Updated KEYNOTE-564 Data Continue to Underscore Benefit of Adjuvant Pembrolizumab in RCC


Toni K. Choueiri, MD, discusses follow-up data from the pivotal phase 3 KEYNOTE-564 examining adjuvant pembrolizumab in patients with clear cell RCC and additional areas that are ripe for further research.

Toni K. Choueiri, MD.

Toni K. Choueiri, MD.

Adjuvant pembrolizumab (Keytruda) continued to improve disease-free survival (DFS) over placebo in patients with clear cell renal cell carcinoma (RCC) enrolled to the phase 3 KEYNOTE-564 trial (NCT03142334) at 30.1 months of follow-up,1 according to Toni K. Choueiri, MD, who added that biomarker analyses are planned to identify which subsets will derive the most benefit from the immunotherapy.

In November 2021, the FDA approved pembrolizumab for use as an adjuvant treatment in those with RCC who are at intermediate-high or high risk of recurrence after nephrectomy or following nephrectomy and resection of metastatic lesions.2 The regulatory decision was based on earlier data from KEYNOTE-564, which showed that the hazard ratio (HR) for DFS favored the PD-1 inhibitor over placebo (HR, 0.68; 95% CI, 0.53-0.87; P = .0010).

With additional follow-up, the HR for DFS continued to favor the immunotherapy, with a HR of 0.63 (95% CI, 0.50-0.80; P < .0001). The median DFS has not yet been reached in either of the treatment arms. The immunotherapy was also found to improve DFS over placebo in key subgroups analyzed, including those at intermediate-high recurrence risk (HR, 0.68; 95% CI, 0.52-0.89), those at high risk (HR, 0.60; 95% CI, 0.33-1.10), and those at M1 no evidence of disease (HR, 0.28; 95% CI, 0.12-0.68). Notably, pembrolizumab improved DFS over placebo irrespective of whether sarcomatoid features were present (HR, 0.54; 95% CI, 0.29-1.00) or absent (HR, 0.63; 95% CI, 0.48-0.83).

“We are planning additional [analyses with this study, to examine] biomarkers and see whether we can tease out the patients who really need pembrolizumab and can benefit exclusively from [the agent],” Choueiri, director of the Lank Center for Genitourinary Oncology, director of the Kidney Cancer Center, and senior physician at Dana-Farber Cancer Institute, said. “This is in the works.”

In an interview with OncLive®, Choueiri, who is also the Jerome and Nancy Kohlberg Chair and professor of medicine at Harvard Medical School, discussed follow-up data from the pivotal phase 3 KEYNOTE-564 examining adjuvant pembrolizumab in patients with clear cell RCC and additional areas that are ripe for further research.

OncLive®: Could you speak to the design of the KEYNOTE-564 trial?

Choueiri: [KEYNOTE-564 was] a large adjuvant study [that included] almost 1000 patients with clear cell RCC who were intermediate high-risk, high-risk, and M1 NED [and who had] locoregional disease. [Patients] were randomized [1:1] to receive [approximately] 1 year of pembrolizumab, the PD-1 inhibitor, or placebo. The primary end point [of the trial was] DFS per investigator [assessment].

The first results [from the trial] were presented during a plenary session at the 2021 ASCO Annual Meeting, [and we shared updated] data during the 2022 Genitourinary Cancers Symposium.

What were the key efficacy and safety findings to come out of the updated analysis?

An additional interim analysis [for the trial] was performed, as agreed upon by health agencies. The median follow-up went from 24 months to 30 months, and we continue to see the benefit in DFS [at this later time point]. The HR [for DFS] was 0.68 [at 24 months, and] became 0.63 with 6 additional [months] of follow-up.

When we looked at key subgroups, [such as those with or without] sarcomatoid features, the benefit was in favor of pembrolizumab. We also [presented] updated OS results. From 24 months to 30 months of follow-up, the HR stayed stable, [going] from 0.54 to 0.52; that is [not] statistically significant because we need a stringent P value for OS, and only 33% of [the] events needed [had occurred].

We also looked at [safety] and additional treatment-related adverse [effects] with additional follow-up, and the same toxicity profile [was observed]; there were no major changes.

What are the next steps for this research?

The most important thing is to have more follow-up, with more events, to look clearly at OS; that is going to be [crucial]. We are also going to [examine] additional end points in the future, such as PFS2 and others. [We will have] more information [with more follow-up].

We also delivered a presentation during the 2021 ESMO Congress about the quality of life [QOL] with pembrolizumab. We saw no decrease, or no drop in QOL, for the year that the patients were on [pembrolizumab].


Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab as post nephrectomy adjuvant therapy for patients with renal cell carcinoma: results from 30-month follow-up of KEYNOTE-564. J Clin Oncol. 2022;40(suppl 6):290. doi:10.1200/JCO.2022.40.6_suppl.290

  1. FDA approves pembrolizumab for adjuvant treatment of renal cell carcinoma. News release. FDA; November 17, 2021. Accessed March 20, 2022.
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