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Exposure–Response Analysis of Osimertinib in EGFR Mutation Positive Non-Small Cell Lung Cancer Patients in a Real-Life Setting

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Abstract

Background

Osimertinib, an irreversible inhibitor of the epidermal growth factor receptor (EGFR) is an important drug in the treatment of EGFR-mutation positive non-small cell lung cancer (NSCLC). Clinical trials with osimertinib could not demonstrate an exposure-efficacy relationship, while a relationship between exposure and toxicity has been found. In this study, we report the exposure–response relationships of osimertinib in a real-life setting.

Methods

A retrospective observational cohort study was performed, including patients receiving 40 - 80 mg osimertinib as ≥ 2 line therapy and from whom pharmacokinetic samples were collected during routine care. Trough plasma concentrations (Cmin,pred) were estimated and used as a measure of osimertinib exposure. A previously defined exploratory pharmacokinetic threshold of 166 µg/L was taken to explore the exposure-efficacy relationship.

Results

A total of 145 patients and 513 osimertinib plasma concentration samples were included. Median progression free survival (PFS) was 13.3 (95% confidence interval (CI):10.3 – 19.1) months and 9.3 (95% CI: 7.2 – 11.1) months for patients with Cmin,pred < 166 µg/L and Cmin,pred ≥ 166 µg/L, respectively (p = 0.03). In the multivariate analysis, a Cmin,pred < 166 µg/L resulted in a non-statistically significant hazard ratio of 1.10 (95% CI: 0.60 – 2.01; p = 77). Presence of a EGFR driver-mutation other than the exon 19 del or L858R mutations, led to a shorter PFS with a hazard ratio of 2.89 (95% CI: 1.18 – 7.08; p = 0.02). No relationship between exposure and toxicity was observed (p = 0.91).

Conclusion

In our real-life cohort, no exposure–response relationship was observed for osimertinib in the current dosing scheme. The feasibility of a standard lower fixed dosing of osimertinib in clinical practice should be studied prospectively.

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Data Availability

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

References

  1. Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361(10):958–67. https://doi.org/10.1056/NEJMoa0904554.

    Article  CAS  PubMed  Google Scholar 

  2. Douillard JY, Ostoros G, Cobo M, Ciuleanu T, McCormack R, Webster A, et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer. 2014;110(1):55–62. https://doi.org/10.1038/bjc.2013.721.

    Article  CAS  PubMed  Google Scholar 

  3. Urata Y, Katakami N, Morita S, Kaji R, Yoshioka H, Seto T, et al. Randomized phase III study comparing gefitinib with erlotinib in patients with previously treated advanced lung adenocarcinoma: WJOG 5108L. J Clin Oncol. 2016;34(27):3248–57. https://doi.org/10.1200/jco.2015.63.4154.

    Article  CAS  PubMed  Google Scholar 

  4. Park K, Tan EH, O’Byrne K, Zhang L, Boyer M, Mok T, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016;17(5):577–89. https://doi.org/10.1016/s1470-2045(16)30033-x.

    Article  CAS  PubMed  Google Scholar 

  5. European Medicine Agency. Tagrisso: EPAR- Product information. 2021.

  6. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113–25. https://doi.org/10.1056/NEJMoa1713137.

    Article  CAS  PubMed  Google Scholar 

  7. Food and Drug Administration. Center for Drug Evaluation and Research. Osimertinib Clinical Pharmacology and Biopharmaceutics Review. 2015:available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208065Orig1s000ClinPharmR.pdf.

  8. Brown K, Comisar C, Witjes H, Maringwa J, de Greef R, Vishwanathan K, et al. Population pharmacokinetics and exposure-response of osimertinib in patients with non-small cell lung cancer. Br J Clin Pharmacol. 2017;83(6):1216–26. https://doi.org/10.1111/bcp.13223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Narjoz C, Cessot A, Thomas-Schoemann A, Golmard JL, Huillard O, Boudou-Rouquette P, et al. Role of the lean body mass and of pharmacogenetic variants on the pharmacokinetics and pharmacodynamics of sunitinib in cancer patients. Invest New Drugs. 2015;33(1):257–68. https://doi.org/10.1007/s10637-014-0178-2.

    Article  CAS  PubMed  Google Scholar 

  10. Shiroyama T, Nagatomo I, Koyama S, Hirata H, Nishida S, Miyake K, et al. Impact of sarcopenia in patients with advanced non-small cell lung cancer treated with PD-1 inhibitors: A preliminary retrospective study. Sci Rep. 2019;9(1):2447. https://doi.org/10.1038/s41598-019-39120-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mitchell AP, Harrison MR, Walker MS, George DJ, Abernethy AP, Hirsch BR. Clinical trial participants with metastatic renal cell carcinoma differ from patients treated in real-world practice. J Oncol Pract. 2015;11(6):491–7. https://doi.org/10.1200/jop.2015.004929.

    Article  PubMed  Google Scholar 

  12. National Center for Health Statistics (NHIS). NHIS - Adult Tobacco Use - Glossary. Available via: https://www.cdc.gov/nchs. Accessed on October 15th 2021.

  13. Verheijen RB, Yu H, Schellens JHM, Beijnen JH, Steeghs N, Huitema ADR. Practical recommendations for therapeutic drug monitoring of kinase inhibitors in oncology. Clin Pharmacol Ther. 2017;102(5):765–76. https://doi.org/10.1002/cpt.787.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Janssen JM, de Vries N, Venekamp N, Rosing H, Huitema ADR, Beijnen JH. Development and validation of a liquid chromatography-tandem mass spectrometry assay for nine oral anticancer drugs in human plasma. J Pharm Biomed Anal. 2019;174:561–6. https://doi.org/10.1016/j.jpba.2019.06.034.

    Article  CAS  PubMed  Google Scholar 

  15. Wang Y, Chia YL, Nedelman J, Schran H, Mahon FX, Molimard M. A therapeutic drug monitoring algorithm for refining the imatinib trough level obtained at different sampling times. Ther Drug Monit. 2009;31(5):579–84. https://doi.org/10.1097/FTD.0b013e3181b2c8cf.

    Article  CAS  PubMed  Google Scholar 

  16. Moeskops P, de Vos B, Veldhuis WB, May AM, Kurk S, Koopman M, et al. Automatic quantification of 3D body composition from abdominal CT with an ensemble of convolutional neural networks. European Congress of Radiology-ECR 2020. 2020. https://doi.org/10.26044/ecr2020/C-09334.

  17. Martin L, Birdsell L, MacDonald N, Reiman T, Clandinin MT, McCargar LJ, et al. Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol. 2013;31(12):1539–47. https://doi.org/10.1200/jco.2012.45.2722.

    Article  PubMed  Google Scholar 

  18. Greig MJ, Niessen S, Weinrich SL, Feng JL, Shi M, Johnson TO. Effects of activating mutations on EGFR cellular protein turnover and amino acid recycling determined using SILAC mass spectrometry. Int J Cell Biol. 2015;2015: 798936. https://doi.org/10.1155/2015/798936.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hirano T, Yasuda H, Tani T, Hamamoto J, Oashi A, Ishioka K, et al. In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer. Oncotarget. 2015;6(36):38789–803. https://doi.org/10.18632/oncotarget.5887.

  20. Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18):1689–99. https://doi.org/10.1056/NEJMoa1411817.

    Article  PubMed  Google Scholar 

  21. European Medicine Agency. Tagrisso: Assessment report. 2016.

  22. Sonobe S, Taniguchi Y, Saijo N, Naoki Y, Tamiya A, Omachi N, et al. The efficacy of a reduced dose (40mg) of osimertinib with T790M-positive advanced non-small-cell lung cancer. Ann Oncol. 2017;28: x130. https://doi.org/10.1093/annonc/mdx671.016.

    Article  Google Scholar 

  23. Coutant DE, Kulanthaivel P, Turner PK, Bell RL, Baldwin J, Wijayawardana SR, et al. Understanding disease-drug interactions in cancer patients: implications for dosing within the therapeutic window. Clin Pharmacol Ther. 2015;98(1):76–86. https://doi.org/10.1002/cpt.128.

    Article  CAS  PubMed  Google Scholar 

  24. van Veggel B, Madeira RSJFV, Hashemi SMS, Paats MS, Monkhorst K, Heideman DAM, et al. Osimertinib treatment for patients with EGFR exon 20 mutation positive non-small cell lung cancer. Lung Cancer. 2020;141:9–13. https://doi.org/10.1016/j.lungcan.2019.12.013.

  25. Floc’h N, Martin MJ, Riess JW, Orme JP, Staniszewska AD, Ménard L, et al. Antitumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR Exon 20 insertions. Mol Cancer Ther. 2018;17(5):885–96. https://doi.org/10.1158/1535-7163.Mct-17-0758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Harrison PT, Vyse S, Huang PH. Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer. Semin Cancer Biol. 2020;61:167–79. https://doi.org/10.1016/j.semcancer.2019.09.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Janssen JM, Dorlo TPC, Beijnen JH, Huitema ADR. Evaluation of extrapolation methods to predict trough concentrations to guide therapeutic drug monitoring of oral anticancer drugs. Ther Drug Monit. 2020;42(4):532–9. https://doi.org/10.1097/ftd.0000000000000767.

    Article  PubMed  Google Scholar 

  28. Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4(9):1046–61. https://doi.org/10.1158/2159-8290.Cd-14-0337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank everyone who contributed to the logistics of collecting and measuring the osimertinib concentrations, in particular Julie Janssen and Laura Molenaar-Kuijsten. In addition, we thank Jasper van der Zwet for his assistance with the collection of the data.

Author information

Author notes

  1. René J. Boosman and Merel Jebbink contributed equally.

Authors and Affiliations

  1. Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    René J. Boosman, Jos H. Beijnen & Alwin D. R. Huitema

  2. Department of Thoracic Oncology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek, Amsterdam, The Netherlands

    Merel Jebbink, Bianca A. M. H. van Veggel, Adrianus J. de Langen & Egbert F. Smit

  3. Department of Radiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

    Wouter B. Veldhuis

  4. Department of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek, Amsterdam, The Netherlands

    Stefanie L. Groenland & Neeltje Steeghs

  5. Quantib, Rotterdam, The Netherlands

    Pim Moeskops

  6. Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    Jos H. Beijnen

  7. Department of Pharmacology Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

    Alwin D. R. Huitema

  8. Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

    Alwin D. R. Huitema

Authors
  1. René J. Boosman
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Contributions

R.J. Boosman, M. Jebbink, W.B. Veldhuis, S.L. Groenland, B.A.M.H. van Veggel, P. Moeskops, A.J. de Langen, J.H. Beijnen, E.F. Smit, A.D.R. Huitema and N. Steeghs wrote the manuscript. R.J. Boosman, M. Jebbink, S.L. Groenland, B.A.M.H. van Veggel, E.F. Smit, A.D.R. Huitema and N. Steeghs designed the research. R.J. Boosman, M. Jebbink, W.B. Veldhuis, P. Moeskops, A.D.R. Huitema and N. Steeghs performed the research. R.J. Boosman, M. Jebbink, E.F. Smit, A.D.R. Huitema and N. Steeghs analyzed the data.

Corresponding authors

Correspondence to René J. Boosman or Merel Jebbink.

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Conflict of Interest

R.J. Boosman, M. Jebbink, S.L. Groenland, B.A.M.H. van Veggel, E.F. Smit and A.D.R. Huitema declare they have no conflict of interest to report.

W.B. Veldhuis is a Cofounder and minority shareholder of Quantib BV.

P. Moeskops is an employee of Quantib BV.

A.J. de Langen received grants from BMS, MSD, Boehringer, AstraZeneca and non-financial support from Merck Serono and Roche, outside the submitted work.

J.H. Beijnen has received payment for expert testimony for Hoyng Tokh Monegier (paid to their institution), is a part-time employee and (in)direct stockholder of Modra Pharmaceuticals and (jointly) holds a patent on oral taxane formulations, which are clinically developed by Modra Pharmaceuticals. Modra Pharmaceuticals is a small spin-off company of the Netherlands Cancer Institute. All of these conflicts are outside of the submitted work.

N. Steeghs provided consultation or attended advisory boards for Boehringer Ingelheim, Ellipses Pharma. N Steeghs received research grants for the institute from AB Science, Abbvie, Actuate Therapeutics, ADCtherapeutics, Amgen, Array, Ascendis Pharma, Astex, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BridgeBio, Bristol-Myers Squibb, Cantargia, Celgene, CellCentric, Cresecendo, Cytovation, Deciphera, Eli Lilly, Exelixis, Genentech, Genmab, Gilead, GlaxoSmithKline, Incyte, InteRNA, Janssen/Johnson&Johnson, Kinate, Merck, Merck Sharp & Dohme, Merus, Molecular Partners, Novartis, Numab, Pfizer, Pierre Fabre, Regeneron, Roche, Sanofi, Seattle Genetics, Servier, Taiho, Takeda (outside the submitted work).

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Boosman, R.J., Jebbink, M., Veldhuis, W.B. et al. Exposure–Response Analysis of Osimertinib in EGFR Mutation Positive Non-Small Cell Lung Cancer Patients in a Real-Life Setting. Pharm Res 39, 2507–2514 (2022). https://doi.org/10.1007/s11095-022-03355-2

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