EAU 2021: Pembrolizumab vs. Placebo as Post Nephrectomy Adjuvant Therapy for Patients with RCC: Randomized, Double-Blind, Phase 3 KEYNOTE-564 Study

(UroToday.com) At the 2021 European Association of Urology annual meeting Game Changing session, Dr. Tom Powles presented results of the KEYNOTE-564 trial evaluating pembrolizumab versus placebo as adjuvant therapy for patients with RCC. In 2018, kidney cancer was responsible for 175,000 deaths worldwide. Nephrectomy is the standard of care treatment for locoregional RCC, however, there is no globally accepted standard adjuvant therapy supported by high levels of evidence. Studies of adjuvant immunotherapy with cytokines have yielded negative results and VEGF-targeted therapy has not shown a consistent benefit in the adjuvant setting. Importantly, nearly half of patients eventually experience disease recurrence after surgery, with risk factors including tumor stage/size, nodal involvement, and nuclear grade. Patients with M1 stage and no evidence of disease after resection of oligometastatic sites are also at high risk of relapse.

KEYNOTE-564 is a phase III multicenter trial of pembrolizumab versus placebo in patients with histologically confirmed ccRCC. Risk groups were defined as follows:

  • Intermediate-high risk disease: pT2, grade 4 or sarcomatoid, N0 M0; or pT3, any grade, N0 M0
  • High-risk disease: pT4, any grade, N0 M0; or pT any stage, any grade, N+ M0
  • M1 no evidence of disease: primary tumor + soft tissue metastases completely resected ≤1 year from nephrectomy
The trial schema for KEYNOTE-564 is as follows:


Patients had undergone surgery ≤12 weeks prior to randomization, had no prior systemic therapy, and had ECOG performance status 0 or 1. Study treatment was given for up to 17 cycles (approximately 1 year). The primary endpoint was disease-free survival (DFS) per investigator assessment in all randomized patients (intention to treat population). Overall survival (OS) was a key secondary endpoint. Safety/tolerability were secondary endpoints, assessed in all treated patients.

The first prespecified interim analysis was planned after ~265 DFS events and a minimum follow-up of 12 months from the last participant enrolled. After 15 months of follow-up, 260 DFS events had occurred (78% of the planned final analysis) and 51 OS events had occurred (26% of the planned final analysis). The study had 95% power to detect a HR of 0.67 at alpha = 2.5% (one-sided) for the primary endpoint of DFS for ~990 patients. DFS was tested first at alpha = 2.5%, then alpha was passed to OS if null DFS hypothesis was rejected. The DFS and OS were estimated by the Kaplan-Meier method, and HRs and 95% confidence intervals were estimated using a stratified Cox proportional hazard model. Between-arm differences were assessed using the log-rank test.

Between June 30, 2017 and September 20, 2019, 994 patients were randomized 1:1 to pembrolizumab (n=496) or placebo (n=498). As of the data cutoff date of December 14, 2020, the median follow-up, defined as the time from randomization to data cutoff, was 24.1 (range: 14.9−41.5) months. No patients remain on study treatment and baseline characteristics were generally balanced between arms. Of note, the majority of patients were M0 intermediate-high risk (86.1% in the pembrolizumab arm and 86.9% in the placebo arm). Additionally, most patients had a PD-L1 status of CPS >=1 (73.6% in the pembrolizumab arm and 76.9% in the placebo arm). At the first prespecified interim analysis, the primary endpoint of DFS was met (median not reached for both arms, HR 0.68, 95% CI 0.53−0.87; p = 0.0010 [one-sided]). The estimated DFS rate at 24 months was 77.3% with pembrolizumab vs 68.1% with placebo:


Overall, DFS benefit was consistent across subgroups:


A total of 51 OS events were observed (18 in the pembrolizumab arm, 33 in the placebo arm). Median OS was not reached for both arms (HR 0.54, 95% CI 0.30−0.96; p = 0.0164 [one-sided]); the p-value did not cross the statistical hypothesis testing boundary. The estimated OS rate at 24 months was 96.6% with pembrolizumab versus 93.5% with placebo:


There were 470 patients (96.3%) and 452 patients (91.1%) who experienced ≥1 all-cause adverse events with pembrolizumab versus placebo, respectively. Grade 3-5 all-cause adverse events occurred in 158 patients (32.4%) with pembrolizumab and 88 patients (17.7%) with placebo. No deaths related to pembrolizumab occurred. The most common immune-mediated adverse events were hypothyroidism (grade 1-2: 21.1% pembrolizumab arm; 3.6% placebo arm) and hyperthyroidism (grade 1-2: 11.9% pembrolizumab arm; 0.2% placebo arm).

Dr. Powles concluded this presentation of the KEYNOTE-564 trial with the following take-home messages:

  • Adjuvant pembrolizumab post nephrectomy demonstrated a statistically significant and clinically meaningful improvement in DFS versus placebo in patients with intermediate-high, high risk, or M1 no evidence of RCC
  • Additional follow-up is planned for the key secondary endpoint of OS
  • The benefit was consistent across subgroups, including the M1 no evidence of disease population, potentially extending the use of pembrolizumab to these patients
  • Safety results were in line with expectations and no new safety signals were observed, with a low incidence of high-dose corticosteroid treatment for immune-mediated adverse events
  • KEYNOTE-564 is the first positive phase III study with a checkpoint inhibitor in adjuvant RCC, and these results support pembrolizumab as a potential new standard of care for patients with RCC in the adjuvant setting

Clinical trial information: NCT03142334

Presented by: Thomas Powles, MBBS, MRCP, MD, Professor of Genitourinary Oncology, Lead for Solid Tumour Research at Barts Cancer Institute, Director of Barts Cancer Institute, London, United Kingdom

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.

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