Adjuvant Pembrolizumab Offers Improved OS in KEYNOTE-564 Trial of ccRCC


Adjuvant pembrolizumab had an estimated 91.2% overall survival rate after 4 years compared with 86.0% for patients with clear-cell renal cell carcinoma who received a placebo.

Toni Choueiri, MD

Toni Choueiri, MD

Treatment with adjuvant pembrolizumab (Keytruda) led to a significant and clinically meaningful improvement in overall survival (OS) when compared with placebo in patients with clear-cell renal cell carcinoma (ccRCC), according to findings from KEYNOTE-564 (NCT03142334).1

The estimated OS in the pembrolizumab arm at 48 months was 91.2% compared with 86.0% in the placebo group (HR, 0.62; 95% CI, 0.44-0.87; P =.005). The observed benefit was consistent across key subgroups.

“KEYNOTE-564 with its overall survival benefit establishes 1 year of pembrolizumab as the standard practice in intermediate-high, high and M1 with no evidence of disease clear-cell renal cancer. This will open more options to extended survival for our patients,” Toni Choueiri, MD, lead study author and the director of the Lank Center for Genitourinary Oncology, co-leader of the Kidney Cancer Program, and a senior physician at Dana-Farber Cancer Institute in Boston, Massachusetts, told Targeted OncologyTM.

"Patients who have high- and intermediate-risk clear-cell renal cancer should have a discussion about the benefits and risks of adjuvant therapy . They should know that pembrolizumab is associated with a significant survival advantage which is attractive for patients," added Thomas Powles, MD, MBBS, MRCP, professor of genitourinary oncology, Queen Mary University of London and director, Barts Cancer Center, in an interview with Targeted OncologyTM.

Thomas Powles, MD, MBBS, MRCP

Thomas Powles, MD, MBBS, MRCP

At a median follow-up of 57.2 months as of September 15, 2023, in this third prespecified interim analysis, 496 patients with ccRCC who were at increased risk for recurrence after surgery were treated with pembrolizumab while 498 received placebo. Among these patients, the disease-free survival (DFS) benefit was consistent with that in previous analyses (HR, 0.72; 95% CI, 0.59-0.87).

For safety, pembrolizumab was associated with a higher incidence of serious adverse events of any cause (20.7% vs. 11.5% with placebo) and of grade 3 or 4 adverse events related to pembrolizumab or placebo (18.6% vs. 1.2%). No deaths were attributed to pembrolizumab therapy.

Previously, KEYNOTE-564 met its primary end point of DFS.2 The pembrolizumab group had longer DFS vs placebo at 24 months (77.3% vs 68.1%; HR, 0.68; 95% CI, 0.53-0.87; P = .002).2 In the pembrolizumab arm, the estimated percentage of patients who remained alive at 24 months was 96.6% compared with 93.5% in the placebo group (HR, 0.54; 95% CI, 0.30-0.96). Additionally, the corresponding percentages at 12 months were 85.7% (95% CI, 82.2%-88.5%) and 76.2% (95% CI, 72.2%-79.7%).

“Now, we can build on pembrolizumab as standard, and not placebo, for future studies,” added Choueiri.

About the Phase 3 KEYNOTE-564 Trial in ccRCC

Illustration of kidneys with cancer cells -

Illustration of kidneys with cancer cells -

"There have been a series of previous trials with a plethora of agents. They type of agent, duration of therapy and study design are all likely to be responsible for the previous negative studies," added Powles.

The landmark KEYNOTE-564 study is a double-blind, placebo-controlled trial which randomized patients with ccRCC with an increased risk of recurrence after surgery in a 1:1 fashion to receive 200 mg of pembrolizumab or placebo every 3 weeks for up to 17 cycles.3 Treatment could also continue until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent.

Patients were eligible for enrollment in the study if they have a histologically confirmed diagnosis of ccRCC with or without sarcomatoid features; intermediate-high risk, high-risk, or M1 no evidence of disease RCC; and received no prior systemic therapy for advanced RCC. Patients must have also undergone a partial nephroprotective or radical complete nephrectomy with negative surgical margins, have undergone a nephrectomy and/or metastasectomy ≥28 days prior to signing informed consent and ≤12 weeks prior to randomization, and be tumor-free ≤28 days from randomization.

Additional eligibility requirements included having provided adequate tissue, an ECOG performance status of 0 or 1, and adequate organ function.

“We do have 2 ongoing randomized studies with pembrolizumab as backbone adding a HIF2 inhibitor in 1 and adding a personalized cancer vaccine in the other. So, the field is moving on. We also must not forget to test biomarkers on KEYNOTE-564 that can enrich for patients that benefit, since some patients do not need pembrolizumab and even if at high risk, surgery may still be enough,” said Choueiri.

1. Choueiri TK, Tomczak P, Park SH, et al. Overall survival with adjuvant pembrolizumab in renal-cell carcinoma. N Engl J Med. 2024;390(15):1359-1371. doi:10.1056/NEJMoa2312695
2. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385(8):683-694. doi:10.1056/NEJMoa2106391
3. Safety and efficacy study of pembrolizumab (MK-3475) as monotherapy in the adjuvant treatment of renal cell carcinoma post nephrectomy (MK-3475-564/KEYNOTE-564). Updated June 29, 2023. Accessed April 18, 2024.
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