Why SU11248 works when Gleevec fails

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)

In his presentation last June (see the link above) at the 40th annual meeting of the American Society of Clinical Oncology, Dr. George Demetri speculated on why Pfizer’s SU11248 works where Gleevec fails: — SU11248 could interact differently with structural variants of new kinase mutants in GIST clones resistant to Gleevec. — The simultaneous inhibition of multiple signaling pathways (such as VEGF, in addition to PDGFRA and KIT) by SU11248 may be important for controlling GIST.

Mutations in the c-kit gene (85-90 percent), or a closely related gene, PDGFRA (5 percent), appear to be the primary genetic defects that cause GIST. Mutations typically occur in exon 11 (67 percent) or exon 9 (18 percent) of the c-kit gene. One of the most common forms of resistance to Gleevec appears to be the acquisition of a second mutation in the c-kit gene. In these cases, in addition to the initial primary mutation (typically in exon 11 or exon 9), a second mutation occurs in some tumors.

These secondary mutations typically result in resistance to Gleevec. Secondary mutations have been reported in exons 13, 14, 15, and 17 of the c-kit gene.

While surgery or other intervention, such as radiofrequency ablation (RFA), may be a way to deal with some of these rogue tumors, these approaches may not be feasible due to location, size or other problem. SU11248 appears to have activity against at least some of these secondary mutations.

At the ASCO meeting, Demetri reported that tumors with secondary KIT mutations in exons 13 and 14 were “highly sensitive” to SU11248, with a 56 percent of patients benefiting. Of 16 patients, two had a “RECIST response” (significant shrinkage), and nine had stable disease for at least six months. Demetri found that patients with secondary KIT mutations in exon 17 were less sensitive to SU11248. In this small group, three of eight patients (38 percent) had stable disease lasting at least six months, but there were no RECIST responses.

Treatment with Gleevec is typically more effective in patients with an exon 11 mutation and somewhat less effective in patients with an exon 9 mutation. Interestingly, SU11248 appears to have the opposite activity profile, at least in Gleevec-resistant patients. In these patients, it appears to be more effective in those with exon 9 mutations, with a 40 percent RECIST response and another 40 percent achieving stable disease. It appears to be less effective in Gleevec resistant patients with exon 11 mutations.

Patients without KIT or PDGFRA mutations (called “wild-type” KIT/ PDGFRA), are another group of GIST patients that typically do not respond to Gleevec but seem to benefit from SU11248. In the small group reported at ASCO, four of nine patients had stable disease for at least six months, and one had a RECIST response.