline phosphatase. HR was not computed for subset (except age, race, region, and sex) category with fewer than 11 patients per treatment group. †The statistical analysis plan prespecified that subgroup analyses for stratification factors (TNM staging and type of nephrectomy) would only be displayed using subgroups based on case report form data. Analysis of disease-free survival by high and moderate risk groups and by Fuhrman grade were also per case report form. ‡Disease-free survival was assessed in the high and moderate risk subgroups using the following risk staging system: high risk (pT3, G3 or G4, N0 M0; pT4, Gany, N0 M0; pTany, Gany, N1 M0) and moderate risk (pT2a, G3 or G4, N0 M0; pT2b, Gany, N0 M0; pT3, G1 and G2, N0 M0). DFS=disease-free survival. ECOG=Eastern Cooperative Oncology Group. LDH=lactate dehydrogenase. LLN=lower limit of normal. ULN=upper limit of normal.