On December 19, 2008, the U.S. Food and Drug Administration (FDA) approved imatinib mesylate tablets for oral use (Gleevec, Novartis Pharmaceuticals) for the adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive Gastrointestinal Stromal Tumor (GIST).
Imatinib mesylate was investigated as an adjuvant treatment of GIST in a randomized, double-blind, placebo-controlled study enrolling 713 patients. Three hundred fifty-nine patients were randomized to receive imatinib mesylate and 354 to receive placebo. The primary objective of the clinical trial was to compare recurrence-free survival (RFS) of the two groups. Overall survival (OS) was a secondary objective. Eligible patients were > 18 years of age with a histological diagnosis of GIST (+KIT), resected tumor size > 3 cm, and a complete gross resection within 14-70 days prior to registration. Imatinib mesylate, 400 mg orally once daily, was administered for one year.
The study was terminated after the third protocol specified interim analysis. At the time of the final analysis of RFS, 100 events were confirmed by a blinded central independent review. With a median follow up of 14 months, 30 RFS events were observed in the imatinib group and 70 in the placebo group (HR=0.398, 95% CI: 0.259 - 0.610; two-sided p value < 0.0001). Based on these results, the trial was terminated. Patients still receiving placebo were allowed to cross over to imatinib mesylate. OS results are immature with 5 deaths in the imatinib mesylate group and 8 deaths in the placebo group.
Most patients in both groups experienced at least one adverse reaction and 31% in the imatinib group and 18% in the placebo group experienced adverse reactions of > grade 3. The most frequently reported adverse reactions (>20%) were diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting and abdominal pain. No new adverse reactions were reported in the adjuvant GIST treatment setting that had not been previously noted in other patient populations, including those with unresectable and/or malignant metastatic GIST. Drug was discontinued for adverse reactions in 17% and 3% of the imatinib and placebo-treated patients, respectively. Edema, gastrointestinal disturbances (nausea, vomiting, abdominal distention, and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of treatment discontinuation.
This current approval for adjuvant treatment of resected GIST is an accelerated approval with the requirement that follow-up of RFS and OS from this study and results of an ongoing study of 1 year vs. 3 years of adjuvant imatinib mesylate be submitted to FDA.
Imatinib mesylate was originally approved for the treatment of adult Ph+ chronic myelogenous leukemia in 2001 and pediatric Ph+ chronic myelogenous leukemia in 2003. Imatinib mesylate was approved for the treatment Kit+ unresectable and/or metastatic GIST tumors in 2002. Indications approved in 2006 include Ph+ acute lymphoblastic leukemia, myelodysplastic/myeloproliferative diseases, hypereosinophilic syndrome, aggressive systemic mastocytosis, and dermatofibrosarcoma protuberans.
Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at Drugs@FDA
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Date created: December 23, 2008