Skip to main content

Advertisement

SpringerLink
Log in

A PK-PD model linking biomarker dynamics to progression-free survival in patients treated with everolimus and sorafenib combination therapy, EVESOR phase I trial

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The objective was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model linking everolimus and sorafenib exposure with biomarker dynamics and progression-free survival (PFS) based on data from EVESOR trial in patients with solid tumors treated with everolimus and sorafenib combination therapy and to simulate alternative dosing schedules for sorafenib.

Patients and methods

Everolimus (5–10 mg once daily, qd) and sorafenib (200–400 mg twice daily, bid) were administered according to four different dosing schedules in 43 solid tumor patients. Rich PK and PD sampling for serum angiogenesis biomarkers was performed. Baseline activation of RAS/RAF/ERK (MAPK) pathway was assessed by quantification of mRNA specific gene panel in tumor biopsies. The PK-PD modeling was performed using NONMEM® software.

Results

An indirect response PK-PD model linking sorafenib plasma exposure with soluble vascular endothelial growth factor receptor 2 (sVEGFR2) dynamics was developed. Progression-free survival (PFS) was described by a parametric time-to-event model. Higher decreases in sVEGFR2 at day 21 and higher baseline activation of MAPK pathway were associated with longer PFS (p = 0.002 and p = 0.007, respectively). The simulated schedule sorafenib 200 mg bid 5 days-on/2 days-off + continuous everolimus 5 mg qd was associated with median PFS of 4.3 months (95% CI 1.6–14.4), whereas the median PFS in the EVESOR trial was 3.6 months (95% CI 2.7–4.2, n = 43).

Conclusion

Sorafenib 200 mg bid 5 days-on/2 days-off + everolimus 5 mg qd continuous was selected for an additional arm of EVESOR trial to evaluate whether this simulated schedule is associated with higher clinical benefit.

Trial registration

ClinicalTrials.gov Identifier: NCT01932177.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Yap TA, Omlin A, de Bono JS (2013) Development of therapeutic combinations targeting major cancer signaling pathways. Proc Am Soc Clin Oncol 31:1592–1605. https://doi.org/10.1200/JCO.2011.37.6418

    Article  CAS  Google Scholar 

  2. Frances N, Woloch C, Marouani H, Mercier C, Iliadis A (2012) Optimize administration protocol of capecitabine plus docetaxel combination in metastatic breast cancer patients. Curr Top Med Chem 12:1665–1668

    Article  CAS  PubMed  Google Scholar 

  3. Garralda E, Dienstmann R, Tabernero J (2017) Pharmacokinetic/pharmacodynamic modeling for drug development in oncology. Am Soc Clin Oncol Educ B 37:210–215

    Article  Google Scholar 

  4. Tanaka C, O’Reilly T, Kovarik JM, Shand N, Hazell K, Judson I et al (2016) Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol 26:1596–1602

    Article  Google Scholar 

  5. Chappell WH, Steelman LS, Long JM, Kempf RC, Abrams SL, Franklin RA et al (2011) Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget 2:135–164

    Article  PubMed  PubMed Central  Google Scholar 

  6. Courtney KD, Corcoran RB, Engelman JA (2010) The PI3K pathway as drug target in human cancer. J Clin Oncol 28:1075–1083. https://doi.org/10.1200/JCO.2009.25.3641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pawaskar DK, Straubinger RM, Fetterly GJ, Hylander BH, Repasky EA, Ma WW et al (2013) Synergistic interactions between sorafenib and everolimus in pancreatic cancer xenografts in mice. Cancer Chemother Pharmacol 71:1231–1240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. CHMP. ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS Afinitor; INN-everolimus (2022) Available online: https://www.ema.europa.eu/en/documents/product-information/afinitor-epar-product-information_en.pdf

  9. CHMP. ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS INN-Sorafenib; Nexavar (2022) Available online: https://www.ema.europa.eu/en/documents/product-information/nexavar-epar-product-information_en.pdf

  10. Chan JA, Mayer RJ, Jackson N, Malinowski P, Regan E, Kulke MH (2013) Phase I study of sorafenib in combination with everolimus (RAD001) in patients with advanced neuroendocrine tumors. Cancer Chemother Pharmacol 71:1241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Amato RJ, Flaherty AL, Stepankiw M (2012) Phase I trial of everolimus plus sorafenib for patients with advanced renal cell cancer. Clin Genitourin Cancer 10:26–31

    Article  PubMed  Google Scholar 

  12. Finn RS, Poon RTP, Yau T, Klümpen H-J, Chen L-T, Kang Y-K et al (2013) Phase I study investigating everolimus combined with sorafenib in patients with advanced hepatocellular carcinoma. J Hepatol 59:1271–1277

    Article  CAS  PubMed  Google Scholar 

  13. DePrimo SE, Bello CL, Smeraglia J, Baum CM, Spinella D, Rini BI et al (2007) Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J Transl Med 5:1–11

    Article  Google Scholar 

  14. Hansson EK, Amantea MA, Westwood P, Milligan PA, Houk BE, French J et al (2013) PKPD modeling of VEGF, sVEGFR-2, sVEGFR-3, and sKIT as predictors of tumor dynamics and overall survival following sunitinib treatment in GIST. CPT Pharmacomet Syst Pharmacol. https://doi.org/10.1038/psp.2013.61

    Article  Google Scholar 

  15. Ait-Oudhia S, Mager D, Pokuri V, Tomaszewski G, Groman A, Zagst P et al (2016) Bridging sunitinib exposure to time-to-tumor progression in hepatocellular carcinoma patients with mathematical modeling of an angiogenic biomarker. CPT Pharmacomet Syst Pharmacol 5:297–304

    Article  CAS  Google Scholar 

  16. Peña C, Lathia C, Shan M, Escudier B, Bukowski RM (2010) Biomarkers predicting outcome in patients with advanced renal cell carcinoma: results from sorafenib phase III treatment approaches in renal cancer global evaluation trial. Clin Cancer Res 16:4853–4863

    Article  PubMed  Google Scholar 

  17. Raut CP, Boucher Y, Duda DG, Morgan JA, Quek R, Ancukiewicz M et al (2012) Effects of sorafenib on intra-tumoral interstitial fluid pressure and circulating biomarkers in patients with refractory sarcomas (NCI protocol 6948). PLoS One 7:e26331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Xu W, Puligandla M, Manola J, Bullock AJ, Tamasauskas D, McDermott DF et al (2019) Angiogenic factor and cytokine analysis among patients treated with adjuvant VEGFR TKIs in resected renal cell carcinoma. Clin Cancer Res 25:6098–6106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Boulay A, Zumstein-Mecker S, Stephan C, Beuvink I, Zilbermann F, Haller R et al (2004) Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 64:252–261

    Article  CAS  PubMed  Google Scholar 

  20. O’Donnell A, Faivre S, Howard AB III, Rea D, Papadimitrakopoulou V, Shand N et al (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 26:1588–1595. https://doi.org/10.1200/JCO.2007.14.0988

    Article  CAS  PubMed  Google Scholar 

  21. Dong S, Zhang X, Cheng H, Guo A, Zhu J, Yang S et al (2010) Effect of everolimus and gefitinib on PI3K/akt/mTOR and raf/MEK/ERK pathways in NSCLC cells. J Clin Oncol 28:e13654. https://doi.org/10.1200/jco.2010.28.15_suppl.e13654

    Article  Google Scholar 

  22. Yates JWT, Holt SV, Logie A, Payne K, Woods K, Wilkinson RW et al (2017) A pharmacokinetic–pharmacodynamic model predicting tumour growth inhibition after intermittent administration with the mTOR kinase inhibitor AZD8055. Br J Pharmacol 174:2652–2661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. El-Madani M, Colomban O, Tod M, Maillet D, Peron J, Rodriguez-Lafrasse C et al (2017) EVESOR, a model-based, multiparameter, phase I trial to optimize the benefit/toxicity ratio of everolimus and sorafenib. Future Oncol 13:679–693. https://doi.org/10.2217/fon-2016-0357

    Article  CAS  PubMed  Google Scholar 

  24. Varnier R, Puszkiel A, Tod M, Calattini S, Payen L, Lopez J et al (2023) Clinical results of the EVESOR trial, a multiparameter phase I trial of everolimus and sorafenib combination in solid tumors. Cancer Chemother Pharmacol. https://doi.org/10.1007/s00280-023-04508-9

    Article  PubMed  Google Scholar 

  25. Wagle M-C, Kirouac D, Klijn C, Liu B, Mahajan S, Junttila M et al (2018) A transcriptional MAPK pathway activity score (MPAS) is a clinically relevant biomarker in multiple cancer types. NPJ Precis Oncol 2:1–12

    CAS  Google Scholar 

  26. Dosne A-G, Bergstrand M, Karlsson MO (2016) A strategy for residual error modeling incorporating scedasticity of variance and distribution shape. J Pharmacokinet Pharmacodyn 43:137–151

    Article  PubMed  Google Scholar 

  27. Molins EAG, Jusko WJ (2018) Assessment of three-drug combination pharmacodynamic interactions in pancreatic cancer cells. AAPS J 20:1–15

    Article  CAS  Google Scholar 

  28. Jain L, Woo S, Gardner ER, Dahut WL, Kohn EC, Kummar S et al (2011) Population pharmacokinetic analysis of sorafenib in patients with solid tumours. Br J Clin Pharmacol 72:294–305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tanaka A, Yano I, Shinsako K, Sato E, Fukudo M, Masuda S et al (2016) Population pharmacokinetics of everolimus in relation to clinical outcomes in patients with advanced renal cell carcinoma. Ther Drug Monit 38:663–669

    Article  CAS  PubMed  Google Scholar 

  30. Moes DJAR, Press RR, Den Hartigh J, Van Der Straaten T, De Fijter JW, Guchelaar HJ (2012) Population pharmacokinetics and pharmacogenetics of everolimus in renal transplant patients. Clin Pharmacokinet 51:467–480

    Article  CAS  PubMed  Google Scholar 

  31. Robertsen I, Debord J, Åsberg A, Marquet P, Woillard JB (2018) A limited sampling strategy to estimate exposure of everolimus in whole blood and peripheral blood mononuclear cells in renal transplant recipients using population pharmacokinetic modeling and Bayesian estimators. Clin Pharmacokinet 57(11):1459–1469

    Article  CAS  PubMed  Google Scholar 

  32. Kovarik JM, Hsu CH, McMahon L, Berthier S, Rordorf C (2001) Population pharmacokinetics of everolimus in de novo renal transplant patients: impact of ethnicity and comedications. Clin Pharmacol Ther 70:247–254

    Article  CAS  PubMed  Google Scholar 

  33. de Wit D, Schneider TC, Moes DJAR, Roozen CFM, den Hartigh J, Gelderblom H et al (2016) Everolimus pharmacokinetics and its exposure–toxicity relationship in patients with thyroid cancer. Cancer Chemother Pharmacol 78:63–71

    Article  PubMed  PubMed Central  Google Scholar 

  34. van Erp NP, van Herpen CM, de Wit D, Willemsen A, Burger DM, Huitema ADR et al (2016) A semi-physiological population model to quantify the effect of hematocrit on everolimus pharmacokinetics and pharmacodynamics in cancer patients. Clin Pharmacokinet 55:1447–1456

    Article  PubMed  PubMed Central  Google Scholar 

  35. Lemaitre F, Bezian E, Goldwirt L, Fernandez C, Farinotti R, Varnous S et al (2012) Population pharmacokinetics of everolimus in cardiac recipients: comedications, ABCB1, and CYP3A5 polymorphisms. Ther Drug Monit 34:686–694

    Article  CAS  PubMed  Google Scholar 

  36. Hornecker M, Blanchet B, Billemont B, Sassi H, Ropert S, Taieb F et al (2012) Saturable absorption of sorafenib in patients with solid tumors: a population model. Invest New Drugs 30:1991–2000

    Article  CAS  PubMed  Google Scholar 

  37. FDA. NEXAVAR (sorafenib) tablets, for oral use (2022) Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021923s020lbl.pdf

  38. Centanni M, Krishnan SM, Friberg LE (2020) Model-based dose individualization of sunitinib in gastrointestinal stromal tumors. Clin Cancer Res 26:4590–4598

    Article  CAS  PubMed  Google Scholar 

  39. Hénin E, Blanchet B, Boudou-Rouquette P, Thomas-Schoemann A, Freyer G, Vidal M et al (2013) Fractionation of daily dose increases the predicted risk of severe sorafenib-induced hand–foot syndrome (HFS). Cancer Chemother Pharmacol 73:287–97

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The study has been supported by the Hospices Civils de Lyon (bourse Actions Incitatives), Ligue contre le Cancer, Association de Recherche contre le Cancer, Novartis SAS (everolimus furniture) and the Institut National du Cancer.

Author information

Authors and Affiliations

  1. EA 3738 CICLY, Faculté de Médecine Lyon Sud, Université Claude Bernard Lyon 1, Lyon, France

    Alicja Puszkiel, Benoit You, Olivier Colomban, Gilles Freyer & Michel Tod

  2. Medical Oncology, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), CITOHL, Centre Hospitalier Lyon Sud, 165 Chemin du Grand Revoyet, Pierre-Benite, 69495, Lyon, France

    Benoit You, Julien Péron, Denis Maillet, Sophie Tartas, Nathalie Bonnin, Veronique Trillet-Lenoir, Diane Augu-Denechere & Gilles Freyer

  3. Laboratoire d’Oncologie Moléculaire et Transfert, Centre de Biologie Lyon Sud, Hospices Civils de Lyon, Lyon, France

    Léa Payen

  4. Centre de Recherche en Cancérologie de Lyon - INSERM U1052 CNRS U5286, Service de Biochimie et Biologie moléculaire, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, France

    Jonathan Lopez

  5. Laboratoire de Biochimie-Toxicologie, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, France

    Jérôme Guitton

  6. Department of Radiology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, France

    Pascal Rousset

  7. Department of Pathology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, France

    Juliette Fontaine

  8. Pharmacie de l’Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France

    Michel Tod

Authors
  1. Alicja Puszkiel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Benoit You
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Léa Payen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jonathan Lopez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jérôme Guitton
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pascal Rousset
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Juliette Fontaine
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Julien Péron
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Denis Maillet
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sophie Tartas
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Nathalie Bonnin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Veronique Trillet-Lenoir
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Olivier Colomban
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Diane Augu-Denechere
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Gilles Freyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Michel Tod
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Benoit You.

Ethics declarations

Conflict of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Ethical approval

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 148156 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Puszkiel, A., You, B., Payen, L. et al. A PK-PD model linking biomarker dynamics to progression-free survival in patients treated with everolimus and sorafenib combination therapy, EVESOR phase I trial. Cancer Chemother Pharmacol 91, 413–425 (2023). https://doi.org/10.1007/s00280-023-04520-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-023-04520-z

Keywords

Search

Navigation