IUPAC_name = "N"- [2-(diethylamino)ethyl] -5- [("Z")-(5-fluoro-1,2-
CAS_number = 341031-54-7
ATC_prefix = L01
ATC_suffix = XE04
PubChem = 5329102
C = 22 | H = 27 | F = 1 | N = 4 | O = 2
molecular_weight = 398.474 g/mol
532.561 g/mol (
bioavailability = Unaffected by food
protein_bound = 95%
metabolism = Hepatic (
elimination_half-life = 40 to 60 hours (sunitinib)
80 to 110 hours (metabolite)
excretion = Fecal (61%) and renal (16%)
licence_EU = Sutent
licence_US = Sunitinib
pregnancy_AU = D
pregnancy_US = D
legal_US = Rx-only
routes_of_administration = Oral
Sunitinib (marketed as Sutent, and previously known as SU11248) is an oral, small-molecule, multi-targeted
receptor tyrosine kinase(RTK) inhibitor that was approved by the FDA for the treatment of renal cell carcinoma(RCC) and imatinib-resistant gastrointestinal stromal tumor(GIST) on January 26, 2006. Sunitinib was the first cancer drug simultaneously approved for two different indications. cite journal | author = US Food and Drug Administration | title = FDA approves new treatment for gastrointestinal and kidney cancer | journal = Available at: http://www.fda.gov/bbs/topics/news/2006/NEW01302.html ] Sunitinib has become the standard of care for both of these cancers, and is currently being studied for the treatment of many others.
Mechanism of action
Sunitinib inhibits cellular signaling by targeting multiple RTKs. These include all
platelet-derived growth factorreceptors (PDGF-R) and vascular endothelial growth factorreceptors (VEGF-R), which play a role in both tumor angiogenesisand tumor cell proliferation. The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularization and cancer cell death, and ultimately tumor shrinkage. Sunitinib also inhibits KIT ( CD117), the RTK that drives the majority of GISTs. In addition, sunitinib inhibits other RTKs including RET, CSF-1R, and flt3. cite journal | title = Prescribing information for Sutent (sunitinib malate) | journal = Pfizer, Inc, New York NY ]
Renal cell carcinoma
Sunitinib has become the new standard of care in the first-line treatment of metastatic RCC.
RCC is generally resistant to chemotherapy or radiation. Prior to RTKs, metastatic disease could only be treated with the cytokines interferon alpha (IFNα) or
Interleukin 2(IL-2). However, these agents demonstrated low rates of efficacy (5%-20%) and are associated with severe infusion-related adverse events. cite journal | author = Motzer RJ "et al." | title = Sunitinib versus interferon alfa in metastatic renal-cell carcinoma | journal = N Engl J Med | volume = 356 | issue = 2 | pages = 115–124 | year = 2007 | pmid = 17215529 | doi = 10.1056/NEJMoa065044 ]
In two separate Phase II studies, sunitinib demonstrated consistent response rates of approximately 40% in patients who had already failed cytokine therapy. Although these were Phase II studies, these results were impressive enough for the FDA to approve sunitinib for first-line use even before Phase III data were available.
The results of the Phase III study, published in the "
New England Journal of Medicine" in 2007, proved that sunitinib offers superior efficacy compared with IFNα. Progression-free survival (primary endpoint) was more than doubled: 11 months for sunitinib compared with 5 months for IFNα ("P"<.000001). The benefit for sunitinib was significant across all major patient subgroups, including those with a poor prognosis at baseline.
Secondary endpoints also favored sunitinib. 28% of sunitinib patients had significant tumor shrinkage (objective response) compared with only 5% of patients who received IFNα ("P"<.001). Although overall survival data are not yet mature, there is a clear trend toward improved survival with sunitinib. Patients receiving sunitinib also reported a significantly better quality of life than those treated with IFNα ("P"<.001).
Sunitinib was generally better tolerated than IFNα. Significantly more patients discontinued IFNα due to adverse events ("P"=.05), withdrawal of consent ("P"<.001), or disease progression ("P"<.001). Serious fatigue was significantly more common with IFNα ("P"<.05), while diarrhea was reported more commonly with sunitinib.
Based on these results, lead investigator Dr. Robert Motzer announced at ASCO 2006 that "“Sunitinib is the new reference standard for the first-line treatment of mRCC.”" cite journal | author = Motzer RJ "et al." | title = Phase 3 Randomized Trial of Sunitinib malate (SU11248) versus Interferon-alfa as First-line Systemic Therapy for Patients with Metastatic Renal Cell Carcinoma | journal = Presented at ASCO 2006 | id = Available at: http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=40&index=y&abstractID=30512 ]
At ASCO 2008, Dr Robert Figlin presented updated data from the final study analysis, including overall survival. The primary endpoint of median PFS remained superior with sunitinib: 11 months versus 5 months for IFNα, "P"<.000001. Objective response rate also remained superior: 39-47% for sunitinib versus 8-12% with IFNα, "P"<.000001. cite journal | author = Figlin RA "et al." | title = Overall survival with sunitinib versus interferon alfa (IFN-α) as first-line treatment of metastatic renal cell carcinoma (mRCC). Abstract no. 5024. | journal = Presented at ASCO 2008 | id = Available at: http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=32895 ]
Sunitinib was associated with a clear advantage in overall survival.
* Median OS was 26 months with sunitinib vs 22 months for IFNα regardless of stratification ("P"-value ranges from .051 to .0132, depending on statistical analysis).
* The first analysis includes 25 patients initially randomized to IFNαwho crossed over to sunitinib therapy, which may have confounded the results; in an exploratory analysis that excluded these patients, the difference is becomes even more robust: 26 vs 20 months, "P"=.0081.
* Patients in the study were allowed to receive other therapies once they had progressed on their study treatment. For a “pure” analysis of the difference between the two agents, an analysis was done using only patients who did not receive any post-study treatment. This analysis demonstrated the greatest advantage for sunitinib: 28 months vs 14 months for IFNα, "P"=.0033.
This was the largest comparative trial in RCC to date, and sunitinib is the first agent to demonstrate an overall survival longer than 2 years in these patients. Dr. Figlin concluded his presentation by reinforcing that "“Sunitinib is the reference standard for the first-line treatment of mRCC.”"
Gastrointestinal stromal tumor
Like RCC, GIST does not generally respond to standard chemotherapy or radiation.
Imatinibwas the first cancer agent proven effective for metastatic GIST and represented a major development in the treatment of this rare but challenging disease. However, approximately 20% of patients do not respond to imatinib (early or primary resistance), and among those who do respond initially, 50% develop secondary imatinib resistance and disease progression within 2 years. Prior to sunitinib, patients had no therapeutic option once they became resistant to imatinib. cite journal | author = Demetri GD "et al." | title = Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial | journal = Lancet | year = 2006 | volume = 368 | pages = 1329–1338 | pmid = 17046465 ]
Sunitinib offers patients with imatinib-resistant GIST a new treatment option to stop further disease progression and, in some cases, even reverse it. This was proven in a large, Phase III clinical trial in which patients who failed imatinib therapy (due to primary resistance, secondary resistance, or intolerance) were treated in a randomized and blinded fashion with either sunitinib or placebo.
The study was unblinded early, at the very first interim analysis, due to the clearly emerging benefit of sunitinib. At that time, patients receiving placebo were offered to switch over to sunitinib. In the primary endpoint of this study, median time to tumor progression (TTP) was more than 4-fold longer with sunitinib (27 weeks) compared with placebo (6 weeks, "P"<.0001). These are based on the assessments of an independent radiology lab assessment. The benefit of sunitinib remained statistically significant when stratified for a multitude of prespecified baseline factors, including:
* Prior dose of imatinib
* Prior duration of imatinib therapy
* ECOG Performance status
* Pain score
* Time since initial diagnosis
* Study location
* ITT vs PP analysis
* Investigator vs independent radiology lab assessment
Among the secondary endpoints, the difference in PFS was similar to that in TTP (24 weeks vs 6 weeks, "P"<.0001). 7% of sunitinib patients had significant tumor shrinkage (objective response) compared with 0% of placebo patients ("P"=.006). Another 58% of sunitinib patients had disease stabilization vs. 48% of patients receiving placebo. The median time to response with sunitinib was 10.4 weeks. Sunitinib reduced the relative risk of disease progression or death by 67%, and the risk of death alone by 51%. The difference in survival benefit may be diluted by the fact that placebo patients crossed over to sunitinib upon disease progression, and most of these patients subsequently responded to sunitinib.
Sunitinib was relatively well tolerated. 83% of sunitinib patients experienced a treatment-related adverse event of any severity, as did 59% of patients who received placebo. Serious adverse events were reported in 20% of sunitinib patients and 5% of placebo patients. Adverse events were generally moderate and easily managed by dose reduction, dose interruption, or other treatment. 9% of sunitinib patients and 8% of placebo patients discontinued therapy due to an adverse event.
Fatigue is the adverse event most commonly associated with sunitinib therapy. In this study, 34% of sunitinib patients reported any grade of fatigue, compared with 22% for placebo. The incidence of grade 3 (severe) fatigue was similar between the two groups, and there was no grade 4 fatigue reported.
Other solid tumors
The efficacy of sunitinib is currently being evaluated in a broad range of solid tumors, including breast, lung, and colorectal cancers. Early studies have shown single-agent efficacy in a number of different areas.
* A Phase II study in previously-treated patients with metastatic breast cancer found that sunitinib "“has significant single agent activity”" cite journal | author = Miller KD "et al." | title = Phase II study of SU11248, a multi-targeted tyrosine kinase inhibitor in patients with previously treated metastatic breast cancer | journal = Presented at ASCO 2005 | id = Available at: http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=34&abstractID=31881 ]
* A Phase II study of refractory non-small-cell lung cancer found that "“Sunitinib has provocative single-agent activity in previously treated pts with recurrent and advanced NSCLC, with the level of activity similar to currently approved agents.”" cite journal | author = Socinski MA "et al." | title = Efficacy and safety of sunitinib in previously treated, advanced non-small cell lung cancer (NSCLC): preliminary results of a multicenter phase II trial | journal = Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I | volume = 24 | issue = 18S (June 20 suppl) | abstract number = 7001 | year = 2006 | id = Available at: http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=40&abstractID=34252 ]
* In a Phase II study of patients with nonresectable neuroendocrine tumors (NET), 91% of patients responded to sunitinib (9% partial response + 82% stable disease) cite journal | author = Kulke MH "et al." | title = A Phase 2 Study to Evaluate the Efficacy of SU11248 in Patients with Unresectable Neuroendocrine Tumors | journal = Presented at ASCO 2005 | id = Available at: http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=34&abstractID=33268 ]
The most common adverse events associated with sunitinib therapy are fatigue, diarrhea, nausea, anorexia, hypertension, and skin discoloration. In the placebo-controlled Phase III GIST study, adverse events which occurred more often with sunitinib than placebo included diarrhea, anorexia, skin discoloration, mucositis/stomatitis, asthenia, altered taste, and constipation.
Serious (grade 3 or 4) adverse events occur in ≤10% of patients and include hypertension, fatigue, asthenia, diarrhea, and hand-foot syndrome. Lab abnormalities associated with sunitinib therapy include lipase, amylase, neutrophils, lymphocytes, and platelets. Hypothyroidism has also been associated with sunitinib.
* [http://www.sutent.com Sutent.com] — Manufacturer's site
* [http://www.gistsupport.org/treatments/current-treatments/sutent.php GIST Support International] — An international organization for the support of GIST patients, families, and friends. Includes detailed information from some of the foremost experts on GIST, links to research, treatment options, and GIST registry.
* [http://kidneycancer.org/ Kidney Cancer Association] — An organization that educates physicians and patients about kidney cancer; funds, promotes, and collaborates on research projects; and advocates at the federal and state levels on behalf of patient interests.
* [http://mpablog.typepad.com/david_foster] Cancer veteran's blog with two years experience with Sutent, Nexavar and chemo.
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Look at other dictionaries:
Sunitinib — Nombre (IUPAC) sistemático N [2 (diethylamino)ethyl] 5 [(Z) (5 fluoro 1,2 dihydro 2 oxo 3H indol 3 ylidine)methyl] 2,4 dimethyl 1H pyrrole … Wikipedia Español
Sunitinib — Général No CAS … Wikipédia en Français
Sunitinib — Strukturformel Allgemeines Freiname Sunitinib … Deutsch Wikipedia
sunitinib — A drug used to treat gastrointestinal stromal tumors (GIST) that have not responded to treatment with imatinib mesylate (Gleevec). Sunitinib is also used to treat advanced kidney cancer and is being studied in the treatment of other types of… … English dictionary of cancer terms
sunitinib — noun An oral small molecule drug used in the treatment of renal cell carcinoma and imatinib resistant gastrointestinal stromal tumour … Wiktionary
sunitinib malate — A drug used to treat gastrointestinal stromal tumors (GIST) that have not responded to treatment with imatinib mesylate (Gleevec). Sunitinib malate is also used to treat advanced kidney cancer and is being studied in the treatment of other types… … English dictionary of cancer terms
sunitinib malate — su·ni·ti·nib mal·ate (soo nĭґtĭ nib) a tyrosine kinase inhibitor used in treatment for advanced renal cell carcinoma and gastrointestinal stromal tumor; administered orally … Medical dictionary
341031-54-7 — Sunitinib Sunitinib Général No CAS … Wikipédia en Français
C22H27FN4O2 — Sunitinib Sunitinib Général No CAS … Wikipédia en Français
Sutent — Sunitinib Sunitinib Général No CAS … Wikipédia en Français