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Originally published as JCO Early Release 10.1200/JCO.2007.15.7461 on October 27 2008 © 2008 American Society of Clinical Oncology. Primary and Secondary Kinase Genotypes Correlate With the Biological and Clinical Activity of Sunitinib in Imatinib-Resistant Gastrointestinal Stromal Tumor
From the Oregon Health and Science University Cancer Institute and Portland Veterans Affairs Medical Center, Portland, OR; Memorial Sloan-Kettering Cancer Center, New York, NY; Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; and Pfizer Global Research and Development, La Jolla, CA Corresponding author: Michael C. Heinrich, MD, Division of Hematology/Oncology, Departments of Medicine and Cell and Developmental Biology, Portland Veterans Affairs Medical Center and Oregon Health and Science University Cancer Institute, R&D-19, 3710 SW US Veterans Hospital Rd, Portland, OR 97239; e-mail: Heinrich{at}ohsu.edu
Purpose Most gastrointestinal stromal tumors (GISTs) harbor mutant KIT or platelet-derived growth factor receptor Patients and Methods Tumor responses were assessed radiologically in a phase I/II trial of sunitinib in 97 patients with metastatic, imatinib-resistant/intolerant GIST. KIT/PDGFRA mutational status was determined for 78 patients by using tumor specimens obtained before and after prior imatinib therapy. Kinase mutants were biochemically profiled for sunitinib and imatinib sensitivity.
Results Clinical benefit (partial response or stable disease for Conclusion The clinical activity of sunitinib after imatinib failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases, which has implications for optimization of the treatment of patients with GIST. published online ahead of print at www.jco.org on October 27, 2008 Supported in part by Pfizer Inc, by National Cancer Institute (NCI) Grant No. CA 47179, by NCI Specialized Program of Research Excellence in Gastrointestinal Cancer Grant No. 1P50CA127003-01, by a Veterans Affairs Merit Review Grant, by the Life Raft Group, and by philanthropic support from the following sources: the Virginia and Daniel Ludwig Trust for Cancer Research, the Rubenstein Foundation, the Katz Foundation, the Quick Family Fund for Cancer Research, the Ronald O. Perelman Fund for Cancer Research at Dana-Farber, the Stutman GIST Cancer Research Fund, Leslie's Links, Abolish Cancer Today, and the Shuman Family Fund for GIST Research. Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL; the 13th European Cancer Conference, October 30-November 3, 2005, Paris, France; the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA; and the 1st American Association for Cancer Research Conference on Molecular Diagnostics in Cancer Therapeutic Development, September 12-15, 2006, Chicago, IL. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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(PDGFRA) kinases, which are imatinib targets. Sunitinib, which targets KIT, PDGFRs, and several other kinases, has demonstrated efficacy in patients with GIST after they experience imatinib failure. We evaluated the impact of primary and secondary kinase genotype on sunitinib activity. 
6 months) with sunitinib was observed for the three most common primary GIST genotypes: KIT exon 9 (58%), KIT exon 11 (34%), and wild-type KIT/PDGFRA (56%). Progression-free survival (PFS) was significantly longer for patients with primary KIT exon 9 mutations (P = .0005) or with a wild-type genotype (P = .0356) than for those with KIT exon 11 mutations. The same pattern was observed for overall survival (OS). PFS and OS were longer for patients with secondary KIT exon 13 or 14 mutations (which involve the KIT-adenosine triphosphate binding pocket) than for those with exon 17 or 18 mutations (which involve the KIT activation loop). Biochemical profiling studies confirmed the clinical results. 
