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Inferring Target Occupancy for Pembrolizumab

Background

Pembrolizumab (Pembro), an anti-PD-1 antibody, is approved for several cancer indications at 200 mg or 2 mg/kg IV every 3 weeks (Q3W).

Understanding the percent target receptor occupancy (RO) for PD-1 at this approved dose can help with dose selection for anti-PD-1 combination studies and other anti-PD-1 drugs in development. However, RO can be challenging to determine through direct experimental measurements.

Results

    1. A semi-mechanistic PKRO model was developed to fit Pembro phase 1 PK data. The model was then used to predict RO.
    2. For the clinically approved dose of 2 mg/kg Q3W, the model predicted that the range of sPD-1 concentration has no significant impact on PD-1 RO in tumor.
    3. The impact of Kd and drug:PD-1 turnover rate on predicted RO was explored. When either of the parameters varied by 10-fold higher or lower from its nominal value, the model still predicted greater than 90% RO at 2 mg/kg dose.