The relationship between drug exposure and clinical outcomes of non-small cell lung cancer patients treated with gefitinib.
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 (Cminss 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' Cminss (Cminss≥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' Cminsswas longer than that with 'low' Cminss (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.
Zhao
Yuan-Yuan
YY
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.
Li
Su
S
Zhang
Yang
Y
Zhao
Hong-Yun
HY
Liao
Hai
H
Guo
Ying
Y
Shi
Yan-Xia
YX
Jiang
Wei
W
Xue
Cong
C
Zhang
Li
L
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D053719:Tandem Mass Spectrometry; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
J Natl Cancer Inst. 2006 Dec 6;98(23):1714-23
17148773
J Clin Oncol. 2005 Apr 10;23(11):2493-501
15710947
Clin Pharmacokinet. 2006;45(6):633-44
16719544
Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13306-11
15329413
Clin Cancer Res. 2007 Jun 15;13(12):3731-7
17575239
J Clin Oncol. 2004 Mar 1;22(5):785-94
14990633
Science. 2004 Jun 4;304(5676):1497-500
15118125
J Clin Oncol. 2005 Oct 1;23(28):6838-45
15998906
J Clin Oncol. 2004 Mar 1;22(5):777-84
14990632
J Natl Cancer Inst. 2005 May 4;97(9):643-55
15870435
Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2166-71
16609030
J Clin Oncol. 2009 Jun 1;27(16):2653-9
19414683
J Clin Oncol. 2002 Nov 1;20(21):4292-302
12409327
J Clin Oncol. 2003 Jun 15;21(12):2237-46
12748244
J Clin Oncol. 2002 Jan 1;20(1):110-24
11773160
J Pharm Biomed Anal. 2002 Jun 20;29(1-2):221-8
12062681
Clin Pharmacokinet. 2005;44(11):1165-77
16231967
J Clin Pharm Ther. 2004 Apr;29(2):95-103
15068398
Clin Pharmacol Ther. 2006 Aug;80(2):136-45
16890575
N Engl J Med. 2004 May 20;350(21):2129-39
15118073
J Natl Cancer Inst. 2005 Mar 2;97(5):339-46
15741570