Pembrolizumab vs. Placebo in ccRCC: KEYNOTE-564

The phase 3 KEYNOTE-564 study, a randomized, multicenter, double-blind, investigated the impact of adjuvant pembrolizumab on disease-free survival (DFS) following nephrectomy in clear cell renal cell carcinoma (ccRCC) patients (pts) at an elevated risk of recurrence. Results from the third prespecified interim analysis, with a median follow-up of approximately 57 months, revealed a significant improvement in DFS compared to placebo.

Furthermore, Toni K. Choueiri and his team aimed to assess the efficacy of adjuvant pembrolizumab in this context, recognizing the critical need for improved treatment strategies for ccRCC pts post-surgery.

The study performed an inclusive analysis involving participants aged ≥18 years diagnosed with histologically confirmed ccRCC, with or without sarcomatoid features, presenting an increased risk of recurrence. Eligible individuals had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1, underwent nephrectomy and/or metastasectomy within ≤12 weeks before randomization, and had no prior systemic therapy for RCC.

Participants were randomly assigned in a 1:1 ratio to receive either intravenous pembrolizumab (200 mg) or placebo every 3 weeks for ≥ 17 cycles (~1 year) or until disease recurrence, intolerable toxicity, or withdrawal of consent. The primary endpoint was DFS, assessed by the investigator, while overall survival (OS) served as a key secondary endpoint. Safety constituted a secondary endpoint, with thorough monitoring throughout the study period.

About 994 pts were randomized in a 1:1 ratio, with 496 receiving pembrolizumab and 498 receiving placebo. The median time from randomization to the data cut-off date of September 15, 2023, was 57.2 months, (range, 47.9−74.5). A statistically significant improvement in OS was observed with pembrolizumab compared to placebo, as indicated by medians not being reached (HR 0.62, 95% CI 0.44–0.87; P = .0024). The pembrolizumab arm had 55 OS events, whereas the placebo arm had 86.

The estimated OS rate at 48 months was 91.2% for pembrolizumab and 86.0% for placebo. Notably, the OS benefit was consistent across key subgroups, including pts with M0 disease (HR 0.63, 95% CI 0.44–0.90) or M1 non-evaluable disease (NED) (HR 0.51, 95% CI 0.15–1.75), those with PD-L1 combined positive score (CPS) <1 (HR 0.65, 95% CI 0.31–1.38) or CPS ≥1 (HR 0.62, 95% CI 0.42–0.91), and individuals with or without sarcomatoid features (HR 0.69, 95% CI 0.28–1.70 and HR 0.57, 95% CI 0.39–0.84, respectively).

The observed DFS benefit with pembrolizumab versus placebo remained consistent with prior interim analyses (HR 0.72; 95% CI 0.59–0.87). Importantly, no new safety signals were identified during the course of the study, underscoring the favorable safety profile of pembrolizumab in this setting.

The study concluded that, after approximately 57 months of follow-up, adjuvant pembrolizumab had demonstrated both statistically significant and clinically meaningful enhancements in OS compared to placebo in participants with renal cell carcinoma (RCC) at an elevated risk of recurrence post-surgery. Notably, KEYNOTE-564 marks a groundbreaking milestone as the first phase 3 trial showcasing improved survival with any adjuvant therapy in RCC. These findings affirm and further underscore adjuvant pembrolizumab’s pivotal role as a standard of care in the postoperative management of RCC pts at increased risk of recurrence.

The study is sponsored by Merck Sharp & Dohme LLC

Source: https://meetings.asco.org/abstracts-presentations/229896

Clinical Trial: https://clinicaltrials.gov/study/NCT03142334

Choueiri T K,Tomczak P, Park S H, et al. (2023). “Overall survival results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab versus placebo for the treatment of clear cell renal cell carcinoma (ccRCC).”  Presented at ASCO (Abstract LBA359).