BETHESDA, Maryland—Researchers have closed early a randomized clinical trial investigating the use of imatinib(Drug information on imatinib) mesylate (Gleevec) as an adjuvant therapy following the resection of primary gastrointestinal stromal tumors (GISTs). They acted after an interim analysis found significantly fewer GIST recurrences among patients getting the drug. Preliminary data showed that 97% of patients treated for 1 year with imatinib did not experience a recurrence of their disease vs 83% of placebo patients.
The data monitoring committee overseeing the multicenter trial conducted in the United States and Canada (ACOSOG Z9001) recommended release of the results from the prespecified analysis, which examined data from more than 600 patients enrolled in the study. The analysis found the trial had met its primary endpoint of increased recurrence-free survival. The current standard treatment for primary GIST is complete surgical removal of the tumor without any additional therapy.
"These results have major implications for patients with primary GIST," said principal investigator Ronald DeMatteo, MD, vice chair of surgery and head of the Division of General Surgical Oncology at Memorial Sloan-Kettering Cancer Center. "Conventional chemotherapy agents have been notoriously ineffective in GIST. This study for the first time demonstrated that targeted molecular therapy reduces the rate of recurrence after complete removal of a primary GIST."
More than 90% of GISTs are positive for Kit, the protein that imatinib targets to block cellular communication and prevent cell proliferation. The US Food and Drug Administration approved the drug in 2002 for use in treating unresectable or metastatic GIST on the basis of an objective response rate. No controlled trial has demonstrated increased survival or other clinical benefit from imatinib use.
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"With these new data, we see that Gleevec may help patients with early GIST," said Diane Young, MD, head of global medical affairs at Novartis Oncology. "We will now work with the investigators on a submission to gain regulatory approval for Gleevec as adjuvant treatment for GIST."
The National Cancer Institute sponsored the clinical trial, which was led by the American College of Surgeons Oncology Group and included researchers from five NCI-supported North American Cooperative Oncology Groups.
The protocol for the multicenter, placebo-controlled, double-blind trial called for the enrollment of 732 patients at sites in 40 states and 5 Canadian provinces. Accrual began in June 2002 and ended in April 2007. The study's primary endpoint was recurrence-free survival as measured by serial CT scans at 3 to 6 months. Overall survival, measured by serial doctor visits at 3 to 6 months, served as the secondary endpoint.
Entry requirements included a confirmed primary GIST tumor of at least 3 cm in maximum diameter, no peritoneal or distant metastasis, complete resection of the tumor within the past 14 to 70 days, and a positive tumor stain for Kit receptor tyrosine kinase. Exclusion criteria included no concurrent anticancer biologic agents, no prior postoperative or current anticancer chemotherapy, and no prior postoperative radiotherapy.
Study patients were randomized to receive either one 400 mg tablet of imatinib or placebo daily for 1 year. Researchers unblinded the records of patients who developed a recurrence of GIST during the trial. Those patients taking imatinib continued on the drug but at a higher dose, and those receiving placebo had the option to receive imatinib for 1 year. With closure of the study, patients in the placebo arm were given the choice of switching to imatinib therapy to try to forestall a recurrence.
Most of the imatinib-treated patients in the trial tolerated the drug well, according to investigators, although the majority of those taking the 400 mg daily dose experienced adverse events at some time. These side effects were similar to those observed in other clinical trials of the agent, including nausea, diarrhea, and edema, and most of them ranked mild to moderate in severity.
Novartis provided the drug and partial funding for the trial under an existing agreement with NCI. The American College of Surgeons also provided support. The investigators plan to present the full results of the trial at a future medical meeting.