Researchers involved in a North American Intergroup Phase III trial (ACOSOG Z9001) have reported that the adjuvant administration of Gleevec (imatinib) may decrease the recurrence rate following surgical resection of gastrointestinal stromal tumors (GIST) that are 3 cm or larger. The details of this study were presented at the 2007 meeting of the American Society of Clinical Oncology in June.[1]  

Palliative Gleevec treatment has improved the survival of patients with recurrent or metastatic GIST. In a recent retrospective study, adjuvant Gleevec was administered to 23 patients with high-risk GIST.[2] These authors observed recurrences in only one of these 23 patients receiving adjuvant Gleevec compared to 67% in historical controls.  

ACOSOG Z9001 is a randomized double blind trial of Gleevec or placebo in patients with GIST tumors 3 cm or larger. The study accrual was terminated in April of 2007 when the Data Safety Monitoring Board determined that the treatment arm had a statistically significant improved risk in progression-free survival (PFS). The study had accrued 644 patients from 230 sites. The median age in the two groups was 58-59, with slightly more men in the placebo cohort (54% versus 46%). The range in tumor sizes was not significantly different. Sixty seven percent of patients completed one year of Gleevec versus 71% in the placebo group. There were 14.5% of patients who required a dose reduction of Gleevec versus 4% in the placebo group. Of the patients that did not complete the 12 months of therapy, the most common reason in the Gleevec cohort was toxicity, whereas in the placebo group it was tumor recurrence; equivalent numbers withdrew their consent or discontinued study participation for other reasons. Toxicities were more frequent in the Gleevec cohort, however there were still approximately 15% of patients reporting grade 3 toxicities and 1-2% grade four toxicities in the placebo group. These toxicities were typically abdominal pain, whereas the grade 3 and 4 toxicities for the Gleevec group were more typically hematologic toxicities. At a median of 1.3 years follow up, there is no difference in the overall survival of the two groups. However, when comparing PFS, 97% of the patients receiving Gleevec were free of recurrence compared to only 83% in the placebo group. In an unplanned analysis, PFS was analyzed based on tumor size: 3-6 cm, 6-10 cm, and greater than or equal to 10 cm in size. Although the hazard ratio for the smallest tumors was 0.44 (0.14-1.4), this was not statistically significant (p=0.15). In the two cohorts with intermediate and large sized tumors, improvement in PFS was reported to be statistically significant (HR= 0.37, (0.17-0.81); p=0.01 for 6-10 cm, and HR=0.19, (0.09-0.41); p<0.001). 

 Analyzing the PFS curves, it appears that there is a significant benefit in the first 18 months following entry onto study, but then the recurrence rate in patients receiving Gleevec increases and the slope of this curve approximates the recurrence seen in the placebo arm. This observation will have to be followed given the relatively few patients that have long-term follow up.  

Comments: This will be a very important study and will surely be followed with adjuvant studies with new agents such as Sutent.

References: 

Related News:

Sutent® Effective for Gleevec®-Resistant Gastrointestinal Stromal Tumor (10/16/2006)

Sutent® Approved by FDA for Treatment of Renal Cell Carcinoma and Gastrointestinal Stromal Tumor (4/4/2006)

Site of Mutation Within KIT Associated with Response and Time to Progression with Gleevec® in Gastrointestinal Stromal Tumors (5/17/2005)  

Interruption of Treatment with Gleevec® Not Recommended for GIST (03/27/2007)