A 2-mg/kg dosage of pembrolizumab given to adult patients with non–small-cell lung cancer (NSCLC) every 3 weeks is optimal to both reduce tumor size and avoid treatment-related adverse events, according to a new method of analysis.

Current methods for determining the maximum tolerated dose (MTD) based on dose-limiting toxicities may be outmoded for targeted therapies and immunotherapies, where the biologically effective dose (BED) may be much lower than the MTD.

“Using the MTD rather than the BED could expose patients to a higher dose than that necessary to achieve clinical effect and may increase toxicity, which could lower overall clinical effectiveness. Therefore, dose determination in oncology should use a multifactorial approach that includes not only clinical data from the first treatment cycle but extended clinical data, preclinical models, pharmacokinetics, pharmacodynamics, and integrated modeling and simulation,” said Dr. Manash Chatterjee of Merck, and associates (Ann Oncol. 2016 April 26. doi: 10.1093/annonc/mdw174 ).

Dr. Chatterjee and associates analyzed data from KEYNOTE-001 using various statistical and mathematical modeling techniques to determine the lowest effective drug dosage of pembrolizumab, a highly selective humanized IgG4 monoclonal antibody that targets the programmed death-1 receptor, for treatment of patients with NSCLC.

Patients enrolled in the KEYNOTE-001 trial received pembrolizumab at doses of 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression or intolerable toxicity, or until the patient or investigator decided to stop treatment. Sixty-one patients were treated with pembrolizumab at 2 mg/kg every 3 weeks, 287 patients were treated at 10 mg/kg every 3 weeks, and 202 patients were treated at 10 mg/kg every 2 weeks. PD-1 expression was assessed from biopsy samples using a prototype assay.

Decreases from baseline tumor size were observed for 67% of patients with known PD-L1 expression treated with pembrolizumab at 2 mg/kg every 3 weeks, 66% for patients treated at 10 mg/kg every 3 weeks, and 63% for patients treated at 10 mg/kg every 2 weeks.

Data on occurrence and severity of adverse events were collected throughout the study and up to 60 days after treatment was discontinued. Adverse events were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (version 4.0). Treatment-related adverse events were reported for 47% of patients treated at 2 mg/kg every 3 weeks. The frequency and severity of adverse events were similar for all dosages, the investigators reported.

Exposure-efficacy was evaluated by way of exploratory regression analyses followed by nonlinear mixed effects modeling. The model found no significant difference in the exposure-efficacy relationship based on dosage. PD-L1 expression and EGFR mutation were the only two factors that explained a significant portion of interindividual variability in tumor size decrease.

Exposure-safety was evaluated via logistic regression modeling where safety was defined as the frequency of adverse events. The model revealed that there was no significant relationship between adverse events and exposure to pembrolizumab or dosage. Overall duration of treatment was the only factor that was significantly related to adverse events.

“These results support the use of a 2-mg/kg Q3W dosage in patients with previously treated, advanced NSCLC,” the investigators concluded.

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