A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Pembrolizumab (MK-3475) as Monotherapy in the Adjuvant Treatment of Renal Cell Carcinoma Post Nephrectomy (KEYNOTE-564)

Merck Sharp & Dohme Corp
Study Design: 
This is a phase III, randomized, double-blind, multicenter trial (KEYNOTTE-564) evaluating the efficacy of pembrolizumab compared to placebo in improving survival in patients who have undergone a partial nephroprotective or radical complete nephrectomy with intermediate- to high-risk clear-cell RCC, as defined as pT2N0M0 disease of Fuhrman Grade 4 or with sarcomatoid features, pT3N0M0 disease of any grade, pT4N0M0 disease of any grade, or any pT stage with N+, M0 disease. Patients with M1 disease who have completely resectable disease in a synchronous or metachronous fashion are also eligible. Those with residual thrombus post-nephrectomy in the renal vein or vena cava are excluded. Surgery must have been performed within 12 weeks prior to randomization. Patients will be randomized 1:1 to receive either placebo or pembrolizumab every 3 weeks for up to 17 cycles unless there is disease recurrence or unacceptable toxicity. Patients will be stratified by metastasis stage.
While strides have been made in the treatment of metastatic RCC, there remains no standard adjuvant systemic therapy that has demonstrated an overall survival benefit in the non-metastatic setting. Most patients with intermediate- to high-risk advanced RCC will progress within 3 years following nephrectomy. Pembrolizumab, an anti-PD-1 antibody, has demonstrated benefit in treating metastatic RCC. It is thought that there may be benefit to immune checkpoint inhibitor therapy after resection of localized disease, the hypothesis being that such therapy may allow for eradication of micrometastatic disease and thus translate to improvements in disease-free (DFS) and overall survival (OS).
The primary outcome of the trial is DFS by investigator assessment, with OS as a secondary endpoint. OS will also be assessed by PD-L1 expression status.