On November 17, 2021, the immunotherapeutic agent pembrolizumab was granted approval for adjuvant treatment of patients with renal cell carcinoma at intermediate-high or high risk of recurrence following nephrectomy or nephrectomy and resection of metastatic lesions.1
Supporting Efficacy Data
Approval was based on findings from the phase III double-blind KEYNOTE-564 trial (ClinicalTrials.gov identifier NCT03142334).1 A total of 994 patients with intermediate-high or high risk of recurrence or M1 no evidence of disease after nephrectomy or nephrectomy and resection of metastatic lesions were randomly assigned to receive pembrolizumab at 200 mg every 3 weeks (n = 496) or placebo (n = 498) for up to 1 year or until disease recurrence or unacceptable toxicity.
At a prespecified interim analysis, investigator-assessed disease-free survival events had occurred in 22% of the pembrolizumab group vs 30% of the placebo group (hazard ratio = 0.68, 95% confidence interval = 0.53–0.87, P = .0010). Median disease-free survival was not reached in either group; the 24-month disease-free survival rate was 77% vs 68%. Overall survival data were not mature, with death having occurred in 5% of the total population.
How It Is Used
The recommended dose is 200 mg every 3 weeks or 400 mg every 6 weeks until disease recurrence, unacceptable toxicity, or up to 12 months.
No dose reductions of pembrolizumab are recommended. In general, pembrolizumab should be withheld for grade 3 immune-mediated adverse reactions and permanently discontinued grade 4 immune-mediated adverse reactions, recurrent grade 3 immune-mediated reactions requiring systemic immunosuppressive treatment, or an inability to reduce the corticosteroid dose to ≤ 10 mg of prednisone or equivalent daily within 12 weeks of initiating steroids. Prescribing information provides instructions on dosage modifications for immune-mediated adverse reactions and infusion-related reactions.
In KEYNOTE-564, the most common adverse events of any grade (≥ 20%) in the pembrolizumab group were musculoskeletal pain (41% vs 36% in the placebo group), fatigue (40% vs 31%), rash (30% vs 15%), diarrhea (27% vs 23%), pruritus (23% vs 13%), and hypothyroidism (21% vs 4%). The most common grade 3 or 4 adverse events included hepatotoxicity (3.4%) and diarrhea (2.7%). The most common grade 3 or 4 laboratory abnormalities were increased glucose (8%), increased alanine aminotransferase (ALT; 3.8%), and hyponatremia (3.3%).
Serious adverse events occurred in 20% of patients receiving pembrolizumab, most commonly acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Adverse events led to discontinuation of pembrolizumab in 21% of patients, most commonly because of increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). A fatal adverse event (pneumonia) occurred in one patient.
Pembrolizumab has warnings or precautions for immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, dermatologic reactions, and solid organ transplant rejection; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation; and embryofetal toxicity.
1. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck & Co, Inc. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s113lbl.pdf. Accessed November 29, 2021.