EAU 2021: Discussant: Phase 3 KEYNOTE-564 Study

Meeting: European Association of Urology - 2021 Virtual Meetings

Date: July 8-12, 2021

Session: Game Changing Session 4

Presentation Title: Discussant: Phase 3 KEYNOTE-564 Study

 The Game Changing session at the European Association of Urology’s 2021 virtual annual meeting included a discussion by Dr. Alberto Breda of the important phase 3 KEYNOTE-564 clinical trial. Dr. Breda notes that based on several failed TKI trials, the EAU guidelines do not recommend adjuvant therapy (sorafenib, pazopanib, everolimus, girentuximab, axitinib, or sunitinib) for high-risk RCC given a lack of survival benefit. Data from Zisman et al. [1] notes that the natural history of intermediate-high risk RCC is a 55%-80% 5-year DFS rate on the basis of UCLA Integrated Staging System risk categorization:




Looking at the Kaplan-Meier curve for disease-free survival in KEYNOTE-564, Dr. Breda notes that the benefit starts at 12 weeks and is maintained for up to two years. Beyond two years, and specifically at three years, the benefit is less clear for pembrolizumab:




Dr. Breda highlighted that for the first time M1 no evidence of disease (defined as no evidence of disease after primary tumor + soft tissue metastases completely resected <=1 year from nephrectomy) was assessed as a specific subgroup in the Forest plot analysis. In KEYNOTE-564, M1 NED patients (29 patients in each arm of the trial) had a significant benefit favoring pembrolizumab (HR 0.29, 95% CI 0.12-0.69).

Although there is much excitement regarding the DFS benefit of pembrolizumab from the KEYNOTE-564 trial, Dr. Breda notes that to truly make an impact, we must see an overall survival. For context and by way of caution, we previously saw that sunitinib in the S-TRAC trial had a significant DFS benefit (HR 0.76, 95% CI 0.59-0.98), but this did not translate into a survival benefit (HR 1.014, 95% CI 0.716-1.435) [2]. Dr. Breda is cautiously optimistic that we will eventually see an OS benefit in the KEYNOTE-564 trial, although it may take 4-5 years of follow-up to see this benefit. Encouraging data from the melanoma literature has recently shown an OS benefit for adjuvant pembrolizumab for stage III melanoma, but after 10 years of follow-up.

With regards to adverse events, Dr. Breda notes that in the S-TRAC trial 28.1% of patients in the sunitinib arm discontinued treatment secondary to adverse events. In the KEYNOTE-564 trial, a non-insignificant 18.9% of patients receiving pembrolizumab had grade 3-5 adverse events and 17.6% of patients had treatment-related adverse events leading to treatment discontinuation. As we have historically seen, patients (and likely physicians) are less likely to accept/tolerate side effects/adverse events of adjuvant treatment, specifically when the control arm is placebo and there is a yet to be proven survival benefit.


Dr. Breda concluded his discussant presentation of the KEYNOTE-564 trial with the following take home messages:

  • Additional follow-up is needed to assess the impact on overall survival despite adjuvant pembrolizumab post nephrectomy/metastasectomy positively impacting DFS
  • Subset analysis by stage, grade and clinical parameters are needed to understand the benefit for the target population and sub-groups
  • Safety results were acceptable with an expected immune-mediated adverse event profile


  1. Zisman A, Pantuck AJ, Wieder J, et al. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol. 2002 Dec 1;20(23):4559-4566.
  2. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med 2016;375(23):2246-2254.


Presented By: Alberto Breda, Autonomous University of Barcelona, Barcelona, Spain


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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