Pembrolizumab as a potential new standard of care for patients with renal cell carcinoma in the adjuvant setting
Keynote-564 is the first positive phase III study of an adjuvant immunotherapy for patients with renal cell cancer (RCC). In this trial, postoperative treatment with pembrolizumab significantly improved the disease-free survival (DFS) of patients with high-risk, clear cell RCC relative to placebo. In addition, safety findings were in line with expectations overall, without any new toxicities.
For patients with locoregional RCC, nephrectomy is the current standard of care. However, eventually, nearly half of patients experience disease recurrence after surgery. Risk factors for recurrence include tumour stage and size, nodal involvement and nuclear grade. In addition, patients with M1 stage and no evidence of disease (NED) after resection of oligometastatic sites are also at high risk of relapse. Keynote-564 is a phase III, double-blind, multicentre trial of pembrolizumab vs. placebo following nephrectomy in participants with clear cell RCC (ccRCC).
Keynote-564 study design
Keynote-564 enrolled patients with histologically confirmed ccRCC, with intermediate-high risk (pT2, Grade 4 or sarcomatoid, N0 M0; or pT3, any Grade, N0 M0), high risk (pT4, any Grade, N0 M0; or pT any stage, any Grade, N+ M0), or M1 NED (no evidence of disease after resection of oligometastatic sites ≤1 year from nephrectomy). Patients had undergone surgery ≤12 weeks prior to randomisation, had no prior systemic therapy and had an ECOG performance status of 0 or 1. Between June 30, 2017 and September 20, 2019, 994 patients were randomised (1:1) to pembrolizumab 200 mg once every three weeks (N= 496), or placebo (N= 498). Study treatment was given for up to 17 cycles, corresponding to approximately one year. At the data cut-off (December 14, 2020), the median follow-up, defined as the time from randomisation to data cut-off, was 24.1 months. No patients remained on study treatment. Baseline patient characteristics were generally balanced between arms.
Safety and efficacy of pembrolizumab
Median disease-free survival (DFS) by investigator in the intention to treat (ITT) population was not reached in either arm. The stratified hazard ratio (HR) for DFS was 0.68 (95%CI: 0.53-0.87) with a statistically significant difference in favour of pembrolizumab (p= 0.0010). The estimated 12-month DFS rates in the pembrolizumab and placebo groups were 85.7% and 76.2%, respectively, while the corresponding 24-month rates were 77.3% and 68.1%. This DFS benefit with pembrolizumab was consistent across subgroups. The median overall survival (OS) was not reached and the number of events was only modest. However, a 46% reduction in the risk of death with pembrolizumab compared to placebo was reported (HR[95%CI]: 0.54[0.30-0.96], p= 0.0164). Of note, this p-value did not cross the prespecified boundary for statistical significance and additional follow-up is planned for this key secondary endpoint. The OS curves clearly separate after the 24-month landmark, with almost no events in either arm prior to this time point.
As expected, pembrolizumab was associated with more Grade 3-5 adverse events (AEs) of any cause (32.4% vs. 17.7%), serious all-cause AEs (20.5% vs. 11.3%) and treatment-related AEs (TRAEs, 18.9% vs. 1.2%). In total, 17.6% of patients in the pembrolizumab arm discontinued treatment due to TRAEs. No fatal TRAEs were reported in either arm. The pembrolizumab safety profile in the adjuvant setting was in line with expectations and no new safety signals were observed. The most common TRAEs included fatigue, pruritus and thyroid abnormalities and were all of low grade. The most common immune-mediated AEs consisted of hypo- and hyperthyroidism (as could be expected with pembrolizumab) and were manageable. In total, 7.4% of pembrolizumab-treated patients received high-dose systemic corticosteroid treatment for immune-mediated AEs.
Adjuvant pembrolizumab post nephrectomy demonstrated a statistically significant and clinically meaningful improvement in DFS vs. placebo. This benefit was consistent across all investigated subgroups, including the M1 NED population, potentially extending the use of pembrolizumab to these patients. Safety results were in line with expectations and no new safety signals were observed. Keynote-564 thereby is the first positive phase III study of adjuvant immunotherapy in RCC. Finally, pembrolizumab is a potential new standard of care for patients with RCC in the adjuvant setting.
Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: Randomized, double-blind, phase III KEYNOTE-564 study. Presented at ASCO 2021; Abstract LBA5.