Setting the Dose of Checkpoint Inhibitors: The Role of Clinical Pharmacology

  • Etienne ChatelutEmail author
  • Félicien Le Louedec
  • Gérard Milano
Review Article


Cancer immunotherapy is based on checkpoint inhibitors (CPIs) that significantly improve the clinical outcome of several malignant diseases. These inhibitors are monoclonal antibodies (mAbs) directed at cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), or programmed death-ligand 1 (PD-L1), sharing most of the clinical pharmacokinetic characteristics of mAb targeted therapies, all of which differ from those of cytotoxics and small molecules. Establishing the labeled dose of mAbs, and particularly of the CPIs, represents a true challenge. This review therefore examines the main criteria used for dose selection, along with their limits. The relationships between CPI pharmacokinetic parameters and treatment outcome (efficacy and/or toxicity) differ somewhat among the various drugs, but general features can be identified. Nevertheless, the interpretation of these relationships remains quite controversial. A first interpretation asserts that inter-individual pharmacokinetic variability in clearance has an impact on outcome and should be taken into consideration for dosing individualization. The second considers that higher clearance values observed in some patients result from characteristics associated with poor predictive factors of efficacy. Finally, the schedule, and particularly its frequency of administration, merits rethinking.



The authors would like to thank Dr Gail Taillefer, a native English-speaking medical writer (Professor emeritus of English), for her language and editorial support.


No funding was received that is directly relevant to the content of this review.

Compliance with Ethical Standards

Conflict of interest

Etienne Chatelut, Félicien Le Louedec, and Gérard Milano declare that they have no conflict of interests related to the content of this review.


  1. 1.
    Liu JKH. The history of monoclonal antibody development—progress, remaining challenges and future innovations. Ann Med Surg. 2014;3:113–6.CrossRefGoogle Scholar
  2. 2.
    Ecker DM, Jones SD, Levine HL. The therapeutic monoclonal antibody market. mAbs. 2015;7:9–14.PubMedCrossRefGoogle Scholar
  3. 3.
    Imamura CK. Therapeutic drug monitoring of monoclonal antibodies: applicability based on their pharmacokinetic properties. Drug Metab Pharmacokinet. 2019;34:14–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Wong H, Chow TW. Physiologically based pharmacokinetic modeling of therapeutic proteins. J Pharm Sci. 2017;106:2270–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Tabrizi MA, Tseng CML, Roskos LK. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today. 2006;11:81–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Berinstein NL, Grillo-Lopez AJ, White CA, Bence-Bruckler I, Maloney D, Czuczman M, et al. Association of serum rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol. 1998;9:995–1001.PubMedCrossRefGoogle Scholar
  7. 7.
    Azzopardi N, Lecomte T, Ternant D, Boisdron-Celle M, Piller F, Morel A, et al. Cetuximab pharmacokinetics influences progression-free survival of metastatic colorectal cancer patients. Clin Cancer Res. 2011;17:6329–37.PubMedCrossRefGoogle Scholar
  8. 8.
    Caulet M, Lecomte T, Bouché O, Rollin J, Gouilleux-Gruart V, Azzopardi N, et al. Bevacizumab pharmacokinetics influence overall and progression-free survival in metastatic colorectal cancer patients. Clin Pharmacokinet. 2016;55:1381–94.PubMedCrossRefGoogle Scholar
  9. 9.
    Feng Y, Roy A, Masson E, Chen T-T, Humphrey R, Weber JS. Exposure-response relationships of the efficacy and safety of ipilimumab in patients with advanced melanoma. Clin Cancer Res. 2013;19:3977–86.PubMedCrossRefGoogle Scholar
  10. 10.
    Basak EA, Koolen SLW, Hurkmans DP, Schreurs MWJ, Bins S, Oomen-de Hoop E, et al. Correlation between nivolumab exposure and treatment outcomes in non–small-cell lung cancer. Eur J Cancer. 2019;109:12–20.PubMedCrossRefGoogle Scholar
  11. 11.
    Kim H-D, Park S-H. Immunological and clinical implications of immune checkpoint blockade in human cancer. Arch Pharm Res. 2019;42:567–81.PubMedCrossRefGoogle Scholar
  12. 12.
    Sheng J, Srivastava S, Sanghavi K, Lu Z, Schmidt BJ, Bello A, et al. Clinical pharmacology considerations for the development of immune checkpoint inhibitors. J Clin Pharmacol. 2017;57:S26–42.PubMedCrossRefGoogle Scholar
  13. 13.
    Marin-Acevedo JA, Soyano AE, Dholaria B, Knutson KL, Lou Y. Cancer immunotherapy beyond immune checkpoint inhibitors. J Hematol Oncol. 2018;11(1):8. Scholar
  14. 14.
    Centanni M, Moes DJAR, Trocóniz IF, Ciccolini J, van Hasselt JGC. Clinical pharmacokinetics and pharmacodynamics of immune checkpoint inhibitors. Clin Pharmacokinet. 2019;58:835–57.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Tosi D, Laghzali Y, Vinches M, Alexandre M, Homicsko K, Fasolo A, et al. Clinical development strategies and outcomes in first-in-human trials of monoclonal antibodies. J Clin Oncol. 2015;33:2158–65.PubMedCrossRefGoogle Scholar
  16. 16.
    Viala M, Vinches M, Alexandre M, Mollevi C, Durigova A, Hayaoui N, et al. Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection. Br J Cancer. 2018;118:679–97.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Ascierto PA, Del Vecchio M, Robert C, Mackiewicz A, Chiarion-Sileni V, Arance A, et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2017;18:611–22.PubMedCrossRefGoogle Scholar
  18. 18.
    Deng R, Bumbaca D, Pastuskovas CV, Boswell CA, West D, Cowan KJ, et al. Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor. mAbs. 2016;8:593–603.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Stroh M, Winter H, Marchand M, Claret L, Eppler S, Ruppel J, et al. Clinical pharmacokinetics and pharmacodynamics of atezolizumab in metastatic urothelial carcinoma. Clin Pharmacol Ther. 2017;102:305–12.PubMedCrossRefGoogle Scholar
  20. 20.
    Patnaik A, Kang SP, Rasco D, Papadopoulos KP, 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 Cancer Res. 2015;21:4286–93.PubMedCrossRefGoogle Scholar
  21. 21.
    Elassaiss-Schaap J, Rossenu S, Lindauer A, Kang S, de Greef R, Sachs J, et al. Using model-based “learn and confirm” to reveal the pharmacokinetics-pharmacodynamics relationship of pembrolizumab in the KEYNOTE-001 trial. CPT Pharmacometr Syst Pharmacol. 2017;6:21–8.CrossRefGoogle Scholar
  22. 22.
    Baverel PG, Dubois VFS, Jin CY, Zheng Y, Song X, Jin X, et al. Population pharmacokinetics of durvalumab in cancer patients and association with longitudinal biomarkers of disease status. Clin Pharmacol Ther. 2018;103:631–42.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Bajaj G, Wang X, Agrawal S, Gupta M, Roy A, Feng Y. Model-based population pharmacokinetic analysis of nivolumab in patients with solid tumors. CPT Pharmacometr Syst Pharmacol. 2017;6:58–66.CrossRefGoogle Scholar
  24. 24.
    Agrawal S, Feng Y, Roy A, Kollia G, Lestini B. Nivolumab dose selection: challenges, opportunities, and lessons learned for cancer immunotherapy. J Immunother Cancer. 2016;4:72.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti–programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167–75.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Heery CR, O’Sullivan-Coyne G, Madan RA, Cordes L, Rajan A, Rauckhorst M, et al. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 2017;18:587–98.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Long GV, Tykodi SS, Schneider JG, 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(11):2208–13. Scholar
  28. 28.
    Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol. 2009;49:1012–24.PubMedCrossRefGoogle Scholar
  29. 29.
    Li J, Zhi J, Wenger M, Valente N, Dmoszynska A, Robak T, et al. Population pharmacokinetics of rituximab in patients with chronic lymphocytic leukemia. J Clin Pharmacol. 2012;52:1918–26.PubMedCrossRefGoogle Scholar
  30. 30.
    Dirks NL, Nolting A, Kovar A, Meibohm B. Population pharmacokinetics of cetuximab in patients with squamous cell carcinoma of the head and neck. J Clin Pharmacol. 2008;48:267–78.PubMedCrossRefGoogle Scholar
  31. 31.
    Bruno R, Washington CB, Lu J-F, Lieberman G, Banken L, Klein P. Population pharmacokinetics of trastuzumab in patients With HER2 + metastatic breast cancer. Cancer Chemother Pharmacol. 2005;56:361–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Passot C, Azzopardi N, Renault S, Baroukh N, Arnoult C, Ohresser M, et al. Influence of FCGRT gene polymorphisms on pharmacokinetics of therapeutic antibodies. mAbs. 2013;5:614–9.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Wilkins JJ, Brockhaus B, Dai H, Vugmeyster Y, White JT, Brar S, et al. Time-varying clearance and impact of disease state on the pharmacokinetics of avelumab in merkel cell carcinoma and urothelial carcinoma. CPT Pharmacometr Syst Pharmacol. 2019;8(6):415–27. Scholar
  34. 34.
    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;44:403–14.PubMedCrossRefGoogle Scholar
  35. 35.
    Ogasawara K, Newhall K, Maxwell SE, Dell’Aringa J, Komashko V, Kilavuz N, et al. Population pharmacokinetics of an anti-PD-L1 antibody, durvalumab in patients with hematologic malignancies. Clin Pharmacokinet. 2019. 2019 Jul 22).CrossRefPubMedGoogle Scholar
  36. 36.
    Leven C, Padelli M, Carré J-L, Bellissant E, Misery L. Immune checkpoint inhibitors in melanoma: a review of pharmacokinetics and exposure–response relationships. Clin Pharmacokinet. 2019. 2019 Jun 10).CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Le Louedec F, Alix-Panabières C, Lafont T, Allal BC, Garrel R, Digue L, et al. Cetuximab pharmacokinetic/pharmacodynamics relationships in advanced head and neck carcinoma patients. Br J Clin Pharmacol. 2019;85:1357–66.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Han K, Peyret T, Marchand M, Quartino A, Gosselin NH, Girish S, et al. Population pharmacokinetics of bevacizumab in cancer patients with external validation. Cancer Chemother Pharmacol. 2016;78:341–51.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Garg A, Quartino A, Li J, Jin J, Wada DR, Li H, et al. Population pharmacokinetic and covariate analysis of pertuzumab, a HER2-targeted monoclonal antibody, and evaluation of a fixed, non-weight-based dose in patients with a variety of solid tumors. Cancer Chemother Pharmacol. 2014;74:819–29.PubMedCrossRefGoogle Scholar
  40. 40.
    Turner DC, Kondic AG, Anderson KM, Robinson AG, Garon EB, Riess JW, et al. Pembrolizumab exposure–response assessments challenged by association of cancer cachexia and catabolic clearance. Clin Cancer Res. 2018;24:5841–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Liu C, Yu J, Li H, Liu J, Xu Y, Song P, et al. Association of time-varying clearance of nivolumab with disease dynamics and its implications on exposure response analysis. Clin Pharmacol Ther. 2017;101:657–66.PubMedCrossRefGoogle Scholar
  42. 42.
    Bins S, Koolen SLW, Mathijssen RHJ. Pembrolizumab exposure–response assessments challenged by association of cancer cachexia and catabolic clearance—letter. Clin Cancer Res. 2019;25:3192–3192.PubMedCrossRefGoogle Scholar
  43. 43.
    Tardivon C, Desmée S, Kerioui M, Bruno R, Wu B, Mentré F, et al. Association between tumor size kinetics and survival in patients with urothelial carcinoma treated with atezolizumab: implication for patient follow-up. Clin Pharmacol Ther. 2019;106:810–20.PubMedCrossRefGoogle Scholar
  44. 44.
    Hertz DL, McLeod HL. Use of pharmacogenetics for predicting cancer prognosis and treatment exposure, response and toxicity. J Hum Genet. 2013;58:346–52.PubMedCrossRefGoogle Scholar
  45. 45.
    Refae S, Gal J, Brest P, Milano G. Germinal immunogenetics as a predictive factor for immunotherapy. Crit Rev Oncol Hematol. 2019;141:146–52. Scholar
  46. 46.
    Refae S, Gal J, Ebran N, Otto J, Borchiellini D, Peyrade F, et al. Germinal immunogenetics predict treatment outcome for PD-1/PD-L1 checkpoint inhibitors. Invest New Drugs. 2019. 2019 Aug 11).CrossRefPubMedGoogle Scholar
  47. 47.
    Iafolla MAJ, Selby H, Warner K, Ohashi PS, Haibe-Kains B, Siu LL. Rational design and identification of immuno-oncology drug combinations. Eur J Cancer. 2018;95:38–51.PubMedCrossRefGoogle Scholar
  48. 48.
    European Medecines Agency. YERVOY® (ipilimumab): summary of product characteristics. Accessed 22 Jul 2019.
  49. 49.
    Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122–33.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Hammers HJ, Plimack ER, Infante JR, Rini BI, McDermott DF, Lewis LD, et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study. J Clin Oncol. 2017;35:3851–8.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Brahmer JR, Tykodi SS, Chow LQM, Hwu W-J, Topalian SL, Hwu P, et al. Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Weber JS, O’Day S, Urba W, Powderly J, Nichol G, Yellin M, et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008;26:5950–6.PubMedCrossRefGoogle Scholar
  53. 53.
    Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1116–27.PubMedCrossRefGoogle Scholar
  54. 54.
    Atkins MB, Plimack ER, Puzanov I, Fishman MN, McDermott DF, Cho DC, et al. Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Lancet Oncol. 2018;19:405–15.PubMedCrossRefGoogle Scholar
  55. 55.
    Long GV, Dummer R, Hamid O, Gajewski TF, Caglevic C, Dalle S, et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 2019;20:1083–97.PubMedCrossRefGoogle Scholar
  56. 56.
    Mitchell TC, Hamid O, Smith DC, Bauer TM, Wasser JS, Olszanski AJ, et al. Epacadostat plus pembrolizumab in patients with advanced solid tumors: phase i results from a multicenter, open-label phase I/II trial (ECHO-202/KEYNOTE-037). J Clin Oncol. 2018. 2018 Sep 28).CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Coosemans A, Vankerckhoven A, Baert T, Boon L, Ruts H, Riva M, et al. Combining conventional therapy with immunotherapy: a risky business? Eur J Cancer. 2019;113:41–4.PubMedCrossRefGoogle Scholar
  58. 58.
    Morrissey KM, Marchand M, Patel H, Zhang R, Wu B, Phyllis Chan H, et al. Alternative dosing regimens for atezolizumab: an example of model-informed drug development in the postmarketing setting. Cancer Chemother Pharmacol. 2019. 2019 Sep 21).CrossRefPubMedGoogle Scholar
  59. 59.
    Lala M, Li M, Sinha V, de Alwis D, Chartash E, Jain L. A six-weekly (Q6 W) dosing schedule for pembrolizumab based on an exposure-response (E-R) evaluation using modeling and simulation. J Clin Oncol. 2018;36:3062–3062.CrossRefGoogle Scholar
  60. 60.
    Ratain MJ, Goldstein DA. Time is money: optimizing the scheduling of nivolumab. J Clin Oncol. 2018;36:3074–6.CrossRefGoogle Scholar
  61. 61.
    Goldstein DA, Ratain MJ. Alternative dosing regimens for atezolizumab: right dose, wrong frequency. Cancer Chemother Pharmacol. Epub. 2019. 2019 Oct 19).CrossRefGoogle Scholar
  62. 62.
    Feng Y, Masson E, Dai D, Parker SM, Berman D, Roy A. Model-based clinical pharmacology profiling of ipilimumab in patients with advanced melanoma: clinical pharmacology profiling of ipilimumab in advanced melanoma. Br J Clin Pharmacol. 2014;78:106–17.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Wang X, Feng Y, Bajaj G, Gupta M, Agrawal S, Yang A, et al. Quantitative characterization of the exposure-response relationship for cancer immunotherapy: a case study of nivolumab in patients with advanced melanoma. CPT Pharmacometr Syst Pharmacol. 2017;6:40–8.CrossRefGoogle Scholar
  64. 64.
    Chatterjee M, Elassaiss-Schaap J, Lindauer A, Turner D, Sostelly A, Freshwater T, et al. Population pharmacokinetic/pharmacodynamic modeling of tumor size dynamics in pembrolizumab-treated advanced melanoma. CPT Pharmacometr Syst Pharmacol. 2017;6:29–39.CrossRefGoogle Scholar
  65. 65.
    Center for Drug Evaluation and Research (CDER), US FDA. Clinical pharmacology and biopharmaceutics review(s): atezolizumab. Silver Springs: US FDA; 2016.Google Scholar
  66. 66.
    Center for Drug Evaluation and Research (CDER), US FDA. Clinical pharmacology and biopharmaceutics review(s): avelumab. Silver Springs: US FDA; 2017.Google Scholar
  67. 67.
    Jin C, Zheng Y, Jin X, Mukhopadhyay P, Gupta AK, Dennis PA, et al. Exposure-efficacy and safety analysis of durvalumab in patients with urothelial carcinoma (UC) and other solid tumors. J Clin Oncol. 2017;35:2568–2568.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Institut Claudius-Regaud, IUCT-Oncopole, and CRCTUniversité de Toulouse, InsermToulouse Cedex 9France
  2. 2.Oncopharmacology UnitCentre Antoine LacassagneNiceFrance

Personalised recommendations