GIST Clinical Trial Update:
Imatinib and Surgery

Clinical Management of GIST
Helsinki and Barcelona 2003-Conference Highlights

Note: *Represents new information added after the Helsinki and Barcelona Conferences. Information known to be out of date has been removed.

A major focus of current clinical studies involving patients with GIST is to clarify the roles of surgery and systemic therapy with imatinib in the management of the disease. Burton Eisenberg, MD, of Norris Cotton Cancer Center in Lebanon, New Hampshire USA, provided an update during the 3rd International Symposium on GIST in Helsinki.

Adjuvant trials

The initial study is the American College of Surgeons Oncology Group (ACOSOG) phase II trial of postoperative, adjuvant imatinib therapy for high-risk GIST patients (Table 3). This trial is now closed, having met its patient accrual goal by mid-2003. Data are now in the accumulation phase. Of interest is the rapidity with which the full cohort of patients was enrolled. It appears that there was a significant number of well-informed patients and physicians who were willing to consider an adjuvant clinical trial.

The ACOSOG phase III trial was initiated in light of an issue that arose with respect to the phase II trial—that a study of adjuvant imatinib therapy needed to be designed in answer to a genuine phase III “question”, entailing comparison with an untreated group. Consequently, the phase III trial enrolled GIST patients who have less overall risk of recurrence. Patient accrual is complete.
The ACOSOG phase III trial addresses the question of whether there is a long-term benefit from adjuvant imatinib use in intermediate-risk GIST patients. Other compelling questions may remain open, however, including timing of therapy. For example, could the drug be started at the time of recurrence for patients in postoperative relapse, with similar results? Dosage is not under investigation in either of the ACOSOG trials; patients begin therapy at 400 mg/d.

*On April 12, 2007, the American College of Surgeons Oncology Group (ACOSOG) announced that the Z9001 phase III trial was closed having successfully met its endpoint. The trial began recruiting GIST patients in 2002 and is ending immediately. An independent data-monitoring committee announced that the trial had crossed the previously established boundary for recurrence-free survival and had thus met its primary endpoint with a highly significant hazard ratio of 3.1. The interim analysis showed a 97 percent recurrence-free survival rate for the Gleevec group as opposed to an 83 percent survival rate for those on the placebo. Taking Gleevec for one year after surgery significantly increased the time before a GIST recurrence.

*Trial organizers will be working with investigators at the many trial sites on a method to notify patients about these developments. The trial investigators will notify patients whether they received Gleevec or a placebo. Patients that are currently receiving placebo will be given the opportunity to receive one year of Gleevec at no cost to them. Novartis is working with the FDA on the process of registering Gleevec for adjuvant treatment. At this time Gleevec is not approved for adjuvant treatment in GIST, however; may GIST patients in the United States take Gleevec on an adjuvant basis. We understand that this is far less common in other countries.

The EORTC Soft Tissue and Bone Sarcoma Group also is comparing adjuvant imatinib administration versus no postoperative pharmacotherapy in a clinical trial with a projected enrollment of 400 patients. Patients with completely resected GIST, stratified according to pathologically complete (R0) or marginal (R1) excision, intermediate or high risk, and gastric or other site, will be assigned randomly to receive either imatinib, 400 mg/d for 2 years, or no treatment. The study is designed to detect an improvement in 5-year survival from 50% to 65%.

The Scandinavian Sarcoma Group trial (SSGXVII), currently open for accrual, is seeking 80 patients from Germany and the Scandinavian countries for an open-label, randomized, phase II, multicenter trial. Following radical surgery, patients with high-risk GIST will be randomly assigned to either 12 or 36 months of adjuvant imatinib at 400 mg/d, with the primary end point being recurrence-free survival. Secondary end points will be safety and overall survival.

Neoadjuvant trial

Under investigation within a phase II trial design by the Radiation Therapy Oncology Group (RTOG) is whether imatinib therapy should be given before surgery for GIST (neoadjuvant therapy). The patients in this study tend to have either a bulky primary GIST or recurrent or metastatic tumors that are potentially operable. The question is how to integrate surgery for GIST with targeted systemic therapy. When does one surgically intervene, and will the result of a dual approach for these very-high-risk patients be evidenced by prolonged survival?

Another objective of the RTOG study is to obtain tissue from patients’ tumors before treatment with imatinib and again during (post-imatinib) surgical resection to further define some of the molecular mechanisms of response to the drug and correlate the molecular data with clinical and FDG-PET findings. The plan is to evaluate each patient’s tumor for mutational status; to examine the phosphorylated protein kinases that are part of the KIT pathway; and to begin to explore some of the differences in gene expression before and after imatinib therapy. These substudies will include microarray analysis. Ultimately, the goal of these investigations is to correlate the mutational status, the protein activation status, and the genomic profile.