Adjuvant Pembrolizumab Prolongs Disease-Free Survival in Renal Cell Carcinoma

Treatment with pembrolizumab (Keytruda) led to improvement in disease-free survival (DFS) in patients with renal cell carcinoma (RCC) following nephrectomy or following nephrectomy and resection of metastatic lesions, meeting the primary end point of the pivotal phase 3 KEYNOTE-564 trial (NCT03142334).

According to interim analysis data announced in a press release by Merck, the result observed with pembrolizumab by the independent Data Monitoring Committee was a statistically significant and clinically meaningful improvement compared with placebo. Safety data appeared consistent with prior reports. Patients will continue to be followed in the study to investigate the overall survival outcome, which is the key secondary end point of the study. The full results of the trial will be announced during an upcoming medical meeting and shared with regulatory agencies.

“Since its first approval in renal cell carcinoma nearly two years ago, Keytruda has become an important first-line treatment option in combination with axitinib for patients with advanced renal cell carcinoma,” saidRoy Baynes, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, in a statement. “These new data are the result of our research to evaluate the role of KEYTRUDA in helping patients with earlier stages of disease and are the first positive results for an anti-PD-1 therapy in the adjuvant treatment of patients with renal cell carcinoma. We look forward to sharing results of KEYNOTE-564 with the medical community and regulatory authorities as soon as possible.”

KEYNOTE-564 was originally designed with the goal of overcoming relapse with metastatic and incurable RCC after standard-of-care nephrectomy. It was hypothesized that an effective adjuvant therapy option might be a drug that targets the PD-1 pathway because it has the potential to prevent recurrence. The randomized, double-blind, placebo-controlled trial explores the efficacy and safety of pembrolizumab as treatment of RCC with outcomes like DFS, OS, event-free survival, the number of patients who experience adverse events (AEs), the number of patients who discontinue treatment in the study due to an AE, and quality of life.

During the study, 950 patients were dosed with pembrolizumab 200 mg intravenously [IV] on day 1 of each 3-week cycle for up to 17 cycles or a saline solution placebo via IV on day 1 of each 3-week cycle for up to 17 cycles.

To be eligible for inclusion in the study while recruitment was ongoing, individuals were required to have a histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features, have intermediate-high risk, high-risk, or M1 NED RCC, and ECOG performance status of 0 or 1, adequate organ function, have adequate tissue available for biopsy, and be tumor-free according to investigator assessment by either computed tomography or MRI. Patients were required to have undergone partial nephroprotective or radical complete nephrectomy with negative surgical margins but could not have received prior systemic therapy for advanced RCC.

Patients who had major surgery, other than nephrectomy and/or resection of pre-existing metastases for M1 NED, within 12 weeks prior to randomization, those who received prior radiotherapy for RC, and those with pre-existing brain or bone metastatic lesions were excluded from the study. Patients were also excluded if they had other comorbidities that may have interfered with study treatment.

Pembrolizumab is humanized monoclonal antibody that blocks the activity between PD-1 and its ligands, PD-L1 and PD-L2, leading to activation of T lymphocytes which may affect both tumor cells and healthy cells. Currently, more than 1,400 clinical trials of pembrolizumab as treatment of various malignancies are ongoing around the world. The drug already has FDA approval in combination with axitinib for the first-line treatment of patients with advanced RCC and is being investigated as a single-agent combination with other cancer treatments across multiple settings and stages of RCC.

_References:

_{1. Merck’s Keytruda® (pembrolizumab) demonstrated superior disease-free survival (DFS) compared with placebo as adjuvant therapy in patients with renal cell carcinoma (RCC) following surgery. News release. Merck. April 8, 2021. Accessed April 8, 2021.}

_{2. Choueri TK, Quinn DI, Zhang T, et al. KEYNOTE-564: A phase 3, randomized, double blind, trial of pembrolizumab in the adjuvant treatment of renal cell carcinoma. J Clin Oncol. 2018; 36 (suppl 5). doi: 10.1200/JCO.2018.36.15_suppl.TPS4599}