title: Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors.
abstract: PURPOSE To study the pharmacokinetics (PK) of imatinib (IM) in patients with advanced GI stromal tumors (GISTs) treated in a randomized phase II study and to explore the potential relationship between IM plasma levels and long-term clinical outcomes. PATIENTS AND METHODS Patients were randomly assigned to receive IM at 400 mg versus 600 mg daily. IM plasma levels were analyzed in a subset of patients (n = 73) for whom PK data on day 1 and at steady-state (SS, day 29) were available. IM PK was evaluated using a population PK approach. The relationship between IM plasma exposure and clinical outcome was explored by grouping patients into quartiles according to IM trough concentration (C(min)). The clinical outcome parameters evaluated include overall objective benefit rate (OOBR; complete response plus partial response plus stable disease) time to progression (TTP), and KIT genotyping. Results IM PK exposure showed a high inter-patient variability, and clinical outcomes were correlated with IM trough levels at SS. The median TTP was 11.3 months for patients in the lowest C(min) quartile (Q1, < 1,110 ng/mL) compared with more than 30 months for Q2 to Q4 (P = .0029). OOBR was also inferior in Q1 patients. In patients with GIST with KIT exon 11 mutations (n = 39), the OOBR was 67% for Q1 patients versus 100% for all others (P = .001). CONCLUSION In patients with advanced GIST, IM trough levels at SS were associated with clinical benefit. Patients with IM C(min) below 1,100 ng/mL showed a shorter TTP and lower rate of clinical benefit (OOBR). Further studies are justified to test whether monitoring IM plasma levels might optimize clinical outcomes for patients with GIST.
authors.affiliation: Ludwig Center, Dana-Farber/Harvard Cancer Center, Dana-Farber Cancer Institute, D1212, 44 Binney St, Boston MA 02115, USA. gdemetri@partners.org
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Wehrle
authors.forename: Amy
authors.initials: A
authors.lastname: Racine
authors.forename: Zariana
authors.initials: Z
authors.lastname: Nikolova
authors.forename: Charles D
authors.initials: CD
authors.lastname: Blanke
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
authors.forename: Margaret
authors.initials: M
authors.lastname: von Mehren
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001549:Benzamides; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000097:blood* / Q000188:drug therapy / Q000235:genetics; D006207:Half-Life; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010879:Piperazines / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011743:Pyrimidines / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit