Pembrolizumab is approved globally in multiple cancer indications at a dose of 200 mg or 2 mg/kg every three weeks (Q3W). An alternative dosing regimen of 400 mg every six weeks (Q6W), which provides convenience and flexibility to patients and prescribers, is also approved in markets including the US and EU based on pharmacokinetic (PK) and exposure-response (E-R) modeling and simulation. KEYNOTE-555 Cohort B is an open-label, clinical study in patients with metastatic melanoma designed evaluate the Q6W dosing regimen. The preliminary PK, efficacy and safety data from this study validate the model-based assessments supporting similar risk-benefit for the Q6W regimen compared to Q3W regimens of pembrolizumab. A 400 mg Q6W regimen of pembrolizumab was selected based on exposure matching and demonstrating the Q6W regimen led to similar Cavg/AUC and Ctorugh exposure as approved Q3W regimens (200 mg or 2 mg/kg) and Cmax well below the highest clinically tested dose of 10 mg/kg with established clinical safety. Backed by the well-established clinical pharmacology profile of pembrolizumab, including thorough characterization of its PK and E-R relationships over a 5-fold dose range from 2 mg/kg to 10 mg/kg in multiple tumor types, regulatory approvals of the new Q6W regimen were based on extensive M&S analyses. Consistency of PK and flat E-R relationships across indications support applicability of the Q6W regimen across all approved adult indications of pembrolizumab. Clinical data from KN555 Cohort B confirmed previous M&S data and inferences. Observed concentration-time profiles from cycle 1 were consistent with predictions from the model, which is based on 2993 patients from 5 clinical trials across tumor types. The associated efficacy and safety with Q6W dosing in patients in this were similar to previous clinical trials in advanced melanoma at the Q3W dosing. Overall, M&S and supportive clinical data indicate that pembrolizumab Q6W is a safe and effective dosing regimen, comparable with the original approved Q3W regimen, and offers a more convenient and flexible dosing option for patients and physicians, to suit individual patient needs.
Apply exposure bridging for alternative dosing regimen selection
Appreciate the value of extensive clinical experience including clinical pharmacology characterization of pembrolizumab to learn from and leverage for unforeseen future applications
Appreciate increasing role of MIDD in oncology, particularly in the IO space with monoclonal antibodies