Original Research| Volume 131, P68-75, May 2020

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A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation

Published:April 15, 2020DOI:


      • 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.



      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.


      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.


      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.


      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.


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      1. Keytruda [package insert]. Merck & Co., Inc., Kenilworth, NJ2017
        • Garon E.B.
        • Rizvi N.A.
        • Hui R.
        • Leighl N.
        • Balmanoukian A.S.
        • Eder J.P.
        • et al.
        Pembrolizumab for the treatment of non-small-cell lung cancer.
        N Engl J Med. 2015; 372: 2018-2028
        • de Greef R.
        • Elassaiss-Schaap J.
        • Chatterjee M.
        • Turner D.C.
        • Ahamadi M.
        • Forman M.
        • et al.
        Pembrolizumab: role of modeling and simulation in bringing a novel immunotherapy to patients with melanoma.
        CPT Pharmacometrics Syst Pharmacol. 2017; 6: 5-7
        • Freshwater T.
        • Kondic A.
        • Ahamadi M.
        • Li C.H.
        • de Greef R.
        • de Alwis D.
        • et al.
        Evaluation of dosing strategy for pembrolizumab for oncology indications.
        J Immunother Cancer. 2017; 5: 43
        • U.S. FDA Guidance Document
        Providing clinical evidence of effectiveness for human drug and biological products.
        • U.S. FDA Guidance Document
        Exposure-response relationships — study design, data analysis, and regulatory applications.
        • Patnaik A.
        • Kang S.P.
        • Rasco D.
        • Papadopoulos K.P.
        • Elassaiss-Schaap J.
        • Beeram M.
        • et al.
        Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors.
        Clin Canc Res. 2015; 21: 4286-4293
        • Joseph R.W.
        • Gangadhar T.C.
        • Puzanov I.
        • Robert C.
        • Hamid O.
        • Dummer R.
        • et al.
        Model-based analysis of the relationship between pembrolizumab (MK-3475) exposure and efficacy in patients with advanced or metastatic melanoma.
        J Clin Oncol. 2015; 33
        • Sachs J.R.
        • Mayawala K.
        • Gadamsetty S.
        • Kang S.P.
        • de Alwis D.P.
        Optimal dosing for targeted therapies in oncology: drug development cases leading by example.
        Clin Canc Res. 2016; 22: 1318-1324
        • Press Release
        European Medicines agency adopts positive opinion for merck's KEYTRUDA® (pembrolizumab) for six-week dosing schedule across all current monotherapy indications.
        March 4,. 2019;
        • Li H.
        • Yu J.
        • Liu C.
        • Liu J.
        • Subramaniam S.
        • Zhao H.
        • et al.
        Time dependent pharmacokinetics of pembrolizumab in patients with solid tumor and its correlation with best overall response.
        J Pharmacokinet Pharmacodyn. 2017; 44: 403-414
        • Ribas A.
        • Puzanov I.
        • Dummer R.
        • Schadendorf D.
        • Hamid O.
        • Robert C.
        • et al.
        Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial.
        Lancet Oncol. 2015; 16: 908-918
        • Robert C.
        • Schachter J.
        • Long G.V.
        • Arance A.
        • Grob J.J.
        • Mortier L.
        • et al.
        Pembrolizumab versus ipilimumab in advanced melanoma.
        N Engl J Med. 2015; 372: 2521-2532
        • Herbst R.S.
        • Baas P.
        • Kim D.W.
        • Felip E.
        • Perez-Gracia J.L.
        • Han J.Y.
        • et al.
        Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
        Lancet. 2016; 387: 1540-1550
        • Li T.
        • Lala M.
        • Chatterjee M.
        • Jain L.
        • de Alwis D.
        • Stone J.
        • et al.
        Application of A Tumor penetration model for the prediction of tumor target engagement and dose justification.
        American Conference on Pharamcometrics (ACoP), Orlando, FL2019
        • Grimwood S.
        • Hartig P.R.
        Target site occupancy: emerging generalizations from clinical and preclinical studies.
        Pharmacol Therapeut. 2009; 122: 281-301
        • Hirsh V.
        • Langleben A.
        • Ayoub J.
        • Cormier Y.
        • Pintos J.
        • Iglesias J.L.
        Flexible chemotherapy regimen with gemcitabine and vinorelbine for metastatic nonsmall cell lung carcinoma: a phase II multicenter trial.
        Cancer. 2001; 92: 830-835
        • Eckardt J.R.
        Emerging role of weekly topotecan in recurrent small cell lung cancer.
        Oncol. 2004; 9: 25-32
        • Long G.V.
        • Tykodi S.S.
        • Schneider J.G.
        • Garbe C.
        • Gravis G.
        • Rashford M.
        • et al.
        Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer.
        Ann Oncol. 2018; 29: 2208-2213

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