Sunitinib Malate as a Second-Line Therapy for Metastatic GIST

        The primary therapy for GIST is surgery, but for cases that are metastatic or unresectable, a tyrosine kinase inhibitor alone or in addition to surgery is the next option. Imatinib mesylate, or Gleevec, is usually the drug given to GIST patients, but as Shiona previously discussed, about 15% of patients with GIST exhibit primary resistance or intolerance to Imatinib. A therapy option available to these patients is Sunitinib malate(Sutent), a multi-targeted tyrosine kinase inhibitor.



        Multi-targeted tyrosine kinase inhibitors are especially advantageous because they target the surrounding supporting cells in addition to the tumor itself, and resistance is less likely to occur. Also, taking one multi-targeted drug is preferable to taking many single-targeted inhibitor because it decreases drug-drug interactions and toxicity. Sunitinib's multi-targeted features include anti-angiogenic and anti-tumor properties. By inhibiting angiogenesis and growth factor receptors, Sunitinib has proven to be an effective GIST therapy(1).
        To prevent angiogenesis, Sunitinib targets tyrosine kinase receptors VEGFR1, VEGFR2, and VEGFR3. VEGFR1&2 are associated with endothelial angiogenesis while VEGFR3 is associated with lymphangiogenesis(2). VEGFR3 inhibition is important in cancer that has metastasized in the lymph nodes. Sunitinib works by binding to the tyrosine kinase receptors which prevents the vascular endothelial growth factors from binding and promoting angiogenesis. In angiogenesis in healthy tissue, it quickly becomes stable and stops growing. However, in cancerous tissue, angiogenic growth factors are over expressed causing rapid and continuous angiogenesis, allowing for tumor progression(1).


        One Phase III clinical trial was performed to test the efficacy of Sunitinib malate vs. a placebo. This double blind RCT was performed by treating the patients with Sunitinib in a 2:1 ratio those treated with the placebo(3).

Table II. Efficacy results for sunitinib malate in patients with gastrointestinal stromal tumour who have developed resistance or who exhibit intolerance to imatinib mesylate

        As seen in Table II, patients treated with Sunitinib had a significantly longer progression-free survivals than those treated with the Placebo, and there was a 4-fold increase in median weeks of progression-free survival with Sunitinib(3). With a p Value of <0.001 the sample size seems to be sufficient, however, the 2:1 ratio of Sunitinib treated patients to placebo treated patients could raise some questions. Is it possible to have the same confidence in both sets of data if one is half the size of the other? That aside, the results from this RCT support that Sunitinib malate is an adequate treatment of GIST in patients who have developed and intolerance or resistance to Imatinib. 

1. Faivre, Sandrine, George Demetri, William Sargent, and Eric Raymond. "Molecular basis for sunitinib efficacy and future clinical development." N.p., Sept. 2007. Web. 21 May 2014. <ftp://sogr.idv.tw/%AEa%B1%DA%C0%C9%AE%D7%B3%C6%A5%F7/%C4%AC%A4h%BB%A8/reference/1.pdf>.

2. "Interactions of VEGF ligands and VEGF receptors." Biooncology. Genentech, 2014. Web. 21 May 2014.                        <http://www.biooncology.com/research-education/vegf/vegf/vegf-pathway/receptors>.

3. Younus, J., S. Verma, J. Franek, and N. Coakley. "Sunitinib malate for gastrointestinal stromal tumour in imatinib mesylate–resistant patients: recommendations and evidence." NCBI. N.p., Aug. 2010. Web. 21 May 2014. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913827/>.