Model-Based Characterization of the Bidirectional Interaction Between Pharmacokinetics and Tumor Growth Dynamics in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab
Ana-Marija Grisic, Wenyuan Xiong, Lénaïg Tanneau, Siv Jönsson, Lena E Friberg, Mats O Karlsson, Haiqing Dai, Jenny Zheng, Pascal Girard, Akash Khandelwal, Ana-Marija Grisic, Wenyuan Xiong, Lénaïg Tanneau, Siv Jönsson, Lena E Friberg, Mats O Karlsson, Haiqing Dai, Jenny Zheng, Pascal Girard, Akash Khandelwal
Abstract
Purpose: Empirical time-varying clearance models have been reported for several immune checkpoint inhibitors, including avelumab (anti-programmed death ligand 1). To investigate the exposure-response relationship for avelumab, we explored semimechanistic pharmacokinetic (PK)-tumor growth dynamics (TGD) models.
Patients and methods: Plasma PK data were pooled from three phase I and II trials (JAVELIN Merkel 200, JAVELIN Solid Tumor, and JAVELIN Solid Tumor JPN); tumor size (TS) data were collected from patients with metastatic Merkel cell carcinoma (mMCC) enrolled in JAVELIN Merkel 200. A PK model was developed first, followed by TGD modeling to investigate interactions between avelumab exposure and TGD. A PK-TGD feedback loop was evaluated with simultaneous fitting of the PK and TGD models.
Results: In total, 1,835 PK observations and 338 TS observations were collected from 147 patients. In the final PK-TGD model, which included the bidirectional relationship between PK and TGD, avelumab PK was described by a two-compartment model with a positive association between clearance and longitudinal TS, with no additional empirical time-varying clearance identified. TGD was described by first-order tumor growth/shrinkage rates, with the tumor shrinkage rate decreasing exponentially over time; the exponential time-decay constant decreased with increasing drug concentration, representing the treatment effect through tumor shrinkage inhibition.
Conclusions: We developed a TGD model that mechanistically captures the prevention of loss of antitumor immunity (i.e., T-cell suppression in the tumor microenvironment) by avelumab, and a bidirectional interaction between PK and TGD in patients with mMCC treated with avelumab, thus mechanistically describing previously reported time variance of avelumab elimination.
Trial registration: ClinicalTrials.gov NCT02155647.
©2021 The Authors; Published by the American Association for Cancer Research.
Figures
References
- Tetzlaff MT, Harms PW. Danger is only skin deep: aggressive epidermal carcinomas. An overview of the diagnosis, demographics, molecular-genetics, staging, prognostic biomarkers, and therapeutic advances in Merkel cell carcinoma. Mod Pathol 2020;33:42–55.
- NCCN Clinical Practice Guidelines in Oncology. Merkel Cell Carcinoma. v1.2021. Available from: .
- Schadendorf D, Lebbe C, Zur Hausen A, Avril MF, Hariharan S, Bharmal M, et al. . Merkel cell carcinoma: Epidemiology, prognosis, therapy and unmet medical needs. Eur J Cancer 2017;71:53–69.
- Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. . Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015;372:320–30.
- Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. . Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:1823–33.
- Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. . Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803–13.
- Burtness B, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G Jr, et al. . Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 2019;394:1915–28.
- Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. . Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017;376:1015–26.
- Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D'Angelo SP, et al. . Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 2016;17:1374–85.
- Bavencio (avelumab). Prescribing information. EMD Serono; 2020.
- Bavencio (avelumab). Summary of product characteristics. Merck KGaA, Darmstadt, Germany; 2021.
- 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.
- Boyerinas B, Jochems C, Fantini M, Heery CR, Gulley JL, Tsang KY, et al. . Antibody-dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells. Cancer Immunol Res 2015;3:1148–57.
- Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci 2004;93:2645–68.
- Ryman JT, Meibohm B. Pharmacokinetics of monoclonal antibodies. CPT Pharmacometrics Syst Pharmacol 2017;6:576–88.
- 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.
- 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 Pharmacometrics Syst Pharmacol 2019;8:415–27.
- 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.
- 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.
- Doi T, Iwasa S, Muro K, Satoh T, Hironaka S, Esaki T, et al. . Phase 1 trial of avelumab (anti-PD-L1) in Japanese patients with advanced solid tumors, including dose expansion in patients with gastric or gastroesophageal junction cancer: the JAVELIN Solid Tumor JPN trial. Gastric Cancer 2019;22:817–27.
- BLA Multidisciplinary Review and Evaluation: BLA 761049 Bavencio (Avelumab). 2017. Avaialble from: .
- Claret L, Girard P, Hoff PM, Van Cutsem E, Zuideveld KP, Jorga K, et al. . Model-based prediction of phase III overall survival in colorectal cancer on the basis of phase II tumor dynamics. J Clin Oncol 2009;27:4103–8.
- Nordgren R, Ueckert S, Yngman G, Assawasuwannakit P, Hooker AC, Karlsson MO. Perl speaks NONMEM (PsN). Abstract 9095. Presented at: PAGE 2019, Stockholm, Sweden. 2019.
- Friberg LE, de Greef R, Kerbusch T, Karlsson MO. Modeling and simulation of the time course of asenapine exposure response and dropout patterns in acute schizophrenia. Clin Pharmacol Ther 2009;86:84–91.
- Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–47.
- Grisic A-M, Khandelwal A, Bertolino M, Huisinga W, Girard P, Kloft C. Semimechanistic clearance models of oncology biotherapeutics and impact of study design: cetuximab as a case study. CPT Pharmacometrics Syst Pharmacol 2020;9:628–38.
- Netterberg I, Li CC, Molinero L, Budha N, Sukumaran S, Stroh M, et al. . A PK/PD analysis of circulating biomarkers and their relationship to tumor response in atezolizumab-treated non-small cell lung cancer patients. Clin Pharmacol Ther 2019;105:486–95.
- Chatterjee MS, Elassaiss-Schaap J, Lindauer A, Turner DC, Sostelly A, Freshwater T, et al. . Population pharmacokinetic/pharmacodynamic modeling of tumor size dynamics in pembrolizumab-treated advanced melanoma. CPT Pharmacometrics Syst Pharmacol 2017;6:29–39.
- Zhang T, Song X, Xu L, Ma J, Zhang Y, Gong W, et al. . The binding of an anti-PD-1 antibody to FcγRI has a profound impact on its biological functions. Cancer Immunol Immunother 2018;67:1079–90.
- Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. . MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014;515:558–62.
- Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. . Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014;515:563–7.
- Chen X, Song X, Li K, Zhang T. FcγR-binding is an important functional attribute for immune checkpoint antibodies in cancer immunotherapy. Front Immunol 2019;10:292.
- Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med 2000;6:443–6.
- Bruhns P, Iannascoli B, England P, Mancardi DA, Fernandez N, Jorieux S, et al. . Specificity and affinity of human Fcγ receptors and their polymorphic variants for human IgG subclasses. Blood 2009;113:3716–25.
- Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, et al. . Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 2002;99:754–8.
- Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 2003;21:3940–7.
- Powles TB, Loriot Y, Bellmunt J, Sternberg CN, Sridhar S, Petrylak DP, et al. . 699O Avelumab first-line (1L) maintenance + best supportive care (BSC) vs BSC alone for advanced urothelial carcinoma (UC): Association between clinical outcomes and exploratory biomarkers. Ann Oncol 2020;31:S552–S3.
- Jin H, D'Urso V, Neuteboom B, McKenna SD, Schweickhardt R, Gross AW, et al. . Avelumab internalization by human circulating immune cells is mediated by both Fc gamma receptor and PD-L1 binding. Oncoimmunology 2021;10:1958590.
Source: PubMed