Pembrolizumab as post-nephrectomy adjuvant therapy results in survival benefit for patients with renal cell carcinoma

After a median follow-up of approximately 57 months, the phase III KEYNOTE-564 study reported that adjuvant pembrolizumab provides a statistically significant and clinically meaningful improvement in overall survival versus placebo for patients with clear cell renal cell carcinoma (ccRCC) at high risk of recurrence after surgery. This study represents the first phase III study to show improved overall survival with any adjuvant therapy in kidney cancer.

Between 1973 and the present, seventeen randomised controlled studies investigated adjuvant therapies in renal cell carcinoma (RCC), with no observed survival improvement. The phase III KEYNOTE-564 study investigated adjuvant pembrolizumab versus placebo in participants with clear cell RCC and increased risk of disease recurrence after surgery. The primary endpoint of disease-free survival was met at the first interim analysis. At ASCO GU 2024, results from the third prespecified interim analysis of this study, including updated overall survival, were presented.

Study design

The  multicentre, double-blind, phase III KEYNOTE-564 trial enrolled adult patients  with clear cell RCC with an increased risk of recurrence. Eligible participants had undergone nephrectomy no longer than twelve weeks before randomisation, and had not received previous systemic therapy for advanced RCC. Participants were randomly assigned (1:1) to receive pembrolizumab (pembro) 200 mg or placebo intravenously every three weeks for up to seventeen cycles or until disease recurrence, intolerable toxicity or withdrawal of consent. The primary endpoint was disease-free survival (DFS). The key secondary endpoint was overall survival (OS) and safety was a secondary endpoint.

Results

In total, 488 patients were treated in the pembrolizumab arm and 496 patients were treated in the placebo arm. Median time from randomisation to data cut-off date was 57.2 months. As of December 2020, all participants had completed or discontinued study therapy. Baseline characteristics were balanced between both groups. Of note, over 94% of patients were M0, and more than 85% of patients were M0 intermediate-high risk.

A statistically significant improvement in OS was observed with pembrolizumab vs. placebo (medians not reached, HR [95% CI]: 0.62[0.44-0.87]; p= 0.002). The estimated 4-year OS rate was 91.2% with pembrolizumab and 86.0% with placebo. Furthermore, the OS benefit was observed across key subgroups, including patients with M0 disease (HR [95% CI]: 0.63[ 0.44-0.90) or M1 NED (HR [95% CI]: 0.51[0.15-1.75]), with PD-L1 CPS <1 (HR [95% CI]: 0.65[0.31-1.38]) or CPS ≥1 (HR [95% CI]: 0.62[0.42-0.91]), and with presence (HR [95% CI]: 0.69[0.28-1.70]) or absence (HR [95%CI]: 0.57[0.39-0.84]) of sarcomatoid features. The DFS benefit with pembrolizumab vs. placebo was consistent with prior interim analyses (HR [95% CI]: 0.72[0.59-0.87]), with 4-year DFS rates of 64.9% and 56.6% in the pembrolizumab and placebo groups, respectively.

In the placebo arm, there were 210 patients with documented recurrence, as compared to 161 patients in the pembrolizumab arm. Approximately 80% of patients received any subsequent therapy on both arms, mostly anti-PD-(L)1 therapy or VEGF targeted therapy. Finally, given the fact that all participants completed or discontinued study therapy by December 2020, safety findings did not change substantially since last analysis.

Conclusions

Adjuvant pembrolizumab significantly prolonged overall survival versus placebo in participants with clear cell RCC at increased risk of recurrence following surgery. In addition, a continued disease-free survival benefit with pembrolizumab versus placebo was observed with further follow-up. KEYNOTE-564 is the first study to show a statistically significant and clinically meaningful survival improvement with an adjuvant therapy in RCC and these results further support pembrolizumab as a standard of care after surgery in this disease setting.

Reference

Choueiri T, et al. 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 GU 2024; Abstract LBA359.