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.

Study A
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.

Study B
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.

Study 1
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
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

• Provide the response rate and duration of response data from the first interim efficacy analysis of study titled "A Phase 3, Randomized Study of SU011248 versus Interferon-a as First-Line Systemic Therapy for Patients with Metastatic Renal Cell Carcinoma". Also, submit the comparative safety data that are available at the time of data cutoff for the interim analysis. This will to include an interim study report as well as raw and derived datasets.
  Protocol Submission: submitted June 2004
  Study Start: August 2004
  Final Report Submission: March 2006
• Submit efficacy data obtained at the final analysis, including progression-free survival, overall survival, response rate and duration of response; as well as updated safety data for study titled "A Phase 3, Randomized Study of SU011248 versus Interferon-a as First-Line Systemic Therapy for Patients with Metastatic Renal Cell Carcinoma". This submission will include the final study report as well as raw and derived data sets.
  Protocol Submission: submitted June 2004
  Study Start: August 2004
  Final Report Submission: July 2006
• Submit raw and derived datasets containing the core imaging facility assessments used to derive the updated response rate and median duration of response on study titled "A Pivotal Study of SU011248 in the Treatment of Patients with Cytokine-Refractory Metastatic Renal Cell Carcinoma".
  Protocol Submission: submitted November 2003
  Study Start: February 2004
  Final Report Submission: March 2006
• Submit follow-up left ventricular ejection fraction (LVEF) data for patients 16, 46, and 81 on the study titled "A Pivotal Study of SU011248 in the Treatment of Patients with Cytokine-Refractory Metastatic Renal Cell Carcinoma". Case narratives should be submitted and should include additional cardiac evaluations that were performed and treatments that were administered for congestive heart failure. Additionally, submit LVEF data and clinical narratives for any patient who, after the data cutoff for the initial NDA submission, had a documented LVEF of = 40% and/or signs and symptoms of cardiac failure.
  Protocol Submission: submitted November 2003
  Study Start: February 2004
  Final Report Submission: by May 2006
• Submit comparative LVEF and cardiac safety data for patients enrolled on the adjuvant renal cell carcinoma trial, E2805 titled "A Randomized, Double-Blind Phase III Trial of Adjuvant Sunitinib versus Sorafenib versus Placebo in Patients with Resected Renal Cell Carcinoma". The protocol will be revised to include a plan acceptable to the FDA for ejection fraction monitoring at baseline and follow-up.
  Initial Protocol Submission: submitted November 2005
  Revised Protocol Submission: by May 2006
  Study Start: by March 2006
  Final Report Submission: by June 2011
• Provide an analysis of the relationship between exposure and efficacy outcomes from the study titled "A Phase 3, Randomized Study of SU011248 versus Interferon-a as First-Line Systemic Therapy for Patients with Metastatic Renal Cell Carcinoma".
  Protocol Submission: submitted June 2004
  Study Start: August 2004
  Final Report Submission: by July 2006
• Submit the completed report and datasets for study titled "A Phase 1 Study to Evaluate the Effect of SU011248 on QTc Interval in Subjects with Advanced Solid Tumors".
  Protocol Submission: submitted July 2004
  Study Start: August 2004
  Final Report Submission: by March 2006
• Submit the completed report and datasets for study titled "A Phase 1 Study to Evaluate the Pharmacokinetics of SU011248 in Subjects with Impaired Hepatic Function".
  Protocol Submission: submitted August 2005
  Study Start: September 2005
  Final Report Submission: by May 2006
• Submit completed final study report for study titled "A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of SU011248 in the Treatment of Patients with Imatinib Mesylate (Gleevec®, Glivec®)-Resistant or Intolerant Malignant Gastrointestinal Stromal Tumor".
  Protocol Submission: submitted November 2003
  Study Start: December 2003
  Final Report Submission: by December 2006

Adverse events associated with the use of Sutent for the treatment of GIST may include, but are not limited to, the following:

• Fatigue
• Diarrhea
• Anorexia
• Abdominal Pain
• Nausea
• Skin Discoloration
• Mucositis/Stomatitis
• Laboratory Abnormalities

Adverse events associated with the use of Sutent for the treatment of RCC may include, but are not limited to, the following:

• Fatigue
• Diarrhea
• Nausea
• Mucositis/Stomatitis
• Dyspepsia
• Altered Taste
• Rash
• Laboratory Abnormalities

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.

Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. Journal of Clinical Oncology 2006 Jan 1;24(1):16-24. Epub 2005 Dec 5

Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, Bello C, Deprimo S, Brega N, Massimini G, Armand JP, Scigalla P, Raymond E Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. Journal of Clinical Oncology 2006 Jan 1;24(1):25-35. Epub 2005 Nov 28

Marzola P, Degrassi A, Calderan L, Farace P, Nicolato E, Crescimanno C, Sandri M, Giusti A, Pesenti E, Terron A, Sbarbati A, Osculati F Early antiangiogenic activity of SU11248 evaluated in vivo by dynamic contrast-enhanced magnetic resonance imaging in an experimental model of colon carcinoma. Clinical Cancer Research 2005 Aug 15;11(16):5827-32

Osusky KL, Hallahan DE, Fu A, Ye F, Shyr Y, Geng L The receptor tyrosine kinase inhibitor SU11248 impedes endothelial cell migration, tubule formation, and blood vessel formation in vivo, but has little effect on existing tumor vessels. Angiogenesis 2004;7(3):225-33

For additional information regarding Sutent, Gastrointestinal Stromal Tumors or Renal Cell Carcinoma, please visit the Sutent web page.