Longer Progression-Free Survival at Higher-Dose Imatinib in GIST
Results from the two largest clinical trials (combined n=1640) ever conducted in gastrointestinal stromal tumors (GIST) show longer progression-free survival (PFS) with high-dose imatinib (800 mg daily) compared with standard dose (400 mg daily). They suggest also, stated Martine Van Glabbeke, PhD, speaking for the GIST Meta-analysis Group, that high-dose therapy benefits depend on mutation type.
The two randomized, intergroup phase 3 trials were conducted among patients with unresectable or metastatic GIST expressing the KIT receptor tyrosine kinase (CD117). One, conducted in the US and Canada (US-CDN, n=694), had overall survival (OS) as its primary endpoint, and the other, conducted in Europe, Australia, and Asia (EU-AUS, n=946), had PFS as its primary endpoint. The trials, planned together, had wide entry criteria, including performance status up to 3, with no upper age limit and prior therapy permitted. In both trials, patients received either imatinib 400 mg daily or 800 mg daily until progression, with crossover to the higher dose allowed after progression in the 400 mg group. Mutation data were gathered in a total of 772 cases.
The meta-analysis aims were to compare results between the two trials, to build prognostic models for PFS and OS, and to characterize patients who may benefit from the high-dose therapy. Median follow-up was 55/42 months in the US-CDN/EU-AUS trials.
PFS and OS were consistent between the two trials, Dr. Van Glabbeke said. In the combined trials, median PFS was 19/23 months in the 400 mg/800 mg groups, respectively, a small but significant increase for the higher dose (HR 0.89, p=0.04). Median OS was identical (49 months, HR 1.00).
Multivariate prognostic analysis revealed four factors adversely affecting both PFS and OS: poor performance status, high neutrophil count at trial entry, absence of KIT exon 11 mutations, and male gender. Small bowel origin and low hemoglobin at trial entry adversely affected PFS. OS was adversely affected significantly by advanced age, low albumin at trial entry, and large lesions.
Median PFS and median OS (months) for KIT exon 11 mutants/KIT exon 9 mutants/wild-types/other were 26/60, 13/31, 16/43, and 11/34, respectively. Dr. Van
Glabbeke noted that cases with KIT exon 11 mutants had doubled PFS and nearly doubled OS as compared with those with KIT exon 9 mutants.
Because of the modest 11% benefit in PFS, investigators looked for subpopulations with higher potential benefit from high-dose therapy. They found that only the presence or absence of KIT exon 9 mutations significantly affected the relative PFS (p=0.015) benefit of high-dose therapy. The interaction was not significant for OS (p=0.071). PFS with KIT exon 9 mutants was 6 months at 400 mg and 19 months at 800 mg (p=0.017); OS was 28/35 months (p=0.15).
Dr. Van Glabbeke concluded, “Treatment with high- dose imatinib compared with standard dose results in a small but statistically significant PFS advantage, but this does not affect OS. …There is statistically significant evidence that the relative benefit of high-dose therapy depends on the mutation type.” She added that starting imatinib therapy at a daily dose of 800 mg in KIT exon 9 mutants will improve PFS, but there is no evidence that it will prolong survival.
Imatinib Increases Recurrence-Free Survival in Completely Resected GIST
Among patients with resectable gastrointestinal stromal tumors (GIST), adjuvant imatinib mesylate at 400 mg/day for a year increases recurrence-free survival (RFS) and is safe and well tolerated. The finding emerged from the North American Intergroup phase 3 trial ACOSOG Z9001, which included patients with completely resected, localized primary GIST.
Ronald DeMatteo, MD, Memorial Sloan-Kettering Cancer Center, New York, noted that GIST is the most common sarcoma of the intestinal tract, and further that more than 90% of GIST tumors have a KIT or PDGFRa mutation. Clinical trial experience has shown imatinib mesylate to provide benefit in more than 80% of patients with metastatic GIST. For patients with localized primary GIST, surgery has been the gold standard, Dr. DeMatteo said, and currently among patients with unresectable tumors, imatinib is the standard of care.
The question naturally arose whether imatinib would be beneficial given to patients with primary GIST just after surgery. Before the development of imatinib, when there were no therapies available, 5-year survival was
Continued on page 34 Highlights from the American Society of Clinical Oncology Annual Meeting 2007 27
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