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Approval Summary: Imatinib Mesylate in the Treatment of Metastatic and/or Unresectable Malignant Gastrointestinal Stromal Tumors

Office of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA

Key Words. Imatinib • Gleevec • KIT • CD117 • Gastrointestinal stromal tumors

Correspondence: Correspondence: Martin H. Cohen, M.D., Food and Drug Administration, White Oak Campus, 10903 New Hampshire Avenue, Building 22, Room 2102, Silver Spring, Maryland 20993-0002, USA. Telephone: 301-796-1344; Fax: 301-796-9845; email: martin.cohen{at}fda.hhs.gov

Received November 19, 2008; accepted for publication January 15, 2009.

Disclosure: The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.

The purpose of the present application was to fulfill a postmarketing commitment to provide long-term efficacy and safety data on treatment with imatinib mesylate (Gleevec®; Novartis Pharmaceuticals, East Hanover, NJ) in patients with CD117⁺ unresectable and/or metastatic malignant gastrointestinal stromal tumors (GISTs). In addition, this application also provides evidence to support a change in the label to allow for an escalation of imatinib dosing to 800 mg/day for patients with progressive disease on a lower dose. %Two open-label, controlled, multicenter, intergroup, international, randomized phase III studies were submitted—one conducted by the European Organization for Research and Treatment of Cancer (n = 946) and the other by the Southwest Oncology Group (n = 746). These studies compared 400 mg/day of imatinib with 800 mg/day of imatinib. A combined analysis of the two studies was prospectively defined and agreed to by both groups. Both protocols allowed patients randomized to the 400-mg/day imatinib arm to cross over to 800 mg/day imatinib at progression. Objective responses were achieved in >50% of patients receiving either imatinib dose. The median progression-free survival time was approximately 20 months and the median overall survival (OS) time was approximately 49 months. In the combined analysis, 347 patients crossed over to 800 mg/day imatinib at the time of progression. The median OS time after crossover was 14.3 months. The most common adverse events (AEs) were fluid retention, nausea, fatigue, skin rash, gastrointestinal complaints, and myalgia. The most common laboratory abnormality was anemia. Most often the AEs were of mild-to-moderate severity. Fluid retention events and skin rash were numerically reported more often in the 800-mg/day treatment cohort of patients.

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