Primary and Secondary Kinase Genotypes Correlate With the Biological and Clinical Activity of Sunitinib in Imatinib-Resistant Gastrointestinal Stromal Tumor

Abstract

A B S T R A C T PurposeMost gastrointestinal stromal tumors (GISTs) harbor mutant KIT or platelet-derived growth factor receptor ␣ (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. Patients and MethodsTumor 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. ResultsClinical benefit (partial response or stable disease for Ն 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 ϭ .0005) or with a wild-type genotype (P ϭ .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. ConclusionThe 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.

Mutational spectrum and therapy response of metastasized GIST in Central Switzerland – A population-based study

“…The other wild type patient died of disease, showing a rapid tumour progression during tyrosine kinase inhibitor treatment (Imatinib, Sunitinib). This poor response of wild type GIST patients was also repeatedly reported in literature (9,(11)(12).…”

“…This is the rationale for the treatment option with tyrosine kinase inhibitors like Imatinib (Gleevec®, Novartis, Switzerland) or Sunitinib (Sutent®, Pfizer, USA). The localisation of these mutations determines the efficiency of these substances, to inhibit the stimulatory effect of c-kit and PDGFR proteins on cell growth (11)(12).…”

Gastrointestinal stromal tumors: what do we know now?

“…Exon 11-mutant KIT is highly sensitive to imatinib, with an IC 50 of o100 nM, whereas exon 9-mutant KIT and wild-type KIT are less sensitive to the drug (IC 50 B1000 nM for each). 126 Thus, underdosing of imatinib in patients with exon 9 mutations probably accounts for some of the apparent resistance. 112 On the basis of in vitro data, the most common PDGFRA mutation in GISTs, D842V, is fully resistant to the effects of imatinib.…”

What drives the wheel towards long-term outcome in advanced GIST, its size, genotype or may be a pill or two of imatinib?

“…The benefit with sunitinib (27.3 vs. 6.4 weeks), regorafenib (4.8 vs. 0.9 months), while statistically and potentially clinically significant, does not compare with the PFS on first line therapy with imatinib, irrespective of mutation status (7,8). While there is evidence for a preferential benefit of sunitinib in exon 9 mutants, the PFS benefit with firstline imatinib should be maximized and this has been brought out well in the current study (13). It would have been extremely informative if secondary mutation status on repeat biopsies would have been available in patients progressing on imatinib, but this was not feasible when the study was planned.…”