This phase III trial compares the effect of adding tivozanib to standard therapy pembrolizumab versus pembrolizumab alone for the treatment of patients with high-risk renal cell carcinoma (RCC). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Tivozanib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that signals tumor cells to multiply. This helps stop the spread of tumor cells. Giving pembrolizumab and tivozanib together may work better than pembrolizumab alone in treating patients with RCC.
• Histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features following complete resection of the primary tumor (radical or partial nephrectomy)
Note: Patients with microscopically positive soft tissue or vascular margins without gross residual disease are permitted
pT2 grade 4 or sarcomatoid features, N0M0
pT3 any grade N0, M0
None
Parallel
Pembrolizumab
Biological/VaccineGiven intravenously
Tivozanib
DrugGiven orally
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
MRI
Procedure/SurgeryUndergo MRI
Computed Tomography
Procedure/SurgeryUndergo CT scan
Biopsy
Procedure/SurgeryUndergo biopsy
Questionnaire Administration
Other interventionAncillary studies
Disease-free survival (DFS)
The primary analysis will be a comparison of DFS between the two study arms using a stratified log-rank test. The treatment effect will be estimated with a hazard ratio (HR) and corresponding 95% confidence interval obtained from a stratified Cox model with treatment group (experimental group versus control group) as the explanatory variable. Interim analyses: There will be several futility analyses for the trial. These analyses will employ the linear 20% method proposed by Freidlin, Korn and Gray. Based on the current design parameters, the first analysis would be performed at 37% information (99 DFS events), and the trial would be stopped for futility if the observed hazard ratio (experimental versus \[vs.\] control) were worse than 1. Additional analyses will be performed at 50% (133 DFS events), 60% (159 DFS events), and 70% information (186 DFS events), the trial would be stopped for futility if the observed HR were worse than 0.983, 0.971 and 0.959, respectively.
Overall survival (OS)
The OS will be compared between the two treatment arms using a stratified log-rank test. An estimate of the OS difference between the arms will be made with a HR generated by a stratified Cox model. A point estimate and 95% confidence interval will be generated. If there are clinically meaningful imbalances between the treatment arms, a secondary analysis for DFS will be performed with a multivariable Cox model that includes the stratification variable and all baseline variables with meaningful differences. A similar analysis will be done for the OS endpoint. Key subgroup analyses will be performed to determine whether there is evidence that the treatment effect differs among subgroups that correspond to key prognostic variables. This includes the stratification variable.
Incidence of adverse events (AEs)
These will be assessed using Common Terminology Criteria for Adverse Events version 5.0. Adverse events will be summarized with frequencies and relative frequencies. The maximum grade for an AE will be recorded for each patient by treatment arm. The number (percent) of patients that experience each observed adverse event will be summarized by treatment arm. In addition, the proportion of patients that experience a grade 3+, grade 4+, and grade 5 adverse event will be summarized as the number and percent of patients by treatment arm. The primary summary will be regardless of attribution. Will also have an analogous summary for the adverse events that were deemed at least possibly related to treatment.
Proportion of patients that tolerate pembrolizumab and tivozanib
Tolerability will be defined as the ability of a patient to receive at least half the planned doses of tivozanib in combination with pembrolizumab if they have not had a DFS event. This will be determined as the number of patients on arm 2 who received at least one dose of tivozanib, who have not had a DFS within 6 months, and who received at half of the planned doses tivozanib divided by the number of patients on arm 2 who received at least one dose of tivozanib and who have not had a DFS within 6 months. The proportion of patients who tolerated tivozanib in combination with pembrolizumab will be estimated with a binomial point estimate and 95% binomial confidence interval.
Estimates of treatment effect by sex
Estimates of DFS and the corresponding 95% CIs will be evaluated by sex.
Estimates of treatment effect by race
Estimates of DFS and the corresponding 95% CIs will be evaluated by race
Estimates of treatment effect by ethnicity
Estimates of DFS and the corresponding 95% CIs will be evaluated by ethnicity.
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