Originally published as JCO Early Release 10.1200/JCO.2008.20.4818 on May 18 2009

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Imatinib Plasma Levels Are Correlated With Clinical Benefit in Patients With Unresectable/Metastatic Gastrointestinal Stromal Tumors

From the Ludwig Center, Dana-Farber/Harvard Cancer Center, and Harvard Medical School, Boston, MA; Oncology Business Unit, Novartis Pharmaceuticals Corp, Florham Park, NJ; Oncology Business Unit and Biostatistics, Novartis Pharmaceuticals AG, Basel, Switzerland; British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada; Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland; and Fox Chase Cancer Center, Philadelphia, PA.

Corresponding author: George D. Demetri, MD, Ludwig Center, Dana-Farber/Harvard Cancer Center, Dana-Farber Cancer Institute, D1212, 44 Binney St, Boston MA 02115; e-mail: gdemetri{at}partners.org.

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.

Supported in part by Novartis Pharmaceuticals Corp, Oncology Business Unit, Florham Park, NJ. Additional philanthropic support for this work has been provided by the Virginia and Daniel K. Ludwig Trust for Cancer Research and the Stutman Gastrointestinal Stromal Tumor Cancer Research Fund (G.D.D.).

Presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL, as well as the Gastrointestinal Cancer Symposium of the American Society of Clinical Oncology, the American Gastroenterological Association, the American Society for Therapeutic Radiology and Oncology, and the Society of Surgical Oncology, January 25-27, 2008, Orlando, FL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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