KEYNOTE-564: Phase 3 trial of pembrolizumab in the adjuvant treatment of renal cell carcinoma (RCC)

Abstract

Background: Effective adjuvant therapies for patients (pts) with RCC at risk of recurrence after nephrectomy are lacking. Programmed death ligand 1 (PD-L1) and 2 (PDL2) expression predicts poor prognosis in RCC. Programmed death 1 (PD-1) inhibitors have demonstrated activity in metastatic RCC, and PD-1 may represent a novel therapeutic target in the adjuvant setting. Pembrolizumab is a PD-1 inhibitor that directly blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This randomized, double-blind, placebo-controlled phase 3 trial will evaluate the efficacy and tolerability of pembrolizumab as adjuvant therapy in pts with RCC who have T2 grade 4, T3, T4, N (+), or stage M1 with no evidence of disease (M1 NED) following nephrectomy and/or metastasectomy (NCT03142334). Trial design: Key inclusion criteria are: age ≥18 years; histologically confirmed RCC with a clear cell component; intermediate-high or high risk of recurrence, or M1 NED; no prior systemic therapy for advanced RCC; disease-free following complete or partial nephrectomy (and metastasectomy in M1 NED pts) with negative surgical margins; and Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Approximately 950 pts will be randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg every 3 weeks by intravenous infusion, or placebo, continued for up to 17 cycles (∼1 year) or until disease recurrence or treatment discontinuation. Randomization will be stratified by metastasis stage (M0 vs M1 NED); within the M0 group, randomization will be further stratified by ECOG performance status (0 vs 1) and region (US vs rest of world). The primary end point is investigator-assessed disease- free survival (DFS). Radiographic imaging will be performed every 12 weeks. Secondary objectives include overall survival (OS), safety, disease recurrence-specific survival, DFS and OS according to PD-L1 expression status, pharmacokinetics, antidrug antibodies, and patient-reported outcomes. Molecular biomarkers that may be associated with response, safety, pharmacodynamic activity, or mechanism of action will be evaluated as exploratory objectives.