Imatinib efficacy by tumor genotype in Korean patients with advanced gastrointestinal stromal tumors (GIST): The Korean GIST Study Group (KGSG) study.

Abstract

Purpose. To assess the efficacy of imatinib for different tumor genotypes in Korean patients with advanced gastrointestinal stromal tumors (GIST). Material and methods. Clinical data were collected from 370 consecutive patients with locally advanced unresectable, metastatic, or recurrent GIST treated with imatinib 400 mg/day between August 2001 and December 2007 at 20 Korean institutions. Tumor genotypes were determined for 290 patients by direct DNA sequencing of KIT exons 9, 11, 13, and 17, and PDGFRA exons 12, 14, and 18. Results. Of 290 patients assessed for genotype, 261 (90.0%) had mutations in KIT: 222 (76.6%) in exon 11, 35 (12.1%) in exon 9 and two each (0.7%) for exons 13 and 17. Four patients (1.4%) had mutations in the PDGFRA gene: one in exon 12, and three in exon 18. Twenty-five patients (8.6%) had no detectable mutations. The best responses of the 235 patients with measurable lesions were: 15 complete response (6.4%), 126 partial response (53.5%), 86 stable disease (36.6%), and eight progressive disease (3.4%). Patients with KIT exon 9 mutations, compared with patients with KIT exon 11 mutations, had a lower objective response rate (36.7% vs. 63.6%, p = 0.007) and a shorter progression-free survival (median 28.7 months vs. 49.4 months, p = 0.001). No statistical difference in overall survival was observed between these genotypes. Conclusion. This study confirms that imatinib efficacy is dependent on genotype in Korean GIST patients, consistent with results demonstrated by Western patients with GIST.

Gastrointestinal stromal tumors (GIST) are mesenchymal neoplasms that arise mainly in the gastrointestinal tract wall, and are characterized by the expression of the receptor tyrosine kinase (RTK) KIT (CD117) [1

,2

]. Activating mutations of KIT are present in up to 92% of GIST, and these mutations are likely to play a fundamental role in the development of these tumors [3–10

]. For GIST with no detectable KIT mutations, activating mutations of the RTK platelet-derived growth factor receptor alpha (PDGFRA) have also been identified [11

,12

]. Furthermore, a subset of GIST possesses no detectable mutations in either RTK [11

,12

]. Imatinib mesylate (Glivec®/Gleevec®, Novartis Pharma AG, Basel, Switzerland) is a competitive inhibitor of the RTKs BCR-ABL, ARG, KIT, PDGFRA, and PDGFRB [13–16

]. The activity of imatinib in GIST was initially demonstrated in a single-patient pilot study of a heavily pretreated patient with bulky advanced-stage metastatic GIST [17 ]. Thereafter, results from the US-Finland B2222 Phase II study confirmed that imatinib was safe and effective at doses of 400 mg and 600 mg daily, and led to imatinib being widely accepted as standard first-line treatment for patients with advanced GIST [18, 19]. Further analysis from the B2222 study by Heinrich and colleagues revealed that the efficacy of imatinib was dependent on GIST primary genotype, that is patients with KIT exon 11 mutations had a higher objective response rate compared with patients with KIT exon 9 mutations (83.5% vs. 47.8%, p = 0.0006) [20

]. Two large-scale, randomized, Phase III trials (European Organization for Research and Treatment of Cancer [EORTC] 62005 and Southwest Oncology Group [SWOG] S0033) were subsequently initiated to compare the clinical benefits of high-dose [800 mg daily (400 mg twice daily)] to standard-dose imatinib (400 mg daily) [21

,22

]. In the EORTC 62005 trial, a significant improvement in progression-free survival (PFS) was initially observed for patients administered imatinib 800 mg/day [22

]. However, the difference observed for PFS between the two dose groups became statistically insignificant with longer follow-up, and no differences in PFS were observed in the SWOG S0033 trial [21

,23

]. Moreover, no significant differences in objective response or disease control rates (DCRs; defined as percentage of patients with an objective response or stable disease) were observed between the two dose groups in either the EORTC 62005 or SWOG S0033 trial. Although no significant differences in PFS were observed between the dose groups overall, a subanalysis from the EORTC 62005 trial revealed that patients with KIT exon 9 mutations had superior PFS when initially treated with high-dose imatinib [24

]. A pooled meta-analysis of the SWOG S0033 and EORTC 62005 trials (MetaGIST) further revealed that the estimated risk of progression or death was reduced by 42% in the high-dose cohort compared with the standard dose cohort (p = 0.017, Wald test) for patients with KIT exon 9 mutations [25

]. These results spurred the European Society for Medical Oncology and the National Comprehensive Cancer Network to update their guidelines to include the use of high-dose imatinib in patients with KIT exon 9 mutations; this development represented the first major incorporation of mutational status in treatment decision making for GIST [26

,27

]. To date, no large-scale prospective studies have compared the clinical benefit of imatinib treatment for different GIST genotypes in Asian patients [28–30

]. However, in two small retrospective studies of imatinib-treated Korean and Taiwanese patients with GIST, no significant differences were observed in clinical outcomes with regard to primary genotype [response rates, PFS, and overall survival (OS)] [29

,30

]. Genotype-specific differences in the efficacy of imatinib may not have been observed due to the small sample sizes in these studies and/or potentially higher imatinib plasma levels in Asian patients compared with Western patients as a result of a smaller body size. Therefore, to further investigate if treatment outcome is dependent on tumor genotype in Asian patients with GIST, we initiated a large retrospective analysis that evaluated whether a potential relationship between clinical response and genotype exists in a cohort of consecutive Korean patients with advanced GIST who were treated with imatinib.