Sutent is an orally-available small-molecule multiple receptor tyrosine kinase inhibitor. Receptor tyrosine kinases are implicated in a number of cell-cell signaling pathways governing angiogenesis, cell division and growth, and cell survival. By disrupting these systems, Sutent inhibits the ability of tumor cells to divide and grow.
Sutent is specifically indicated for the treatment of a pair on oncology indications: gastrointestinal stromal tumors (GIST) that are refractory to or have relapsed following treatment with imatinib; and advanced renal cell carcinoma (RCC).
Sutent is supplied as a hard gelatin capsule for oral administration. The recommended initial dose regimen is 50 mg once daily for 4 weeks, followed by 2 weeks off treatment. Dose may be adjusted up or down in 12.5 mg increments, based on patient response and tolerability.
FDA Approval: GIST
Approval of Sutent for the treatment of GIST was based on two studies, dubbed Study A and Study B.
This two-arm, international, randomized, double-blind, placebo-controlled study enrolled 312 patients, who received either 50 mg Sutent (n=207) or placebo (n=105) once daily for 4 weeks, followed by 2 weeks off, until evidence of disease progression was observed. Sutent was shown to significantly increase median time to tumor progression, to 27.3 weeks, vs. 6.4 weeks for placebo (p<0.0001). Secondary efficacy was also established, with the drug producing progression free survival (24.1 weeks, vs. 6.0 weeks; p<0.0001) and an objective response rate (6.8% vs. 0%; p=0.006) superior to placebo.
This open-label, multi-center, single-arm, dose-escalation study was designed to investigate the objective tumor response rate for Sutent therapy. The trial enrolled 55 subjects, who received 50 mg Sutent once daily on the 4-weeks on/2-weeks off schedule. Trial data yielded confirmed partial responses in 5 subjects, a 9.1% objective response rate.
FDA Approval: RCC
Approval of single-agent Sutent for the treatment of RCC was based on a pair of single-arm, multi-center studies.
This trial enrolled 106 patients who had failed prior cytokine therapy (as defined by radiographic evidence of disease progression (RECIST or WHO criteria) within 9 months of completion of a cytokine regimen). The trial was designed to investigate the objective response rate of Sutent therapy. Subjects received daily doses of 50 mg Sutent on the 4-weeks-on/2-weeks-off schedule until evidence of disease progression or eligibility for withdrawal was met. Sutent was shown to produce objective tumor responses (Partial responses) in 25.5% of subjects (n=27), with a median duration of response to date of 27.1 weeks (these data were immature at the time of approval, as 41.5% of subjects remained on protocol without evidence of progression to date).
Study 2 utilized a similar design to trial 1, treating 63 RCC patients failing cytokine therapy (as defined by evidence of disease progression or unacceptable treatment-related toxicity) on the 50 mg, 4/2 regimen. This study was also designed to investigate objective response rate and duration of response. In this study, Sutent produced partial tumor responses in 36.5% of subjects (n=23), with a median response duration of 54 weeks. At the time of approval, 11 patients remained on protocol, with ongoing disease responses.
Ongoing Study Commitments
Adverse events associated with the use of Sutent for the treatment of GIST may include, but are not limited to, the following:
Adverse events associated with the use of Sutent for the treatment of RCC may include, but are not limited to, the following:
Significant incidence of serious (Grade 3/4) hematological abnormalities (including neutropenia, anemia, lymphopenia, thrombocytopenia and leukopenia) was observed. Patients should work in close concert with their physicians to manage these effects.
In addition, Sutent has been associated with reductions in left-ventricular ejection fraction, including some falls to levels below the lower limit of normal. Use of Sutent in patients with cardiac conditions, including congestive heart failure (CHF), should be pursued only in close consultation with patients' physicians, and it is recommended that treatment be discontinued in patients who manifest CHF symptoms while on Sutent therapy.
Sutent is designed to inhibit multiple receptor tyrosine kinases, including platelet-derived growth factor receptors (PDGFR-alpha and PDGFR-beta), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). A number of these kinases have been implicated in tumor growth, pathologic angiogenesis, and cancer metastasis.
For additional information regarding Sutent, Gastrointestinal Stromal Tumors or Renal Cell Carcinoma, please visit the Sutent web page.
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