Kidney cancer is one of the most common cancers of the urinary system, with clear cell renal cell carcinoma (ccRCC) being the most frequent pathological type.¹ However, adjuvant therapy after surgery for localized ccRCC has historically been a challenging area of research, with limited success documented.² In 2021, pembrolizumab, an anti-programmed death 1 (PD-1) antibody, was approved as an adjuvant treatment for renal cell carcinoma (RCC) patients based on significant improvements in disease-free survival (DFS) observed in the phase 3 KEYNOTE-564 trial.² The recent publication of the third prespecified interim analysis of the trial has demonstrated that adjuvant pembrolizumab was also associated with a significant and clinically meaningful improvement in overall survival (OS) among ccRCC patients at increased risk for recurrence after surgery.²

Approximately 75% of patients with RCC are diagnosed with ccRCC, which originates in the tubular epithelium of the kidneys and can metastasize to other organs.³ Nephron-sparing surgery, where only part of the diseased kidney tissue is removed, is recommended over a radical nephrectomy, as the latter can increase the load on the contralateral kidney and trigger post-operative kidney injury.¹ Adjuvant therapy after surgery is crucial, but this has been a challenging area of investigation, with limited success documented.² For example, while the tyrosine kinase inhibitor sunitinib showed significant improvement in DFS when used as an adjuvant in the S-TRAC trial, the larger phase 3 ASSURE trial did not report prolongation in OS.² Similarly, while a previous interim analysis of the phase 3 KEYNOTE-564 trial had previously shown significant improvements in DFS with adjuvant pembrolizumab compared to placebo, the improvements in OS did not meet statistical significance and the data were not sufficiently mature.^2,3

The KEYNOTE-564 trial was a phase 3, double-blind, randomized, placebo-controlled trial, involving ccRCC patients who had undergone surgery within the past 12 weeks and were assessed to be disease-free after surgery.² A total of 994 participants were randomly assigned 1:1 to receive adjuvant intravenous pembrolizumab 200mg or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until disease recurrence, unacceptable toxic effects, or withdrawal of consent.² The median follow-up time of the trial was 57.2 months, during which 55 participants in the pembrolizumab group and 86 participants in the placebo group had died.² The DFS benefit observed in the current analysis was consistent with the previous analysis (hazard ratio [HR]=0.72; 95% CI: 0.59-0.87).² Importantly, the risk of death was estimated to be 38% lower with pembrolizumab than with placebo, and a significant improvement in OS was observed (HR=0.62; 95% CI: 0.44-0.87; p=0.005).² The estimated OS at 48 months was 91.2% in the pembrolizumab group compared with 86.0% in the placebo group, and the benefit was consistent across key subgroups.² Pembrolizumab was associated with a higher incidence of serious adverse events from any cause over placebo (20.7% vs. 11.5%), as well as those of any grade (79.1% vs. 53.0%) and those of grade 3 or 4 (18.6% vs. 1.2%) considered to be related to the study treatment.² However, these safety findings remained consistent with previous interim analyses, and no deaths attributed to pembrolizumab had occurred.²

In summary, this phase 3 trial showed that adjuvant pembrolizumab was associated with a significant and clinically meaningful improvement in OS, as compared with placebo, among ccRCC participants at increased risk for recurrence after surgery.² These results support the use of adjuvant pembrolizumab as a standard intervention after surgery in this disease context.²