Approaches to Imatinib-resistant GIST
Gastrointestinal stromal tumors (GIST) are the most common sarcomas, with about 3000 - 3,500 cases reported each year.
The standard of care for locaized GIST is surgical resection.
Unfortunately, the recurrence rate can be as high as 60-80% in some series of high-risk GIST patients (pts).
The standard of care in metastatic GIST is imatinib (Gleevec), a tyrosine kinase inhibitor that blocks several proteins, including c-kit and PDGFR.
Over 90% of GISTs have c-kit and PDGFR mutations.
The accepted dose of imatinib is 400 mg daily, as no improvement in either overall survival (OS) or progression-free survival (PFS) was seen with 800 mg daily in a randomized study of 946 pts (Verweij et al. Lancet 2004).
Studies are underway looking at post-operative administration of imatinib (brand name Gleevec) in the non-metastatic setting.
Imatinib resistance is increasingly seen in pts, and is thought to result from new c-kit mutations or altered tumor kinase activity.
For pts with metastatic disease who are on imatinib but have progression of disease, local surgery is one treatment option if the disease progression is localized. This approach would not be recommended for pts with multiple areas of disease growth. After surgery, many would recommend continuing pts on a higher dose of imatinib.
If surgery is not an option, there are many new agents emerging for imatinib-resistant GIST. Among these are SU11248, or sunitinib, and rapamycin analogues. There are many other anti-kit drugs in various stages of research and development.
A phase I/II study of sunitinib achieved stable disease lasting 6 months in 37% of pts (RECIST trial). The most common adverse effects in this study were grade 1-2 fatigue and diarrhea. Otherwise sunitinib appeared to be well-tolerated. Time to tumor progression (TTP) was much lower for pts with exon 11 kit mutations, as compared to pts with exon 9 mutations or wildtype kit.
A phase III study of sunitinib vs. placebo in pts with imatinib resistance found TTP of 6.3 months vs. 1.5 months, respectively (Demetri, PASCO 2005), with an OS hazard ratio of 0.49 (p<0.007).
Thus sunitinib appears to be very promising in the setting of imatinib resistance. Interestingly, resolution of PET scan activity may be a sensitive way to assess disease response to sunitinib. An open label therapy program is currently underway.