Vol 16, No 6 (2020)
Review paper
Published online: 2021-01-12

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New dosing schedule of pembrolizumab — theoretical basis and scientific evidence

Dorota Szcześ1, Piotr Rutkowski1
Oncol Clin Pract 2020;16(6):358-363.

Abstract

Pembrolizumab among other immunotherapy agents is a breakthrough drug in oncology. Its wide therapeutic index allowed evolution from a dosing schedule based on body mass 2 mg/kg to a fixed-dose 200 mg every 3 weeks. In 2019 the European Medicines Agency approved dosing 400 mg every 6 weeks, despite lack of evidence from clinical trials on safety and efficacy, based only on pharmacokinetic data derived from previous clinical studies. This year, facing the SARS-CoV-2 pandemic, international oncology societies recommended a new dosing schedule in order to minimise patient exposition to health care units. In April 2020 the US Food and Drug Administration also approved a new dosing schedule, based on an interim analysis of clinical trial Keynote-555.

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References

  1. McDermott DF, Atkins MB. PD-1 as a potential target in cancer therapy. Cancer Med. 2013; 2(5): 662–673.
  2. Kang SP, Gergich K, Lubiniecki GM, et al. Pembrolizumab KEYNOTE-001: an adaptive study leading to accelerated approval for two indications and a companion diagnostic. Ann Oncol. 2017; 28(6): 1388–1398.
  3. European Society for Medical Oncology. ESMO Handbook of Immuno-Oncology. Vol. 1, ESMO Handbook Series. 2018: 3–14; 245–296.
  4. Garon EB, Hellmann MD, Rizvi NA, et al. Five-Year overall survival for patients with advanced non‒small-cell lung cancer treated with pembrolizumab: results from the phase i KEYNOTE-001 study. J Clin Oncol. 2019; 37(28): 2518–2527.
  5. Hamid O, Robert C, Daud A, et al. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol. 2019; 30(4): 582–588.
  6. Haanen JB, Carbonnel F, Robert C, et al. ESMO Guidelines Committee, ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017; 28 Suppl 4(suppl_4): iv119–iv142.
  7. Wang Y, Zhou S, Yang F, et al. Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-analysis. JAMA Oncol. 2019; 5(7): 1008–1019.
  8. Naidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015; 26(12): 2375–2391.
  9. Gangadhar T, Mehnert J, Patnaik A, et al. Population pharmacokinetic (popPK) model of pembrolizumab (pembro; MK-3475) in patients (pts) treated in KEYNOTE-001 and KEYNOTE-002. J Clin Oncol. 2015; 33(15_suppl): 3058–3058.
  10. Ahamadi M, Freshwater T, Prohn M, et al. Model-Based Characterization of the Pharmacokinetics of Pembrolizumab: A Humanized Anti-PD-1 Monoclonal Antibody in Advanced Solid Tumors. CPT Pharmacometrics Syst Pharmacol. 2017; 6(1): 49–57.
  11. Elassaiss-Schaap J, Rossenu S, Lindauer A, et al. Using model-based "learn and confirm" to reveal the pharmacokinetics-pharmacodynamics relationship of pembrolizumab in the KEYNOTE-001 trial. CPT Pharmacometrics Syst Pharmacol. 2017; 6(1): 21–28.
  12. Patnaik A, Kang SP, Rasco D, et al. Phase i study of pembrolizumab (MK-3475; anti-pd-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res. 2015; 21(19): 4286–4293.
  13. Keytruda. Highlights of prescribing information [Internet]. 2020 [cited 2020 May 26]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125514s059s064s076s083lbl.pdf?utm_source=Salesforce Marketing Cloud&utm_medium=Email&utm_campaign=&sfmc_s=0031I000017UJHLQA4.
  14. Ogungbenro K, Patel A, Duncombe R, et al. Dose rationalization of pembrolizumab and nivolumab using pharmacokinetic modeling and simulation and cost analysis. Clin Pharmacol Ther. 2018; 103(4): 582–590.
  15. Canadian Agency for Drugs and Technologies in Health. CADTH technology review: optimal use 360 report: dosing and timing of immuno-oncology drugs. [Internet]. 2019 [cited 2020 Jun 27]. Available from: https://www.cadth.ca/sites/default/files/ou-tr/ho0008-dosing-timing-immuno-oncology-drugs.pdf.
  16. Freshwater T, Kondic A, Ahamadi M, et al. Evaluation of dosing strategy for pembrolizumab for oncology indications. J Immunother Cancer. 2017; 5: 43.
  17. Chatterjee M, Turner DC, Felip E, et al. Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer. Ann Oncol. 2016; 27(7): 1291–1298.
  18. Chatterjee MS, Elassaiss-Schaap J, Lindauer A, et al. Population pharmacokinetic/pharmacodynamic modeling of tumor size dynamics in pembrolizumab-treated advanced melanoma. CPT Pharmacometrics Syst Pharmacol. 2017; 6(1): 29–39.
  19. Lala M, Li M, Sinha V, et al. A six-weekly (Q6W) dosing schedule for pembrolizumab based on an exposure-response (E-R) evaluation using modeling and simulation. J Clin Oncol. 2018; 36(15_suppl): 3062–3062.
  20. Lala M, Li TR, de Alwis DP, et al. A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. Eur J Cancer. 2020; 131: 68–75.
  21. Mallika Lala, Omobolaji Akala, Elliot Chartash, Mizuho Kalabis, Shu-Chih Su, Dinesh De Alwis, Vikram Sinha LJ. CT042 - Pembrolizumab 400 mg Q6W dosing: First clinical outcomes data from Keynote-555 cohort B in metastatic melanoma patients. AACR website [Internet]. 2020 AACR Virtual Meeting. Abstract CT042. Presented April 28, 2020. 2020 [cited 2020 Jun 26]. Available from: https://www.abstractsonline.com/pp8/#!/9045/presentation/10751.
  22. Bach PB, Conti RM, Muller RJ, et al. Overspending driven by oversized single dose vials of cancer drugs. BMJ. 2016; 352: i788.
  23. Goldstein DA, Ratain MJ, Saltz LB. Weight-Based dosing of pembrolizumab every 6 weeks in the time of COVID-19. JAMA Oncol. 2020 [Epub ahead of print].