Weight-Based Pembrolizumab Dosing at 4 mg/kg Every 6 Weeks Leads to Exposures Below Approved Doses with Unestablished...

Pembrolizumab is approved globally at a dose of 200 mg every 3 weeks (Q3W) or 400 mg every 6 weeks (Q6W) intravenously (IV). These dosing recommendations are based on established regimens that have demonstrated efficacy in clinical trials. Recently, pembrolizumab dosing at 4 mg/kg Q6W has been suggested as an alternative regimen; however, efficacy has not been evaluated in any prospective, controlled clinical trial.

The objective was to describe the pharmacokinetic model-based analyses of pembrolizumab 4 mg/kg Q6W IV compared with approved dosing regimens.

The pharmacokinetic profiles for pembrolizumab were simulated for 4 mg/kg Q6W, 400 mg Q6W, 200 mg Q3W, and 2 mg/kg Q3W IV in 3607 participants from clinical trials of pembrolizumab across tumor types and were based on an established pharmacokinetic model informed by extensive clinical data that supported the approved pembrolizumab IV doses. Pharmacokinetic exposure measures evaluated were trough concentration (C_trough) and area under the curve (AUC) after initial dosing (first 6 weeks of treatment) and at steady state (weeks 13-18).

Pembrolizumab 4 mg/kg Q6W IV resulted in C_trough levels consistently below the lowest clinically evaluated thresholds associated with the approved fixed dose of 400 mg Q6W and weight-based dose of 2 mg/kg Q3W and well below those of 200 mg Q3W, which is the gold-standard dose with the most extensive pan tumor clinical data. In the overall population, the geometric mean steady state C_trough for 4 mg/kg Q6W was 26% lower than 400 mg Q6W (9% fell below fifth percentile) and 53% lower than 200 mg Q3W (33% fell below fifth percentile), while geometric mean steady state AUC was ~ 25% lower than both fixed doses (18% of participants fell below fifth percentile). The reduction was more pronounced in participants weighing under 50 kg, with geometric mean steady state C_trough 55% lower than 400 mg Q6W (17% of participants fell below fifth percentile) and 72% lower than 200 mg Q3W (54% of participants fell below fifth percentile), while the geometric mean steady state AUC was ~ 55% lower than both fixed doses (~ 50% of participants fell below fifth percentile). While AUC for 4 mg/kg Q6W was similar to that of 2 mg/kg Q3W, as expected with dose proportional pharmacokinetics, C_trough, which is a relevant efficacy driver, does fall below even this lowest clinically evaluated pembrolizumab dose regardless of body weight: ~ 37% lower than 2 mg/kg Q3W (~ 20% of participants fell below fifth percentile). Similar trends were seen in participants weighing 50-80 kg. Results were consistent after initial dosing.

Pharmacokinetic modeling suggests pembrolizumab 4 mg/kg Q6W IV results in reduced exposures with an uncertain impact upon efficacy. Participants with lower body weight were increasingly impacted, with meaningful exposure reductions below the clinically established threshold doses of 400 mg Q6W, 200 mg Q3W, and 2 mg/kg Q3W IV. In the absence of robust clinical data on pembrolizumab efficacy at doses with exposures below those of the approved dosing regimens, weight-based dosing at 4 mg/kg Q6W poses a potential risk to treatment efficacy.