# KEYNOTE-564: a year of pembrolizumab after kidney cancer surgery

Source: https://onco.cc/key-papers/paper-keynote-564-nejm-2021/  
OnCo record `paper-keynote-564-nejm-2021` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

One year of pembrolizumab after surgery for high-risk kidney cancer reduced relapses by about a third and, in later follow-up, became the first adjuvant treatment to help kidney cancer patients live longer.

## Summary

Double-blind, placebo-controlled phase 3 trial of 994 patients with clear-cell renal cell carcinoma at intermediate-high or high risk of recurrence after nephrectomy, or with resected metastatic disease (M1 NED), randomised to one year of pembrolizumab or placebo. Primary endpoint was disease-free survival.

24-month DFS was 77.3% vs 68.1% (HR 0.68). The 2024 overall survival analysis showed HR 0.62 with 48-month OS 91.2% vs 86.0%. It was the first adjuvant therapy in kidney cancer to improve survival, after decades of negative trials with cytokines and VEGF inhibitors, and it stands alone: three other adjuvant checkpoint inhibitor trials (IMmotion010, CheckMate 914, PROSPER) were negative.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: New England Journal of Medicine
- Year: 2021
- DOI: 10.1056/NEJMoa2106391
- Authors: Choueiri TK, Tomczak P, Park SH, et al.
- Findings: 24-month disease-free survival 77.3% vs 68.1%; HR 0.68 (95% CI 0.53-0.87).; Overall survival (NEJM 2024): HR 0.62 (95% CI 0.44-0.87); 48-month OS 91.2% vs 86.0%.; Largest DFS benefit in the small M1 NED group (HR 0.28) and in sarcomatoid tumours.; Grade 3 or higher adverse events 32.4% vs 17.7%; about 21% discontinued pembrolizumab for adverse events.; Endocrine immune-related events (hypothyroidism, adrenal insufficiency) were the most frequent lasting toxicities.
- What it means: Patients whose kidney cancer has been removed but who are at high risk of recurrence (large or high-grade tumours, node involvement, or resected metastases) can now be offered a year of pembrolizumab, which increases the chance of being alive and cancer-free several years later. Roughly nine patients need treatment to prevent one recurrence at two years, and some will have permanent side effects, so shared decision-making matters. Why pembrolizumab succeeded where similar drugs failed is not fully understood.
- Caveats: The three other adjuvant checkpoint inhibitor trials in kidney cancer were negative, and the reasons (drug, population, chance) are debated.; Absolute DFS benefit of about 9 points; most patients treated would not have relapsed anyway.; The trial predated widespread use of immunotherapy at relapse in the control arm during the early years, which may exaggerate the OS effect relative to current practice.; Non-clear-cell histology was excluded.

## Sources

- NEJM 2021: https://doi.org/10.1056/NEJMoa2106391
- NEJM 2024 (OS): https://doi.org/10.1056/NEJMoa2312695
- ClinicalTrials.gov NCT03142334: https://clinicaltrials.gov/study/NCT03142334

## Connected records

- cancers: [Clear cell renal cell carcinoma](https://onco.cc/cancers/clear-cell-rcc/), [Renal cell carcinoma](https://onco.cc/cancers/rcc/)
- technologies: [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/)
- targets: [PD-1](https://onco.cc/targets/pd1/)
- drugs: [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- companies: [Merck & Co. (MSD)](https://onco.cc/companies/merck/)
- institutions: [Dana-Farber Brigham Cancer Center](https://onco.cc/institutions/dana-farber/)
- terms: [Immune-related adverse events (irAEs)](https://onco.cc/terms/irae/), [Neoadjuvant / adjuvant / perioperative](https://onco.cc/terms/neoadjuvant-adjuvant/), [Overall survival (OS)](https://onco.cc/terms/os/)
- people: [Jae Lyun Lee](https://onco.cc/people/lee-jae-lyun/), [Toni K. Choueiri](https://onco.cc/people/toni-choueiri/)
- bottlenecks: [Dormant cells and minimal residual disease](https://onco.cc/bottlenecks/b-dormancy-mrd/), [Failures are hidden](https://onco.cc/bottlenecks/b-negative-results/), [Toxicity and quality of life are undervalued](https://onco.cc/bottlenecks/b-toxicity-qol/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)
- ideas: [A single calibrated tumour mutational burden across all sequencing panels](https://onco.cc/ideas/idea-tr2-tmb-calibration-standard/), [Biomarker-selected adjuvant therapy in RCC (ctDNA, CAIX PET, gene signatures)](https://onco.cc/ideas/idea-adjuvant-selection-rcc/), [Make six-weekly immunotherapy the default schedule](https://onco.cc/ideas/idea-cost-extended-interval-default/), [Restore weight-based dosing and vial sharing for immunotherapy in the label](https://onco.cc/ideas/idea-reg-weight-based-io-dosing-label/)

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