Sunitinib (SU) response in imatinib-resistant (IM-R) GIST correlates with KIT and PDGFRA mutation status

Abstract

9502 Background: IM resistance in advanced GIST represents a major clinical problem. SU (SU11248) is an oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities related to KIT, PDGFRs, VEGFRs, RET and FLT3 inhibition. SU has demonstrated efficacy in clinical trials of pts with IM-R GIST. Methods: This study examined the relationship between tumor kinase genotypes and SU clinical activity in 97 pts with metastatic IM-R GIST treated as part of a phase I/II trial. Tumors were imaged by CT or MRI for RECIST-defined response assessment. Tumor specimens were obtained prior to (n=76) and following (n=64) IM therapy and analyzed for primary or secondary KIT and PDGFRA mutations, respectively. Results: Clinical benefit (CB; defined as PR or SD >6 months) with SU was observed for all major molecular GIST subtypes: KIT exon 11 (42 pts, CB 36%), KIT exon 9 (19 pts, CB 42%), PDGFRA (4 pts, CB 25%), no KIT or PDGFRA mutation (wild-type [WT]; 9 pts, CB 56%). Notably, the PR rate for GISTS with primary KIT exon 9 mutations was 37%, vs 5% for KIT exon 11 mutations (P=0.003). PFS and OS were significantly longer for pts with either a primary KIT exon 9 mutation or WT KIT/PDGFRA compared with pts with a KIT exon 11 mutation (exon 9 vs 11: PFS P=0.0007, OS P=0.005; WT vs exon 11: PFS P=0.03, OS P=0.01). Secondary KIT mutations (in exons 13, 14, 17 or 18) were found in 62% of GISTs with a primary KIT exon 11 mutation, but only in 16% with a primary KIT exon 9 mutation (P=0.002). No secondary mutations were found in GISTs lacking a primary KIT/PDGFRA mutation. Biochemical profiling of secondary kinase mutations revealed in-vitro sensitivity of KIT exon 13 and 14 mutations to SU, while secondary KIT exon 17 and 18 mutations were resistant to SU in vitro. These in-vitro results were consistent with clinical results: CB was observed in 65% of pts with secondary KIT mutations in exon 13 or 14 and in only 9% of pts with secondary KIT exon 17 or 18 mutations (P=0.006). Conclusions: Our findings suggest that, similar to prior results observed using imatinib, CB of SU following failure of IM treatment is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinase, the uncontrolled activity of which is a critical etiologic factor for GIST. [Table: see text]