Highlights from ASCO 2007
This year at ASCO, over 50 posters and presentations were given related to GIST. This newsletter covers two of the GIST highlights.
Adjuvant Treatment of GIST 
Ronald DeMatteo, MD, of Memorial Sloan-Kettering Cancer Center in New York, NY., presented late-breaking results from the North American Intergroup phase III trial, ACOSOG Z9001. This was a randomized trial that compared one year of Gleevec to a placebo after complete surgical resection of a primary GIST.
The study found that taking Gleevec for one year after surgery significantly increased the time to a recurrence. Of the patients taking Gleevec, 97 percent had no signs of their cancer returning at one year and 90 percent at two years compared to 83 percent at one year and 71 percent at two years for the patients that received the placebo.
The study began in June 2002 and included 644 patients that were recruited from 230 sites. Based on the highly significant results of the trial, the data safety committee halted further enrollment in April. They recommended that patients in the trial that were on the placebo be offered one year of Gleevec treatment.
At the present time, surgery is the standard treatment for GIST that has not spread. “This highly significant result could prompt re-evaluation of clinical practice recommendations for management of intermediate and high-risk primary resectable GISTs,” said Dr. DeMatteo, the principal investigator of the trial, in a June 4 press release. Based on the results of this trial Novartis expects to file global regulatory submissions for use of Gleevec as adjuvant therapy in GIST patients following surgery to remove primary tumors by early 2008.
Dr. DeMatteo’s presentation also provided the first look at data for different risk categories. The data was broken down into groups by primary tumor size; three cm to six cm, six cm to ten cm and over ten cm. The groups generally represent a range from lower risk (three cm to six cm) to higher risk (over ten cm); however the criteria for these groups is different than other criteria established for risk assessment for GIST (such as the Fletcher/NIH criteria) which almost always includes a measure of how fast the tumor is growing (mitotic rate). This means that while the three cm to six cm group is generally at lower risk of recurrence, there may still be patients in this group that are at an intermediate risk or even at high risk of recurrence and there may even be some patients in the over ten cm group that are at low-to-moderate risk of recurrence (Gastric GISTs over ten cm but with a low mitotic rate are rated as low to moderate malignant potential by the Armed Forces Institute of Pathology Suggested Guidelines).
Notably in patients taking Gleevec, in the six-ten cm group and the less than ten cm group, the slope of the recurrence–free survival curves increased at about the one and a half year mark, perhaps starting to show the effects of being off of Gleevec after the one year adjuvant treatment period. Acknowledging the still somewhat short follow-up time, we asked Dr. DeMatteo for his comments about the change in slope, “All that can be said is that once Gleevec is stopped, there appears to be a higher chance of recurrence”.
To date, there has been no difference in overall survival for patients in the two groups, although it is 
too early to make a definitive conclusion about how adjuvant Gleevec impacts survival. Although all of the groups seemed to benefit, according to DeMatteo, “From what has been analyzed so far, it appears that those at highest risk (defined by large tumors) benefited the most (See table 2).
”We asked Dr. DeMatteo what he would like patients and their doctors to know about this trial and adjuvant Gleevec for GIST. “While there has been considerable investigation of the role of Gleevec in metastatic GIST, we are just beginning to understand its use in the adjuvant setting. Our ultimate goal of course is to prevent, or at least dramatically delay, the development of tumor recurrence after the resection of a primary GIST. Obviously, we would like to thank all the patients who participated in this randomized trial as well.”
“There should be a lot more coming out in the next year from our studies,” said DeMatteo. “The two European studies will take at least several more years.” These studies will look at different durations of adjuvant Gleevec. The EORTC trial will compare two years of Gleevec (Glivec outside the U.S.) to no treatment and the Scandinavian Sarcoma Group trial compares one year of adjuvant Gleevec to three years of adjuvant Gleevec.
Gleevec dosage/MetaGIST Project
Martine Van Glabbeke presented the results of the MetaGIST project. The two large phase III GIST trials, the US/ Canadian (US-CDN) and European/ Australasia (EU-AUS) trials were originally planned to allow the data to be combined to increase the power and precision of the trials. The USCDN trial had 746 patients and the EU-AUS trial had 946 patients.
The purpose of both trials was to compare two doses of Gleevec; 400 mg vs. 800 mg for both safety/ tolerability and efficacy. The MetaGIST analysis showed a small but statistically significant progressionfree survival (PFS) benefit for the higher dose arm as shown in Table 3.
However, there was no difference in overall survival between the two arms, with a median overall survival of 49 months for both 400 mg and 800 mg. Approximately 60 percent of patients survived for three years. The hazard ratio was 1.00 (no difference) with a P value of 0.97.
The study next looked at whether there were other factors that might affect progression-free survival (PFS) and overall survival independently of the treatment arm. They found that four factors adversely affected both:
• Poor performance status (patients that were sicker at the start of the trial did worse) • High neutrophil count at trial entry
• Absence of KIT exon 11 mutations
• Male gender
Factors that adversely affected PFS but not overall survival were:
• Small bowel origin
• Low hemoglobin at trial entry
Factors that adversely affected overall survival but not PFS were:
• Advanced age
• Low albumin at trial entry
• Large lesions
Si
nce the benefit that could be demonstrated with the intent-to-treat analysis was limited to four months of additional progression-free survival, the investigators wanted to see if there was a subset of patients that would benefit the most from high-dose Gleevec. The only group that was statistically significant was patients with a KIT exon 9 mutation. Although the power to detect differences in this group was limited by the small numbers, exon 9 patients did have a significantly longer progression-free survival time on high-dose Gleevec compared to those starting on low-dose Gleevec. When both the EORTC study and the US/Canadian study were combined, the median PFS was six months for lowdose Gleevec and 19 months for highdose Gleevec (p = 0.017, logrank test). While the benefit of high-dose Gleevec was statistically significant for exon 9 patients (and even for all patients, but with a smaller benefit), the overall median survival benefit of 28 months (lowdose) vs. 35 months (high-dose) did not reach statistical significance for exon 9 patients (p = 0.15). This may be due to the small number of patients in the trial.
Dr. Reichardt’s Presentation
Peter Reichardt, MD, was the discussant for the GIST presentations. He noted that both phase III trials showed some benefit from crossover to a higher dose after progression at 400 mg. The median benefit was 81 days in the EORTC study and four months in the S0033 trial (US/ Canadian). What was noteworthy was that a significant percentage of patients experienced longer-term benefit. In the EORTC trial, 18 percent of patients were progressionfree for one year or more after crossover. In the S0033 trial, 20 percent of patients were progressionfree for two years or more.
Dr. Reichardt noted several limitations that might impact these studies. These included:
• Probable impact of cross-over and second- line (or more) treatment, including surgery on overall survival.
• Small numbers in subgroups other than exon 11.
• Correlation of dose and PFS/OS based on intention-to-treat. Dr. Reichardt showed a slide from the EORTC (courtesy A. Le Cesne) that showed a correlation between increased progression- free survival and the dose of Gleevec that patients actually received (See Figure 1).
• Possible impact of individual PK (pharmacokinetics). 
In his summary on dose, Dr. Reichardt noted the controversy about dose but remarked, “that’s all we will get” (referring to the MetaGIST project). It is unlikely that such a large trial will be repeated in GIST. He also concluded that in the future, first-line trials with a primary end-point of PFS would need to compare to 800 mg of Gleevec in the exon 9 subgroup. This means, according to Reichardt, that any patients would need mutational analysis at the start (of the trial) but there is increasing consensus of the necessity of doing this. We can only hope that in the near future, mutational analysis for first diagnosis of GIST or at a minimum, metastatic GIST will become routine, at least in the major GIST centers.
