Relationship between icotinib hydrochloride exposure and clinical outcome in Chinese patients with advanced non-small cell lung cancer.
BACKGROUND
The current study was conducted to explore the relationship between icotinib hydrochloride exposure and therapeutic effects in Chinese patients with advanced non-small cell lung cancer (NSCLC) who were treated with icotinib hydrochloride.


METHODS
A total of 30 patients with NSCLC who were treated with icotinib hydrochloride were chosen from a single-center, open-label, phase 1 dose escalation clinical trial. Different doses of icotinib hydrochloride were administered orally for 28 consecutive days in different groups until disease progression or unacceptable toxicities occurred. Blood samples were collected during the first treatment cycle (day 1-28) for the pharmacokinetic analysis. Tumor responses were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST). The plasma concentrations of icotinib hydrochloride were assessed by liquid chromatography-mass spectrometry.


RESULTS
Thirty patients with a median age of 56 years old (50% of whom were female) were enrolled. For single-dose treatment, the plasma pharmacokinetics demonstrated a median time to maximum concentration of 0.5 to 4 hours and a mean terminal elimination half-life of 6.21±3.44 hours at the 150-mg dose and 10.1±12.18 hours at the 200-mg dose. For multiple-dose treatment, the last measurable concentration (Clast ) was 708±368.67 ng/mL at the 150-mg every 12 hours, 782.73±618.18 ng/mL at the 200-mg every 12 hours, and 1162±658.44 ng/mL at the 125-mg every 8 hours; the under the concentration curve from time 0 to Clast was 14.5±2.43 hour*mg/mL, 13.2±2.5 hour*mg/mL, and 12.19±2.47 hour*mg/mL, respectively. At the dose of 150 mg every 12 hours, 1 patient with an epidermal growth factor receptor (EGFR) exon 19 deletion achieved a complete response for 10 months; another patient who carried the EGFR exon 19 deletion achieved stable disease for 6 months. Univariate analysis demonstrated that the time to maximum plasma concentration (Tmax ) after a single dose of icotinib hydrochloride was significantly correlated with the overall survival (OS) (Spearman correlation coefficient, 0.441; P = .012). The disease control rate was correlated with Tmax after a single dose (Spearman correlation coefficient, 0.518; P = .011). Multivariate analysis demonstrated that the area under the concentration-time curve from 0 to last determination time and the area under the curve from 0 to infinite time after a single dose of icotinib hydrochloride were correlated with OS (P = .037 and .042, respectively). The Clast was found to affect progression-free survival (P = .016). Stratification of these patients according to smoking status indicated significant correlation between OS and the area under the concentration-time curve from 0 to last determination time (Spearman correlation coefficient, -0.709; P = .015).


CONCLUSIONS
Patients with a longer Tmax and higher exposure might experience longer OS and a higher disease control rate. In addition, the increased Clast might prolong the progressive-free survival of patients. However, the relationships between EGFR mutation, pharmacokinetics, and clinical outcomes require further research.
Department of Respiratory Medicine, Peking Union Medical College Hospital, Beijing, China.
Jun
J
Ni
Center of Clinical Pharmacology, Peking Union Medical College Hospital, Beijing, China.
Dong-Yang
DY
Liu
Center of Clinical Pharmacology, Peking Union Medical College Hospital, Beijing, China.
Bei
B
Hu
Department of Respiratory Medicine, Peking Union Medical College Hospital, Beijing, China.
Chen
C
Li
Center of Clinical Pharmacology, Peking Union Medical College Hospital, Beijing, China.
Ji
J
Jiang
Department of Respiratory Medicine, Peking Union Medical College Hospital, Beijing, China.
Han-Ping
HP
Wang
Department of Respiratory Medicine, Peking Union Medical College Hospital, Beijing, China.
Li
L
Zhang
D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D002681:China; D043844:Crown Ethers / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000097:blood / Q000235:genetics; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011799:Quinazolines / Q000008:administration & dosage* / Q000493:pharmacokinetics
D043844:Crown Ethers; D011799:Quinazolines; C531470:icotinib; C512478:EGFR protein, human; D066246:ErbB Receptors
clinical outcomes; icotinib hydrochloride; non-small cell lung cancer; pharmacokinetics