Highlights
- •Extended dosing of pembrolizumab will provide greater convenience and flexibility.
- •Exposure of pembrolizumab 400 mg Q6W and Q3W regimens was compared using modelling.
- •Pembrolizumab 400 mg Q6W leads to similar exposures as 200 mg and 2 mg/kg Q3W.
- •Similar efficacy and safety of the pembrolizumab Q6W and Q3W regimens is expected.
Abstract
Background
Pembrolizumab is approved for multiple cancer types at 200 mg and 2 mg/kg dose every
3 weeks (Q3W). We used a model-based approach to compare the exposure of pembrolizumab
400 mg dose every 6 weeks (Q6W) with the Q3W regimens.
Methods
The Q6W dose was selected by matching exposure with the 200 mg and 2 mg/kg Q3W doses.
Concentration-time profiles were simulated using the established population pharmacokinetic model
of pembrolizumab based on 2993 subjects from five clinical trials across tumour types.
Efficacy was bridged by evaluating projections of average concentration over the dosing
interval (Cavg) and trough concentration (Cmin) at steady state (ss). Safety was bridged by ensuring that concentrations were below those at 10 mg/kg
dose every 2 weeks (Q2W), the maximum clinical dose.
Results
The 400 mg Q6W dose had similar predicted exposure (Cavg,ss, geometric mean ∼1% higher) as the 200 mg Q3W dose. Fewer than 1% of subjects had
transiently lower Cmin,ss than that observed for 200 mg and 2 mg/kg Q3W. Despite these reductions, similar
target saturation is expected. The predicted peak concentrations (Cmax,ss) for 400 mg Q6W were substantially (∼65%) lower than the 10 mg/kg Q2W dose.
Conclusions
Exposures expected for pembrolizumab 400 mg Q6W were similar to the 200 mg and 2 mg/kg
Q3W and below the 10 mg/kg Q2W regimens. Established exposure-response relationships
for pembrolizumab over a 5-fold dose range (2 mg/kg Q3W to 10 mg Q2W) support that
clinical efficacy and safety of 400 mg Q6W would be similar to the 200 mg and 2 mg/kg
Q3W doses across tumour types.
Clinical trial registration numbers
NCT01295827, NCT01704287, NCT01866319, NCT01905657, NCT02142738.
Keywords
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Article info
Publication history
Published online: April 15, 2020
Accepted:
February 10,
2020
Received:
January 16,
2020
Footnotes
☆Previous presentation: ASCO Annual Meeting, 2018, Chicago, IL, USA; abstract 3062.
Identification
Copyright
© 2020 Elsevier Ltd. All rights reserved.
ScienceDirect
Access this article on ScienceDirectLinked Article
- Corrigendum to “A six-weekly (Q6W) dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation” [Eur J Canc 131 (2020) 68–75]European Journal of CancerVol. 144
- Letter to the editor: Comments on ‘A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation’European Journal of CancerVol. 138
- PreviewWith great interest, we read the research article of Lala et al. [1]. The authors present a robust population pharmacokinetic (PPK) model of pembrolizumab with data from 2993 patients and a thorough data interpretation. This research gives a better insight into the exposure––response relationship for pembrolizumab, and they concluded that a dose of 2 mg/kg or a fixed dose of 200 mg every 3 weeks (Q3W) can be extended to a dose of 400 mg Q6W based on pharmacokinetic modelling. Although this study provides clear dosing guidelines, a solid pharmaco-economic analysis was left underexposed to our surprise.
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