Findings from the phase 3 KEYNOTE-564 trial showed that adjuvant pembrolizumab (Keytruda) led to a significant reduction in the risk of disease recurrence or death versus placebo in patients with clear cell renal cell carcinoma (RCC).1
The results, which were shared as part of the 2021 ASCO Annual Meeting, showed that at a median follow-up of approximately 24 months, the median disease-free survival (DFS) was not reached with either pembrolizumab (n = 496) or placebo (n = 498) as per investigator assessment; however, the hazard ratio for DFS showed that pembrolizumab induced a 32% reduction in the risk of disease recurrence or death compared with placebo (HR, 0.68; P = .0010).
“Adjuvant pembrolizumab following surgery demonstrated a statistically significant and clinically meaningful improvement in DFS vs placebo,” lead study author Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology, director of the Kidney Cancer Center, and senior physician at Dana-Farber Cancer Institute, as well as Jerome and Nancy Kohlberg chair and professor of medicine at Harvard Medical School, said during the press briefing. “KEYNOTE-564 is the first positive phase 3 study of an adjuvant immunotherapy for patients with RCC. Pembrolizumab is a potential new standard of care for patients with RCC in the adjuvant setting.”
The standard-of-care treatment for patients with locoregional RCC is surgery; however, nearly half of patients eventually experience disease recurrence. Currently, there is no standard adjuvant systemic therapy that is supported by high levels of evidence worldwide.
In the double-blind, multicenter, phase 3 KEYNOTE-564 study (NCT03142334), investigators explored pembrolizumab vs placebo following nephrectomy in patients with clear cell RCC. Specifically, patients’ disease had to meet criteria that categorized them as high risk for recurrence, which included: pT2, grade 4 or sarcomatoid, N0, M0; pT3, any grade, N0, M0; pT4, any grade, N0, M0; any pT, any grade, N-positive, M0; or M1 with no evidence of disease after surgery.
Patients must have undergone nephrectomy within 12 weeks prior to randomization, could not have previously received systemic treatment, had to have an ECOG performance status of 0 or 1, and a tissue sample must have been obtainable for PD-L1 assessment.
All patients were randomized 1:1 to receive pembrolizumab at 200 mg every 3 weeks or placebo every 3 weeks, both for approximately 1 year. The primary end point of the trial was investigator-assessed DFS; secondary end points were overall survival (OS) and safety.
At 1 year, the estimated DFS rates were 85.7% and 76.2% with pembrolizumab and placebo, respectively. At 2 years, these rates were 77.3% and 68.1%, respectively.
“To give you an idea about the magnitude of DFS, at months 12 and 24, the difference is around 9% to 10%, with both sets favoring pembrolizumab,” Choueiri said.
The OS data are immature, with 3.6% (n = 18) and 6.6% (n = 33) events occurring in the pembrolizumab and placebo arms, respectively. The median OS has not yet been reached in either arm but is trending favorably toward the PD-1 inhibitor (HR, 0.54; 95% CI, 0.30-0.96; P = .0164); however, this has not cross the prespecified boundary of statistical significance.
The estimated 2-year OS rates are 96.6% for pembrolizumab and 93.5% for placebo. Additional follow-up is planned for OS, Choueiri noted.
The data cutoff date was December 14, 2020. Regarding safety, all-grade adverse effects (AEs) with pembrolizumab occurred in 96.3% of patients and in 91.1% of those on placebo; grade 3 to 5 AEs occurred in 32.4% and 17.7%, respectively. AEs led to death in 2 patients on pembrolizumab and in 1 patient on placebo.
Treatment-related AEs (TRAEs) occurred in 79.1% and 53.4% of pembrolizumab- and placebo-treated patients, respectively. A total 18.9% of patients on pembrolizumab had a grade 3 to 5 TRAE vs 1.2% of those on placebo. Notably, no TRAEs led to death in either arm. Overall, the safety profile was consistent with prior data on pembrolizumab.
Julie Gralow, MD, chief medical officer and executive vice president of ASCO, commented on the KEYNOTE-564 findings during the press briefing, which was held on May 28, 2021.
“KEYNOTE-564 is the first phase 3 trial to show improved DFS from the addition of an immune checkpoint inhibitor in the adjuvant setting for clear cell RCC, which is the most common type of kidney cancer,” said Gralow. “Despite surgery, recurrence is common in clear cell RCC, and if it does recur, there are limited curative treatment options. The results of the KEYNOTE-564 trial support consideration of pembrolizumab as a potential new standard of care in the adjuvant setting to reduce disease recurrence in certain patients with kidney cancer.”
Pembrolizumab is currently approved for use in combination with axitinib (Inlyta) for the frontline treatment of patients with advanced RCC.
1. Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab vs placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: randomized, double-blind, phase 3 KEYNOTE-564 study. J Clin Oncol. 2021;39(suppl 15):LBA5.