Skip to main content

Advertisement

SpringerLink
Log in

The relationship between drug exposure and clinical outcomes of non-small cell lung cancer patients treated with gefitinib

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

The objective of this study was to explore the relationship between gefitinib exposure and clinical outcome in gefitinib-treated patients with advanced non-small cell lung cancer. Thirty patients participated in this pharmacokinetic study and received 250-mg oral doses of gefitinib once daily. Blood samples were collected before dosing and on days 7, 14, 21, and 28. The plasma concentrations of gefitinib were evaluated using a validated high-performance liquid chromatographic method with tandem mass spectrometric detection. Univariate and multivariate analyses were performed to determine predictive factors for response and survival of patients. EGFR mutations were analyzed retrospectively. Median survival time (MST) was 9.97 months (95%CI 2.79–17.14 months). The geometric mean trough gefitinib plasma concentration (C ssmin ) was 266 ng/ml (range 94–538 ng/ml). In the multivariate analysis, only skin rash was associated with gefitinib-induced disease control (P = 0.017); Adenocarcinoma, skin rash, and ‘high’ C ssmin (C ssmin  ≥ 200 ng/ml) were independently associated with overall survival (P = 0.004, 0.028,0.007, respectively). MST of EGFR wild-type patients with ‘high’ C ssmin was longer than that with ‘low’ C ssmin (P = 0.002). Our study results show that pharmacokinetic variability may also account for the different outcomes following treatment with gefitinib for patients with wild-type EGFR. Further studies are needed to confirm these results.

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

Similar content being viewed by others

References

  1. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–39.

    Article  PubMed  CAS  Google Scholar 

  2. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–500.

    Article  PubMed  CAS  Google Scholar 

  3. Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L, Haney J, Witta S, Danenberg K, Domenichini I, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst. 2005;97:643–55.

    Article  PubMed  CAS  Google Scholar 

  4. Hirsch FR, Varella-Garcia M, McCoy J, West H, Xavier AC, Gumerlock P, Bunn PA Jr, Franklin WA, Crowley J, Gandara DR. Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest Oncology Group Study. J Clin Oncol. 2005;23:6838–45.

    Article  PubMed  CAS  Google Scholar 

  5. Swaisland HC, Smith RP, Laight A, Kerr DJ, Ranson M, Wilder-Smith CH, Duvauchelle T. Single-dose clinical pharmacokinetic studies of gefitinib. Clin Pharmacokinet. 2005;44:1165–77.

    Article  PubMed  CAS  Google Scholar 

  6. Jones HK, Stafford LE, Swaisland HC, Payne R. A sensitive assay for ZD1839 (Iressa) in human plasma by liquid-liquid extraction and high performance liquid chromatography with mass spectrometric detection: validation and use in Phase I clinical trials. J Pharm Biomed Anal. 2002;29:221–8.

    Article  PubMed  CAS  Google Scholar 

  7. Han SW, Kim TY, Hwang PG, Jeong S, Kim J, Choi IS, Oh DY, Kim JH, Kim DW, Chung DH, et al. Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol. 2005;23:2493–501.

    Article  PubMed  CAS  Google Scholar 

  8. Bai H, Mao L, Wang HS, Zhao J, Yang L, An TT, Wang X, Duan CJ, Wu NM, Guo ZQ, et al. Epidermal growth factor receptor mutations in plasma DNA samples predict tumor response in Chinese patients with stages IIIB to IV non-small-cell lung cancer. J Clin Oncol. 2009;27:2653–9.

    Article  PubMed  CAS  Google Scholar 

  9. Albanell J, Rojo F, Averbuch S, Feyereislova A, Mascaro JM, Herbst R, LoRusso P, Rischin D, Sauleda S, Gee J, et al. Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. J Clin Oncol. 2002;20:110–24.

    Article  PubMed  CAS  Google Scholar 

  10. Baselga J, Rischin D, Ranson M, Calvert H, Raymond E, Kieback DG, Kaye SB, Gianni L, Harris A, Bjork T, et al. Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol. 2002;20:4292–302.

    Article  PubMed  CAS  Google Scholar 

  11. Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, Nishiwaki Y, Vansteenkiste J, Kudoh S, Rischin D, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol. 2003;21:2237–46.

    Article  PubMed  CAS  Google Scholar 

  12. Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, Natale RB, Schiller JH, Von Pawel J, Pluzanska A, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 1. J Clin Oncol. 2004;22:777–84.

    Article  PubMed  CAS  Google Scholar 

  13. Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, Scagliotti G, Rosell R, Oliff I, Reeves JA, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 2. J Clin Oncol. 2004;22:785–94.

    Article  PubMed  CAS  Google Scholar 

  14. Swaisland HC, Cantarini MV, Fuhr R, Holt A. Exploring the relationship between expression of cytochrome P450 enzymes and gefitinib pharmacokinetics. Clin Pharmacokinet. 2006;45:633–44.

    Article  PubMed  CAS  Google Scholar 

  15. Li J, Karlsson MO, Brahmer J, Spitz A, Zhao M, Hidalgo M, Baker SD. CYP3A phenotyping approach to predict systemic exposure to EGFR tyrosine kinase inhibitors. J Natl Cancer Inst. 2006;98:1714–23.

    Article  PubMed  CAS  Google Scholar 

  16. Ranson M, Wardell S. Gefitinib, a novel, orally administered agent for the treatment of cancer. J Clin Pharm Ther. 2004;29:95–103.

    Article  PubMed  CAS  Google Scholar 

  17. Li J, Zhao M, He P, Hidalgo M, Baker SD. Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Clin Cancer Res. 2007;13:3731–7.

    Article  PubMed  CAS  Google Scholar 

  18. Lu JES, Lum BL, Hamilton M, Rakhit A, Gaudreault J. A population pharmacokinetic (PK) model for erlotinib (E), a small molecule inhibitor of the epidermal growth factor receptor (EGFR) [abstract 2032]. JClin Oncol. 2005;23:143s.

    Article  Google Scholar 

  19. Lu JF, Eppler SM, Wolf J, Hamilton M, Rakhit A, Bruno R, Lum BL. Clinical pharmacokinetics of erlotinib in patients with solid tumors and exposure-safety relationship in patients with non-small cell lung cancer. Clin Pharmacol Ther. 2006;80:136–45.

    Article  PubMed  CAS  Google Scholar 

  20. Hamilton M, Wolf JL, Rusk J, Beard SE, Clark GM, Witt K, Cagnoni PJ. Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res. 2006;12:2166–71.

    Article  PubMed  CAS  Google Scholar 

  21. Hamilton M, Wolf JL, Zborowski D. Tarceva2 (erlotinib) exposure/effects (EE) analysis from a phase III study in advanced NSCLC: effect of smoking on the PK of erlotinib [abstract 6165]. Proc Am Assoc Cancer Res. 2005;46:1451.

    Google Scholar 

  22. Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA. 2004;101:13306–11.

    Article  PubMed  CAS  Google Scholar 

  23. Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, Fong KM, Lee H, Toyooka S, Shimizu N, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005;97:339–46.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Mr. Dave Clarke and Mr. Paul Martin from Research & Development Department of AstraZeneca Pharmaceutical Co., Ltd., at Alderly Park, Great Britain, for their technical assistance in Gefitinib PK analysis. We also thank all patients and their families for their participation in this study. Our study was funded by Natural Science Foundation of Guangdong Province, China(07001532).

Author information

Authors and Affiliations

  1. State Key Laboratory of Oncology in South China and Department of Medical Oncology, Cancer Centre, Sun Yat-Sen University, 651 Dong Feng Road East, Guangzhou, 510060, People’s Republic of China

    Yuan-Yuan Zhao, Yan-Xia Shi, Wei Jiang, Cong Xue & Li Zhang

  2. National Anti-Cancer Drug Clinical Research Centre, Cancer Center, Sun Yat-Sen University, 651 Dong Feng Road East, Guangzhou, People’s Republic of China

    Su Li, Yang Zhang, Hong-Yun Zhao, Hai Liao, Ying Guo & Li Zhang

Authors
  1. Yuan-Yuan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Su Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hong-Yun Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hai Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ying Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yan-Xia Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wei Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Cong Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Li Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Li Zhang.

Additional information

Y.-Y. Zhao and S. Li contributed equally to this manuscript.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhao, YY., Li, S., Zhang, Y. et al. The relationship between drug exposure and clinical outcomes of non-small cell lung cancer patients treated with gefitinib. Med Oncol 28, 697–702 (2011). https://doi.org/10.1007/s12032-010-9541-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12032-010-9541-0

Keywords

Search

Navigation