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Doubling the dose of imatinib in patients with unresectable or metastatic gastrointestinal stromal tumors provides a small gain in progression-free survival but does nothing to improve overall survival, according to a meta-analysis of two separate international studies.
Most of the gain was seen in patients with KIT exon 9 mutations, said Dr. Martine M. Van Glabbeke. "Starting imatinib therapy at a daily dose of 800 mg in [those patients with] KIT exon 9 mutants will improve progression-free survival, but there is no evidence that it will prolong overall survival."
At a median follow-up of 45 months, progression-free survival was 23 months in the 800-mg arm and 19 months in the 400-mg arm, said Dr. Van Glabbeke, of the Gastrointestinal Stromal Tumors (GIST) Meta-Analysis Group, Brussels.
The 3-year estimated progression-free survival was 4% higher and the risk reduction for progression was 11% (P = .04).
Median overall survival was 49 months in both arms.
The MetaGIST project, which was funded by Novartis, was based on 1,640 patients in two previously published phase III studies:
Using multivariate analysis, the investigators identified four factors that significantly affected both progression-free and overall survival, including poor performance status, high neutrophil count at trial entry, male gender, and the absence of KIT exon 11 mutations.
Both overall and progression-free survival were doubled in patients with exon 11 mutations, compared with those who had exon 9 mutations, Dr. Van Glabbeke said.
A subpopulation analysis revealed that the only factor to significantly affect the relative benefit of high-dose imatinib was the presence versus absence of KIT exon 9 mutations, which was found to be significant for progression-free survival but not for overall survival, she explained.
"Patients with and without exon 9 mutations had median progression-free survivals of 6 months and 19 months, and produced 3-year progression-free [survival] estimates of 5% and 17%, respectively," she said.
For all other patients, the progression-free survival curves were "completely superimposed," Dr. Van Glabbeke pointed out.
A similar pattern was seen for overall survival, but the differences were not statistically significant.
The crossover of 210 patients to the high-dose arm because of treatment failure is an important aspect of this analysis, according to discussant Dr. Peter Reichardt.
"Both trials consistently show that crossing over provided a benefit of 30% to 40%, and the median duration of the efficacy for this crossover is shorter compared to other second-line treatment options, and that is very important," said Dr. Reichardt, with Charité Campus Buch, Berlin.
"There is a proportion of patients (10% to 20%) who derive a very substantial and durable progression-free survival benefit by the crossover," he said.
Dr. Reichardt added that crossovers and treatments other than imatinib, including surgery, may have confounded the analysis of overall survival.
"Some of these patients who crossed over lived beyond 4 years, and the median survival after crossover was about 1 year," Dr. Reichardt said.
"Any first-line trial using the primary end point of progression-free survival will now need to compare to 800 mg of imatinib in the KIT exon 9 subgroup," Dr. Reichardt concluded.
"This means that patients would need mutational analysis at the start, but there is increasing consensus on the necessity of doing this, and we can only hope that in the near future mutational analysis for first diagnosis of metastatic GIST will become routine, at least in the majority of GIST-specified centers."
Van Glabbeke M.M. et al. Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST): A meta-analyis based on 1,640 patients (pts). Abstract 10004.
Commentary |
At the outset, these two studies were independently conducted, and it's pleasing to see these data brought together to provide a more detailed understanding of the role of imatinib in the multiple, small subgroups that constitute this disease. While progression-free survival showed some apparent benefit from the higher dose of imatinib in this large meta-analysis, most authorities in the field recommend a starting dose of 400 mg in unselected patients. At progression, patients can then be escalated to the 800-mg dose of imatinib. What this analysis clearly demonstrates (albeit in a relatively small number of patients, despite the combined efforts of both trial centers) is that for patients with a tumor carrying an exon 9 mutation, there appears to be a real benefit in starting at the higher dose of imatinib. Less clear from this analysis is whether these patients would have similar outcomes by starting at the lower dose and then escalating to 800 mg versus starting at 800 mg ab initio. The size of the benefit and the rapid progression seen in this group has led most experts in the field to suggest using the higher dose at the outset when possible in this subgroup of patients. Although tumors carrying these mutations represent a less than 10% likelihood of gastrointestinal stromal tumors (GISTs) overall, it's difficult to predict which tumors are likely to have these mutations on clinical grounds (although exon 9 mutations are more common in GISTs arising in the small bowel): hence the recommendations that mutation testing become the standard of care. Access to this technology is not necessarily widespread around the world, although the methodology is not particularly complex or time consuming. — Malcolm J. Moore, M.D.
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