Updated results from the KEYNOTE-564 trial confirm the role of pembrolizumab after surgery
Results of a third prespecified interim analysis of the trial KEYNOTE-564 have been published in The New England Journal of Medicine, reporting that adjuvant pembrolizumab was associated with a 38% lower risk of death than placebo after a median follow-up of 57.2 months among patients with renal-cell carcinoma (RCC) who were at intermediate or high risk for disease recurrence after surgery (N Engl J Med. 2024 Apr 18;390(15):1359-1371).
KEYNOTE-564 confirms to be the first trial to show statistically significant and clinically meaningful survival improvements with an adjuvant therapy in RCC. Eligible participants were adults with clear-cell RCC who had undergone surgery – partial or radical nephrectomy and synchronous or metachronous metastasectomy of any solid, isolated, soft-tissue, nonosseous, nonbrain metastatic lesions that could be resected completely with negative surgical margins – within 12 weeks before randomisation. A total of 994 patients were randomly assigned to receive intravenous adjuvant pembrolizumab or matched placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until disease recurrence, the occurrence of unacceptable toxic effects, or a decision to discontinue pembrolizumab or placebo by the participant or physician.
At a first interim analysis, pembrolizumab was associated with a significantly longer disease-free survival (DFS) – the primary end point – compared to placebo (77.3% vs. 68.1%; hazard ratio for recurrence or death, 0.68; 95% CI, 0.53 to 0.87; P=0.002) (N Engl J Med. 2021 Aug 19;385(8):683-694).
Updated results from the trial confirmed a DFS benefit and also showed that the estimated overall survival (OS) – the key secondary end point – at 48 months was 91.2% in the pembrolizumab group (95% CI, 88.3 to 93.4), as compared with 86.0% in the placebo group (95% CI, 82.6 to 88.8), with a 38% risk reduction of death (hazard ratio, 0.62; 95% CI, 0.44 to 0.87; P=0.005) and a consistent benefit observed across different subgroups, including participants who had less-adverse prognostic features, such as M0 stage disease, an ECOG performance-status score of 0, or an absence of sarcomatoid features.
Safety data were in line with those reported for other PD-1 inhibitors, and pembrolizumab was associated with a higher incidence of serious adverse events of any cause than placebo (20.7% vs. 11.5%), as well as with a higher incidence of adverse events of any grade (79.1% vs. 53.0%) or of grade 3 or 4 (18.6% vs. 1.2%) that were considered by the investigator to be related to pembrolizumab or placebo.
