KEYNOTE-564 paves future role for immunotherapy in adjuvant renal cell carcinoma

Merck &Co.’s Keytruda has practice-changing potential as adjuvant therapy for renal cell carcinoma. As part of our Drugs to Watch™ series, Clarivate oncology experts Priyanka Mehra and Sorcha Cassidy review new data shared at the 2021 ASCO Annual Meeting, and implications for patients and life sciences companies.  

The renal cell carcinoma treatment landscape continues to evolve rapidly, with multiple targeted agents and immunotherapies approved for patients with advanced or metastatic disease. Immune checkpoint inhibitor-based combinations have become the standard of care for metastatic renal cell carcinoma, but this market could be reshaped by the entry of these agents in the adjuvant setting. Following Sutent’s FDA approval for high-risk early-stage patients in 2017, multiple immune checkpoint inhibitors are also anticipated to transition into this setting. If approved in this setting, immunotherapy will help address an unmet need for patients that are at high risk of disease recurrence following surgery.

In April 2021, Merck & Co. announced that the Phase III KEYNOTE-564 trial evaluating Keytruda monotherapy demonstrated improved disease-free survival (DFS) versus placebo in the adjuvant setting.1 The first presented at ASCO 2021 underline the drug’s potential to change clinical practice for the adjuvant treatment of renal cell carcinoma. Table 1 summarizes the key results from KEYNOTE-564 presented at ASCO 2021 (Table 1).


Table 1: Key data from the Phase III KEYNOTE-564 trial presented at the 2021 ASCO Annual Meeting2,3,6

Patient population
and enrollment
Trial design Select efficacy data Select safety data
  • Renal cell carcinoma patients with clear-cell disease who have undergone nephrectomy and have intermediate/high- or high-risk disease or no evidence of disease.
  • Patients enrolled and randomized: 994.
  • Treatment arms: Keytruda (n = 496) vs. placebo (n =498).
  • Treatment duration: up to 17 cycles (≈ 1 year.
  • Primary endpoint: DFS.
  • Secondary endpoints: OS, PD-L1-expression-specific OS and DFS, AEs, treatment discontinuation rate, first local disease recurrence-specific survival, EFS, PK, PD, QOL.
Among all patients

Keytruda vs. placebo:

  • Median DFS: not reached in both arms (HR 0.68; P = 0.0010)
  • DFS rates at:
    • – 1-year: 85.7% vs. 76.2%.
    • 2-year: 77.3% vs. 68.1%
  • Median OS: not reached for both arms (HR 0.54; P = 0.0164)
  • Estimated OS rate at 2 years: 96.6% vs. 93.5%


Among all patients

Keytruda vs. placebo:

  • >1 all cause AEs: 96.3% vs. 91.1%.
  • Grade 3-5 all cause AEs: 32.4% vs. 17.7%.


Note: DFS = disease-free survival; HR = hazard ratio; OS = overall survival; AEs = adverse events; QOL = quality of life; PK = Pharmacokinetics; PD = Pharmacodynamics

Source: Merck & Co., press release, June 3, 2021,, ASCO 2021

Why are the results of KEYNOTE-564 significant and how will they impact medical practice? 

The randomized Phase III KEYNOTE-564 trial is investigating Keytruda versus placebo in patients with intermediate-high and-high risk clear-cell renal cell carcinoma post-nephrectomy with disease-free survival as a primary endpoint and overall survival and safety as key secondary endpoints.

The data presented at ASCO 2021 represent a paradigm shift as these results mark the first positive result for an anti-PD-1/PD-L1 therapy in the adjuvant setting.

  • In the study, the disease-free survival benefit conferred was consistent across all patient subgroups with a statistically significant hazard ratioof 0.68. While data for overall survival are still immature and did not meet statistical significance, the hazard ratio was 0.54, which is encouraging. The safety profile of Keytruda was reported to be consistent with previously reported studies in the metastatic setting.
  • Sutent, the only agent approved in adjuvant renal cell carcinoma, demonstrated a median disease-free survival of 6.8 years versus 5.6 years with placebo (hazard ratio = 0.76) in the Phase III S-TRAC study in high-risk clear-cell renal cell carcinoma patients.8
  • KEYNOTE-564 differed from S-TRAC in that it included a larger patient population (n = 994 vs. 615) and was not limited to those with high-risk localized disease. Although cross trial comparison must be undertaken with caution, KEYNOTE-564 demonstrated a 32% risk reduction in disease-free survival with Keytruda, compared with a 24% risk reduction with Sutent in S-TRAC. Keytruda also demonstrated a favorable toxicity profile in the KEYNOTE-564 study with overall fewer severe adverse events reported in comparison to Sutent. Overall, given the sparse treatment options in the early-stage setting, these data bode well for Keytruda’s potential approval and future prescribing. However, the durability of the disease-free survival benefit and overall survival data will be critical to cement Keytruda’s role in this setting.


What impact will these interim data have on the renal cell carcinoma market?

The renal cell carcinoma adjuvant setting is an untapped market and the data for KEYNOTE-564 build on Keytruda’s use in metastatic renal cell carcinoma where the drug in combination with Inlyta has an existing label in the first-line.7   Keytruda’s dominant use in the metastatic setting combined with oncologist familiarity with the agent are likely to be helpful advantages for future uptake and use in the adjuvant setting.

The key goal of adjuvant therapy is to lower the risk of disease recurrence and improve patient overall survival.  Despite surgery, recurrence is common in clear cell renal cell carcinoma and there are limited curative treatment options available. Depending on the longer-term follow-up and magnitude of survival benefit shown in adjuvant studies, the market for metastatic treatment could be transformed as physicians opt to prescribe immunotherapy in earlier treatment lines.

The results presented poise Keytruda as a potential new standard of care in the adjuvant setting to reduce disease recurrence for patients with clear-cell renal cell carcinoma, and potentially improve survival outcomes. However, this setting is set to become increasingly competitive with other PD-1/PD-L1 inhibitors under evaluation in pivotal studies. Roche is investigating Tecentriq (IMmotion-010)4 and Bristol Myers Squibb is assessing Opdivo with Yervoy (CheckMate-914)5 in this patient setting.

Earlier visibility than expected to data from KEYNOTE-564 may provide Merck & Co. a significant advantage over other competitors vying to enter this space. Coupled with the larger eligible patient population (intermediate-high and high-risk) in the early-stage clear-cell patient setting, this could further accelerate Keytruda’s commercial opportunity and growth over the coming years for renal cell carcinoma.

Overall, we estimate Keytruda will reach more than $1 billion in sales in major markets for renal cell carcinoma by 2029, with considerable future drug sales contributing from the adjuvant setting.9

To learn more about our take on other oncology treatment landscape game changers, follow our ASCO 2021 analysis here.

Clarivate is currently updating its Disease Landscape and Forecast™ content for renal cell carcinoma with a new forecast horizon (2020-2030) and we will capture the many updates from ASCO 2021, including for Keytruda. Learn more about this research here.



  1. Merck,press release, April 8, 2021.
  2. Merck,press release, June 3, 2021.
  3. gov: NCT03142334 (accessed June 9, 2021).
  4. gov: NCT03024996 (accessed June 9, 2021).
  5. gov: NCT03138512 (accessed June 9, 2021).
  6. Choueiri TK, et al. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: Randomized, double-blind, Phase III KEYNOTE-564 study. 2021 ASCO Virtual Scientific Program. Abstract LBA5.
  7. Keytruda (pembrolizumab), FDA Prescribing Information (May 2021).
  8. Ravaud A, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. New England Journal of Medicine. 2016;375(23):2246-2254.
  9. Clarivate’s Market Forecast Assumptions: Disease Landscape & Forecast report, published March 2021.