Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Author(s): Thomas Powles, MD1,2;Piotr Tomczak, MD PhD3;Se Hoon Park, MD PhD4;Balaji Venugopal, MD5,6;Thomas Ferguson, MBBS7;Stefan N Symeonides, MD PhD8,9,10;Jaroslav Hajek, MUDr11;Prof Howard Gurney, MBBS12;Yen-Hwa Chang, MD PhD13;Jae Lyun Lee, MD PhD14;Naveed Sarwar, PhD15;Antoine Thiery-Vuillemin, MD PhD16;Marine Gross-Goupil, MD PhD17;Mauricio Mahave, MD18;Naomi B Haas, MD19;Piotr Sawrycki, MD20;Joseph E Burgents, PhD21;Lei Xu, PhD21;Kentaro Imai, MD21;David I Quinn, MD PhD22;Toni K Choueiri, MD23
Anjan J Patel MD

Dr. Anjan Patel's Thoughts

Pembrolizumab remains the only adjuvant option for high risk RCC after curative surgery. The OS curves seem to be beginning to separate and hope to be positive with longer f/u.  The ongoing Durvalumab + Tremilumumab will be an interesting adjuvant study for RCC when the results are available.


The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints.


In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with, NCT03142334.


Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7–36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 [95% CI 0·50–0·80]). Median disease-free survival was not reached in either group. The most common all-cause grade 3–4 adverse events were hypertension (in 14 [3%] of 496 participants) and increased alanine aminotransferase (in 11 [2%]) in the pembrolizumab group, and hypertension (in 13 [3%] of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (<1%) participant in the placebo group. No deaths were attributed to pembrolizumab.


Updated results from KEYNOTE-564 support the use of adjuvant pembrolizumab monotherapy as a standard of care for participants with renal cell carcinoma with an increased risk of recurrence after nephrectomy.

Author Affiliations

1Royal Free Hospital NHS Foundation Trust, University College London, London, UK;2Barts Cancer Institute, Experimental Cancer Medicine Centre, Queen Mary University of London, St Bartholomew’s Hospital, London, UK;3Poznań University of Medical Sciences, Poznań, Poland;4Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea;5Beatson West of Scotland Cancer Centre, Glasgow, UK;6Institute of Cancer Sciences, University of Glasgow, Glasgow, UK;7Fiona Stanley Hospital, Perth, WA, Australia;8Cancer Research UK Edinburgh Centre, Edinburgh, UK;9Edinburgh Cancer Centre, Edinburgh, UK;10Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK;11Fakultní nemocnice Ostrava, Ostrava, Czech Republic;12Department of Clinical Medicine, Macquarie University, Sydney, NSW, Australia;13Taipei Veterans General Hospital, Taipei, Taiwan;14Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea;15Imperial College Healthcare NHS Trust, London, UK;16University Hospital Jean Minjoz, Besançon, France;17University Hospital Bordeaux—Hôpital Saint-André, Bordeaux, France;18Arturo López Pérez Foundation, Santiago, Chile;19Abramson Cancer Center, Philadelphia, PA, USA;20Wojewódzki Szpital Zespolony im L Rydygiera w Toruniu, Torun, Poland;21Merck & Co, Inc, Rahway, NJ, USA;22USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA;23Dana-Farber Cancer Institute, Boston, MA, USAfor the KEYNOTE-564 Investigators

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