SU11248, a multi-targeted tyrosine kinase inhibitor, can overcome imatinib (IM) resistance caused by diverse genomic mechanisms in patients (pts) with metastatic gastrointestinal stromal tumor (GIST)

Abstract

3001 Background: Resistance to Imatinib mesylate (IM) following initial tumor regression and disease control in GIST is increasingly recognized as an unmet medical need. IM resistance can be correlated with the appearance of secondary mutations in the KIT or PDGFRA tyrosine kinases in GIST lesions refractory to IM; activation of alternative signaling pathways and different structural biology of the new mutant kinases contribute to emergence of IM-resistant GIST clones. Methods: Phase I/II clinical trial of SU11248 in pts with progressing IM-resistant GIST. Tumor biopsies were obtained to define the mutational status of the KIT and PDGFRA kinases by dHPLC and sequencing assays. Results: 98 pts with progressive GIST have been enrolled in this ongoing study; with tumor response data available in 48 pts and GIST genotype determined in 41. The phase II regimen chosen was SU11248 50 mg orally once daily for 4 weeks, followed by a 2 week period off drug in each 6 wk cycle. SU11248 therapy induced clinical benefit (defined by objective response or stable disease for ≥ 6 months) in 26/48 (54%) of these previously progressing pts, with 6/48 (13%) confirmed partial responses (PR). KIT exon 9 mutants had fewer secondary mutations than Exon 11 GIST. Conclusions: SU11248 therapy can induce objective responses and control progressive disease in pts with several mutational variants of GIST with different genomic mechanisms of resistance to IM. These data are the basis for a phase III trial to define further the activity of SU11248 in pts with IM-resistant GIST. Understanding the efficacy of SU11248 in IM-resistant GIST should help to elucidate the structural biology of PDGFRA, KIT and other aberrant signaling pathways in the pathogenesis of GIST and may have relevance to molecularly targeted therapies for other malignancies. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Novartis; Pfizer Pfizer Novartis; Pfizer Pfizer Oncology