ASCO 2021: Pembrolizumab Versus Placebo As Post-Nephrectomy Adjuvant Therapy for Patients With Renal Cell Carcinoma: Randomized, Double-Blind, Phase III Keynote-564 Study

( Locally advanced renal cell carcinoma (RCC) can be surgically resected, but nearly half of patients eventually experience disease recurrence. Risk factors associated with relapse include larger tumors, higher tumor stage, nodal involvement, higher nuclear grade, and initial M1 presentation managed with complete surgical resection. Despite the positive S-TRAC study demonstrating a disease-free survival benefit for adjuvant sunitinib, there is no globally accepted standard of care to delay disease recurrence after surgery given the lack of overall survival benefit and significant toxicity with adjuvant sunitinib.

In this presentation, Dr. Toni Choueiri presented results from KEYNOTE-564, a study of adjuvant pembrolizumab administered for one year after complete surgical resection of clear cell RCC. The eligibility and study design are shown below. The primary endpoint was disease-free survival by investigator assessment. 


Patients were grouped into pre-specified risk categories based on their relative risk of relapse. These risk categories are shown below.


This study was designed to have 95% power to detect a hazard ratio of 0.67 for disease progression with adjuvant pembrolizumab (one-sided alpha 2.5%) tested in approximately 990 patients. This analysis was planned for after 265 disease progression events occurred and a minimum of 12 months of follow-up had been completed for all patients. At the time of this analysis, 51 deaths had occurred, which was 26% of events needed for final analysis.

The baseline characteristics of patients were well-balanced between arms and are shown below.


The study was positive for its primary endpoint of disease-free survival (DFS). There were an approximately 9% difference in DFS at the 12- and 24-month time points. Given limited follow-up to date for a large fraction of patients enrolled on trial, the number of patients at risk for a progression event beyond two years (defined as local or distant recurrence or death) was quite low. This may explain why the DFS curves cross at the later time points. This trend was associated with a statistically significant hazard ratio of 0.68 for progression with adjuvant pembrolizumab.


The trend towards DFS benefit for pembrolizumab was constant across subgroups.


Though the number of survival events is small to date, there is a small absolute difference in overall survival at this analysis time point, as illustrated below.


With regards to adverse events, as expected, more grade 3 and grade 4 events were experienced in the pembrolizumab arm. There were no pembrolizumab-related treatment deaths, and the toxicity signal was similar to what was previously expected from pembrolizumab therapy.



Dr. Choueiri concluded that adjuvant pembrolizumab post nephrectomy demonstrated a statistically significant improvement in disease-free survival relative to placebo and that longer-term follow-up is needed to fully evaluate the overall survival benefit. This DFS benefit was seen consistently across risk subgroups and represents the first positive phase 3 trial of adjuvant immunotherapy in RCC. Based on the longer-term evaluation and FDA review, adjuvant pembrolizumab may represent a new standard of care for patients with RCC.

Presented By: Toni K. Choueiri. MD, Director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School, Boston, MA

Written By: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021