The KEYNOTE-564 trial: the first evidence for the benefit of immunotherapy in high risk clear cell RCC patients

In this episode, Dr Nieves Martinez-Chanza from the Institut Jules Bordet in Brussels provides a summary of the KN-564 trial, a randomized phase 3 clinical trial assessing the addition of pembrolizumab for one year versus placebo in the treatment of patients with clear cell RCC following nephrectomy and with a high risk of recurrence.

The primary endpoint of DFS was achieved during the first interim analysis, demonstrating a reduction in the risk of death or recurrence by approximately 30%. At the third interim analysis, at a median follow-up of 57 months, the consistent benefit of pembrolizumab in median DFS was observed, with no new safety concerns identified. Notably, a significant improvement in OS was observed in the pembrolizumab group, with a HR of 0.6, corresponding to a 38% reduction in the risk of death. This benefit was consistent across all subgroups, including PD-L1 status, presence of sarcomatoid features, or risk classification, encompassing patients ranging from intermediate to high risk of recurrence after nephrectomy, as well as those with post-nephrectomy or post-complete resection of metastasis.

This study represents the first evidence of survival benefit in the adjuvant setting for RCC. However, understanding why adjuvant pembrolizumab demonstrates significant improvements in DFS and OS, while other checkpoint inhibitors like nivolumab do not, remains challenging. Several factors could potentially account for this discrepancy, including patient and histological characteristics or the duration of adjuvant treatment.

Results from translational data analysis are eagerly anticipated, which may yield predictive biomarkers to identify patients at high risk of recurrence who would benefit from and be cured by this adjuvant treatment, as well as those who would derive sufficient benefit from surgery alone, thus sparing them from the potential adverse events associated with additional treatment.

References:

Choueiri TK et al, 2024, 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). ASCO GU2024 #LBA359

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