The evidence for flat dose as opposed to weight based dosing for pembrolizumab comes from pharmacokinetic (PK) analysis of 9 KEYNOTE trials by Freshwater et al. Patients were treated with pembrolizumab IV doses ranging from 2 mg/kg and 10 mg/kg (n=2817 patients) and flat dose 200 mg (n=830 patients) and frequency ranging from every 2 to 3 weeks.r
Population PK modelling simulated the predicted plasma concentration exposure between flat dosing and weight based dosing in patients with advanced melanoma or non-small cell lung cancer (NSCLC) (n=2800 virtual patients). Additionally, individual PK parameters were predicted from observed concentrations in flat dosed head and neck, NSCLC, MSI-H in colorectal cancer and urothelial cancer patients (n=830) to calculate the AUC at the steady state of 6 weeks (AUCss0-6weeks).
The observed exposures for mean AUCss0-6weeks (% CV, n) were 1.87 (37%, 830), 1.38 (38%, 760) and 7.63 (35%, 1405) mcg*day/mL in patients who received pembrolizumab doses of 200 mg, 2 mg/kg and 10 mg/kg every 3 weeks respectively. Patients who weighed > 90 kg had the lowest observed exposure with 200 mg doses but were within the range to achieve near maximal efficacy (as determined by 2 mg/kg dosing in earlier clinical trials). Flat dosing PK was not observed in patients with melanoma.
Predicted population AUCss0-6weeks between flat dosing and weight based dosing demonstrated similar exposure in the 50 to 90 kg group. Predicted AUC was pooled and not displayed for specific cancers.
Observed pembrolizumab exposures from KEYNOTE trialsr
© J Immunother Cancer 2017
Distribution of observed and predicted pembrolizumab AUCss0-6weeksr
Variation in exposures with body weight under weight-based versus fixed dosing. Box: straight middle line = median; edges = 25th and 75th percentiles; whiskers = 10th and 90th percentiles; dots = 5th and 95th percentiles. Horizontal dashed lines (————) represent the range of exposures (5th percentile of 2 mg/kg Q3W and 95th percentile of 10 mg/kg Q2W) from dose regimens demonstrated to have comparable efficacy and tolerability in melanoma and previously treated NSCLC trials. Observed data are based on Table 1. In Panel B, distribution of observed AUCss0-6weeks for light (≤ 50 kg), middle (between 50 and 90 kg) and heavy (≥ 90 kg) body-weight patients
© J Immunother Cancer 2017
The authors concluded that because of exposure-response relationships described in previous studies, flat dosing based on the predicted and observed AUCs could be suggested to maintain the efficacy and safety exposure range described in weight based dosing of pembrolizumab and therefore both dosing methods are appropriate.r