Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group.

Abstract

PURPOSE:

Imatinib mesylate is standard treatment for patients who have advanced gastrointestinal stromal tumor (GIST), but not all patients benefit equally. In previous studies, GIST genotype correlated with treatment outcome and optimal imatinib dosing.

PATIENTS AND METHODS:

We examined the relationship between kinase genotype and treatment outcome for 428 patients enrolled on the North American phase III study SWOG S0033/CALGB 150105 and treated with either 400 mg or 800 mg daily doses of imatinib.

RESULTS:

The presence of KIT exon 11-mutant genotype (n = 283) correlated with improved treatment outcome when compared with KIT exon 9-mutant (n = 32) and wild-type (WT; n = 67) genotypes for objective response (complete response [CR]/partial response [PR], 71.7% v 44.4% [P = .007]; and 44.6% [P = .0002], respectively); time to tumor progression (TTP; median 24.7 months v 16.7 and 12.8 months, respectively); and overall survival (OS; median 60.0 months v 38.4 and 49.0 months, respectively). The survival outcomes for patients with exon 9-mutant, exon 11-mutant or WT GIST were not affected by imatinib dose. However, there was evidence of improved response rates for patients with exon 9-mutant tumors treated with imatinib 800 mg versus 400 mg (CR/PR, 67% v 17%; P = .02). Patients who had CD117-negative GIST had similar TTP but inferior OS compared with patients who had CD117-positive disease, which suggests that patients who have CD117-negative GIST may benefit from imatinib treatment. In addition, we identified novel but rare mutations of the KIT extracellular domain (exons 8 and 9).

CONCLUSION:

We confirmed the favorable impact of KIT exon 11 genotype when compared with KIT exon 9 and wild-type genotype for patients with advanced GIST who are treated with imatinib.

• Authors: Michael C Heinrich, Kouros Owzar, Christopher L Corless, Donna Hollis, Ernest C Borden, Christopher D M Fletcher, Christopher W Ryan, Margaret von Mehren, Charles D Blanke, Cathryn Rankin, Robert S Benjamin, Vivien H Bramwell, George D Demetri, Monica M Bertagnolli, Jonathan A Fletcher
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 26 Issue 33 Pg. 5360-7 (Nov 20 2008) ISSN: 1527-7755 [Electronic] United States
• PMID: 18955451 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Benzamides
• Piperazines
• Pyrimidines
• Imatinib Mesylate
• Proto-Oncogene Proteins c-kit
• Receptor, Platelet-Derived Growth Factor alpha

Topics

• Benzamides
• Disease-Free Survival
• Gastrointestinal Stromal Tumors (drug therapy, genetics, mortality, pathology)
• Genotype
• Humans
• Imatinib Mesylate
• Mutation
• Piperazines (therapeutic use)
• Proto-Oncogene Proteins c-kit (genetics)
• Pyrimidines (therapeutic use)
• Receptor, Platelet-Derived Growth Factor alpha (genetics)
• Survival Rate