The FDA has granted a priority review designation to a supplemental biologics license application (sBLA) for pembrolizumab (Keytruda) for the adjuvant treatment of patients with renal cell carcinoma (RCC) at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.1
The sBLA is supported by data from the phase 3 KEYNOTE-564 trial which showed that at a median follow-up of approximately 24 months, the median disease-free survival (DFS) was not reached with either adjuvant 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).2
The FDA is a scheduled to make a decision on the sBLA on or before December 10, 2021.
“The acceptance of our application demonstrates the progress we are making in earlier lines and earlier stages of certain cancers across our oncology portfolio,” Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, stated in a press release. “We look forward to working with the FDA towards the goal of bringing the first adjuvant immunotherapy option to appropriate patients with renal cell carcinoma in the United States.”
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.
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.
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.
1. FDA Grants Priority Review to Merck’s Supplemental Biologics License Application for KEYTRUDA® (pembrolizumab) as Adjuvant Therapy in Certain Patients With Renal Cell Carcinoma (RCC) Following Surgery. Published online August 10, 2021. Accessed August 10, 2021. https://bit.ly/3CAhr1G.
2. 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.