EORTC Study: Progression-free survival improves for 800 mg vs. 400 mg patients

New study shows initial treatment with 800 mg/ day Gleevec® significantly improved progressionfree survival in group of high-risk GIST patients with exon 9 mutations.

• Investigation of high-dose Gleevec regimen significantly reduces relative risk of progression by 61 percent in patients with exon 9 mutation

• Authors recommend these patients receive 800 mg/day at start of therapy

East Hanover, May 5, 2006 – A higher, investigational starting dose of Gleevec® (imatinib mesylate) tablets can improve outcomes for high-risk patients with advanced Kit-positive gastrointestinal stromal tumor (GIST) expressing exon 9 mutation, according to new findings from the largest clinical trial to evaluate the drug’s effects by mutation. The study findings are now available online and are expected to be published in May. The clinical trial, an EORTC (European Organisation for Research and Treatment of Cancer) Phase III study, compared two doses of Gleevec in patients with unresectable and/or metastatic Kit (CD117) positive GIST. While the majority of patients derived benefit from taking 400 mg/day of Gleevec, the study showed that patients whose tumors expressed a mutation on a certain gene segment called exon 9 had significantly superior progression-free survival (P=0.0013) when administered Gleevec at the investigational dose of 800 mg/ day.

“This latest study provides further evidence that Gleevec is a highly effective therapy for patients with advanced Kitpositive GIST, and offers insight into potential ways to improve long-term outcomes for these patients,” said Diane Young, Vice President and global head of Clinical Development at Novartis Oncology. “These data also highlight that the investigational dose of 800 mg/ day may be more effective for high-risk patients expressing the exon 9 mutation.”

In this study, investigators analyzed data from a recent randomized EORTC Phase III trial comparing two doses of Gleevec (400 mg/day vs. 800 mg/day) in patients with unresectable and/or metastatic Kit-positive GIST, to assess whether tumor genotype correlated with the dose-dependent clinical response to Gleevec. Pre-treatment samples of GISTs from 377 patients enrolled in the clinical trial were analyzed for mutations of Kit and platelet-derived growth factor receptor alpha. The presence of a Kit exon 9 mutation was the strongest adverse prognostic factor for response to Gleevec, increasing relative risk of progression by 171percent (P <0.0001) compared to Kit exon 11 mutations. In patients whose tumors expressed a Kit exon 9 mutation, treatment with the high-dose regimen resulted in a significantly superior progression-free survival (P=0.0013), with a reduction of the relative risk of 61 percent.

Note: This is a very important paper that has been published by the European Journal of Cancer. There is more relevant information in this article than just the link to progression-free survival and exon-9 mutations. We plan to discuss this paper with some key people and we will provide more in-depth coverage in a later issue.