Sunitinib

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Sunitinib
Sunitinib.svg
Sunitinib-3D-balls.png
Systematic (IUPAC) name
N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
Clinical data
Trade names Sutent
AHFS/Drugs.com monograph
MedlinePlus a607052
Licence data EMA:Link, US FDA:link
Pregnancy cat.
Legal status
Routes Oral
Pharmacokinetic data
Bioavailability Unaffected by food
Protein binding 95%
Metabolism Hepatic (CYP3A4-mediated)
Half-life 40 to 60 hours (sunitinib)
80 to 110 hours (metabolite)
Excretion Fecal (61%) and renal (16%)
Identifiers
CAS number 341031-54-7 N
ATC code L01XE04
PubChem CID 5329102
DrugBank DB01268
ChemSpider 4486264 YesY
UNII V99T50803M YesY
KEGG D06402 YesY
ChEBI CHEBI:38940 YesY
ChEMBL CHEMBL535 YesY
Chemical data
Formula C22H27FN4O2 
Mol. mass 398.474 g/mol
532.561 g/mol (malate)
 N (what is this?)  (verify)

Sunitinib (marketed as Sutent by Pfizer, 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.[1]

Mechanism of action[edit]

Sunitinib inhibits cellular signaling by targeting multiple receptor tyrosine kinases (RTKs).

These include all receptors for platelet-derived growth factor (PDGF-Rs) and vascular endothelial growth factor receptors (VEGFRs), which play a role in both tumor angiogenesis and 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),[2] the RTK that (when improperly activated by mutation) drives the majority of gastrointestinal stromal cell tumors.[3] It has been recommended as a second-line therapy for patients whose tumors develop mutations in KIT that make them resistant to imatinib, or who become intolerant to the drug.[4][5]

In addition, sunitinib inhibits other RTKs.[6] These include the following:

The fact that sunitinib targets many different receptors, leads to many of its side effects such as the classic hand-foot syndrome, stomatitis, and other dermatologic toxicities.

Indications[edit]

Gastrointestinal stromal tumor[edit]

Like RCC, GIST does not generally respond to standard chemotherapy or radiation. Imatinib was 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 two years. Prior to sunitinib, patients had no therapeutic option once they became resistant to imatinib.[7]

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 shown 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.[7]

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 four-fold longer with sunitinib (27 weeks) compared with placebo (six 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.[7]

Among the secondary endpoints, the difference in progression-free survival (PFS) was similar to that in TTP (24 weeks vs six weeks, P<.0001). Seven percent 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.[7] 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 because placebo patients crossed over to sunitinib upon disease progression, and most of these patients subsequently responded to sunitinib.[7]

Sunitinib was relatively well tolerated. About 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. Nine percent of sunitinib patients and 8% of placebo patients discontinued therapy due to an adverse event.[7]

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 no grade 4 fatigue was reported.[7]

Meningioma[edit]

Sunitinib is being studied for treatment of meningioma which is associated with neurofibromatosis.[8]

Pancreatic neuroendocrine tumors[edit]

In November 2010, Sutent gained approval from the European Commission for the treatment of 'unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors with disease progression in adults'.[9] In May 2011, the USFDA approved Sunitininb for treating patients with 'progressive neuroendocrine cancerous tumors located in the pancreas that cannot be removed by surgery or that have spread to other parts of the body (metastatic)'.[10]

Renal cell carcinoma[edit]

Sunitinib is approved for treatment of metastatic RCC. Other therapeutic options in this setting are pazopanib (Votrient), sorafenib (Nexavar), temsirolimus (Torisel), interleukin-2 (Proleukin), everolimus (Afinitor), bevacizumab (Avastin), and aldesleukin.

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. However, these agents demonstrated low rates of efficacy (5%-20%).

In a phase 3 study, median progression-free survival was significantly longer in the sunitinib group (11 months) than in the IFNα group (five months), a hazard ratio of 0.42.[6][11] In the secondary endpoints, 28% had significant tumor shrinkage with sunitinib compared to 5% with IFNα. Patients receiving sunitinib had a better quality of life than IFNα.

At ASCO 2008, Dr Robert Figlin presented updated data from the final study analysis, including overall survival. The primary endpoint of median progression-free survival (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.[12][13]

Sunitinib treatment trended towards a slightly longer overall survival, although this was not statistically significant.

  • 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 IFNα who crossed over to sunitinib therapy, which may have confounded the results; in an exploratory analysis that excluded these patients, the difference becomes 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. The number of patients in this analysis was small and this does not reflect actual clinical practice and is therefore not meaningful.

Hypertension (HTN) was found to be a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib.[14] Patients with mRCC and sunitinib-induced hypertension had better outcomes than those without treatment-induced HTN (objective response rate: 54.8% vs 8.7%; median PFS: 12.5 months, 95% confidence interval [CI] = 10.9 to 13.7 vs 2.5 months, 95% CI = 2.3 to 3.8 months; and OS: 30.9 months, 95% CI = 27.9 to 33.7 vs 7.2 months, 95% CI = 5.6 to 10.7 months; P < .001 for all).

Other solid tumors[edit]

The efficacy of sunitinib is currently being evaluated in a broad range of solid tumors, including breast, lung, thyroid and colorectal cancers. Early studies have shown single-agent efficacy in a number of different areas. Sunitinib blocks the tyrosine kinase activities of KIT, PDGFR, VEGFR2 and other tyrosine kinases involved in the development of tumours.

  • A Phase II study in previously treated patients with metastatic breast cancer found sunitinib “has significant single agent activity”.[15]
  • A Phase II study of refractory non-small-cell lung cancer found “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.” [16]
  • In a Phase II study of patients with nonresectable neuroendocrine tumors, 91% of patients responded to sunitinib (9% partial response + 82% stable disease).[17]

Leukemia[edit]

Sunitinib was used to treat the leukemia of a Washington University in St. Louis leukemia researcher who developed the disease himself. His team used genetic sequencing and noticed that the FLT3 gene was hyperactive in his leukemia cells and used sunitinib as a treatment.[18]

Unsuccessful trials[edit]

Between April 2009 and May 2011 Pfizer has reported unsuccessful late-stage trials in breast cancer, metastatic colorectal cancer, advanced non-small-cell lung cancer, and castration-resistant prostate cancer.[19]

History[edit]

The drug was discovered at SUGEN, a biotechnology company which pioneered protein kinase inhibitors. It was the third in a series of compounds including SU5416 (Semaxanib) and SU6668. The concept was of an ATP analogue that would compete with ATP for binding to the catalytic site of receptor tyrosine kinases.[citation needed] This concept led to the invention of many small-molecule tyrosine kinase inhibitors, including Gleevec, Sutent, Tarceva and many other cancer drugs.

Side effects[edit]

Sunitinib adverse events are considered somewhat manageable and the incidence of serious adverse events low.[7][11]

The most common adverse events associated with sunitinib therapy are fatigue, diarrhea, nausea, anorexia, hypertension, a yellow skin discoloration, hand-foot skin reaction, and stomatitis.[20] 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.[6][7]

Dose reductions were required in 50% of the patients studied in RCC in order to manage the significant toxicities of this agent.

Serious (grade 3 or 4) adverse events occur in ≤10% of patients and include hypertension, fatigue, asthenia, diarrhea, and chemotherapy-induced acral erythema. Lab abnormalities associated with sunitinib therapy include lipase, amylase, neutrophils, lymphocytes, and platelets. Hypothyroidism and reversible erythrocytosis have also been associated with sunitinib.[6][21]

Most adverse events can be managed through supportive care, dose interruption, or dose reduction.[7][11] A recent study done at MD Anderson Cancer Center compared the outcomes of metastatic renal cell cancer patients who received sunitinib on the standard schedule (50mg/4 weeks on 2 weeks off) with those who received sunitinib with more frequent and short drug holidays (alternative schedule). It was seen that the overall survival, progression free survival and drug adherence were significantly higher in the patients who received Sunitinib on the alternative schedule. Patients also had a better tolerance and lower severity of adverse events which frequently lead to discontinuation of treatment of metastatic renal cell cancer patients.[22]

Interactions[edit]

Epigallocatechin-3-gallate, a major constituent of green tea, may reduce the bioavailability of sunitinib when they are taken together.[23]


Costs[edit]

Sunitinib is marketed by Pfizer as Sutent, and is subject to patents and market exclusivity as a new chemical entity until February 15, 2021.[24][25] Sutent has been cited in financial news as a potential revenue source to replace royalties lost from Lipitor following the expiration of the latter drug's patent expiration in November 2011.[26][27] Sutent is one of the most expensive drugs widely marketed. Doctors and editorials have criticized the high cost for a drug that does not cure cancer, but only prolongs life.

U.S.[edit]

In the U.S., insurance companies have refused to pay for all or part of the costs of Sutent. Because it is an oral therapy, the copay associated with this therapy can be very substantial. If a patient's secondary insurance does not cover this, the cost burden to the patient can be extreme. Particularly challenging is the "donut hole" for Medicare part D coverage. Patients have to spend thousands of dollars out-of-pocket to get through the donut hole. If this is done at the end of a calendar year, it has to be paid again at the beginning of the next calendar year, which may be burdensome financially.

UK[edit]

In the UK, NICE refused (late 2008) to recommend sunitinib for late-stage renal cancer (kidney cancer) due to the high cost per QALY, estimated by NICE at £72,000/QALY and by Pfizer at £29,000/QALY.[28][29] This was overturned in February 2009 after pricing changes and public responses.[30]

AU[edit]

Sunitinib is available in Australia and is subsidised by the Pharmaceutical Benefits Scheme for Stage IV Renal Cell Carcinoma (RCC). The cost to the patient who meets the clinical criteria of Stage IV RCC is AUD $35.40 for 28 capsules, regardless of dose. Manufacturer pricing for Sunitinib ranges from AUD $1,834.30 to AUD $6897.54, depending on dose (12.5 mg to 50 mg).[31]

Synthesis[edit]

The organic synthesis for this chemical from commercially available precursors is disclosed in US patent 6573293,[32] together with nuclear magnetic resonance and mass spectrometry data to assist in characterizing intermediates. It proceeds in the following conceptual steps:

Sunitinib step 1.png

5-fluoroisatin is reacted with hydrazine hydrate, a highly reactive base which bonds to the compound by opening the indole ring. The resulting compound is then reacted with 12 N HCl, a strong acid which effectively strips away the hydrazine and recloses the ring. The net effect is a net reduction at the 3-position of the indole ring, with two hydrogens replacing the ketone.

Sunitinib step 2.png

3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester is a somewhat uncommon precursor, sometimes sold as a "sunitinib intermediate", citing the U.S. research exemption to patent law.[33] This compound is decarboxylated in the presence of strong acid, losing the t-BOC unit. The compound is then subjected to a formylation reaction (the Vilsmeier-Haack reaction), which uses dimethylformamide in the presence of phosphorus oxychloride to attach a formyl group to the site on the arene ring which was opened by the previous reaction. The product is then extracted by phase separation.

Sunitinib step 3.png

The product of the preceding reaction is now modified at the other carboxylic acid group on the pyrrole ring by refluxing the ester in water with strong base (potassium hydroxide). This hydrolysis releases a free carboxylic acid which is then modified by a 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) in the presence of hydroxybenzotriazole (HOBT). (See carbodiimide for further information) The primary amine of diethylethylenediamine reacts with this over the course of a 20-hour reaction to produce 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide.

The final step, not shown, is to mix the final products from the first and third figures above in ethanol and pyrrolidine at 78 C for three hours, producing sunitinib. (See Aldol condensation)

References[edit]

  1. ^ US Food and Drug Administration (2006). "FDA approves new treatment for gastrointestinal and kidney cancer". 
  2. ^ Hartmann JT, Kanz L (November 2008). "Sunitinib and periodic hair depigmentation due to temporary c-KIT inhibition". Arch Dermatol 144 (11): 1525–6. doi:10.1001/archderm.144.11.1525. PMID 19015436. 
  3. ^ "Gastrointestinal stromal tumor: a clinical overview". Hematol. Oncol. Clin. North Am. 23 (1): 69–78, viii. February 2009. doi:10.1016/j.hoc.2008.11.006. PMID 19248971. 
  4. ^ "Advanced gastrointestinal stromal tumor in Europe: a review of updated treatment recommendations". Expert Rev Anticancer Ther 9 (6): 831–8. June 2009. doi:10.1586/era.09.34. PMID 19496720. 
  5. ^ "Sunitinib in solid tumors". Expert Opin Investig Drugs 18 (6): 821–34. June 2009. doi:10.1517/13543780902980171. PMID 19453268. 
  6. ^ a b c d "Prescribing information for Sutent (sunitinib malate)". Pfizer, Inc, New York NY. 
  7. ^ a b c d e f g h i j Demetri GD et al. (2006). "Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial". Lancet 368 (9544): 1329–1338. doi:10.1016/S0140-6736(06)69446-4. PMID 17046465. 
  8. ^ "Phase II Trial of Sunitinib (SU011248) in Patients With Recurrent or Inoperable Meningioma"
  9. ^ "Pfizer Scores New Approval for Sutent in Europe". 2 Dec 2010. 
  10. ^ FDA approves Sutent for rare type of pancreatic cancer
  11. ^ a b c Motzer RJ et al. (2007). "Sunitinib versus interferon alfa in metastatic renal-cell carcinoma". N Engl J Med 356 (2): 115–124. doi:10.1056/NEJMoa065044. PMID 17215529. 
  12. ^ Figlin RA et al.. "Overall survival with sunitinib versus interferon alfa (IFN-α) as first-line treatment of metastatic renal cell carcinoma (mRCC). Abstract no. 5024.". Presented at ASCO 2008. Available at: http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=32895. 
  13. ^ "Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma". J. Clin. Oncol. 27 (22): 3584–90. August 2009. doi:10.1200/JCO.2008.20.1293. PMID 19487381. 
  14. ^ Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. | CureHunter
  15. ^ Miller KD et al.. "Phase II study of SU11248, a multi-targeted tyrosine kinase inhibitor in patients with previously treated metastatic breast cancer". Presented at ASCO 2005. Available at: http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=34&abstractID=31881. 
  16. ^ Socinski MA et al. (2006). "Efficacy and safety of sunitinib in previously treated, advanced non-small cell lung cancer (NSCLC): preliminary results of a multicenter phase II trial". Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I 24 (18S (June 20 suppl)). Available at: http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=40&abstractID=34252. 
  17. ^ Kulke MH et al.. "A Phase 2 Study to Evaluate the Efficacy of SU11248 in Patients with Unresectable Neuroendocrine Tumors". Presented at ASCO 2005. Available at: http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=34&abstractID=33268. 
  18. ^ "In Gene Sequencing Treatment for Leukemia, Glimpses of the Future". 
  19. ^ GEN | News Highlights: FDA Expands Sutent Label to Include Pancreatic Neuroendocrine Tumors
  20. ^ Dasanu CA, et al. (2007-03-01). "Yellow skin discoloration associated with sorafenib use for treatment of metastatic renal cell carcinoma.". Southern Medical Journal. 
  21. ^ Alexandrescu, DT, McClure, R, Farzanmehr, H, Dasanu, CA (2008). "Secondary erythrocytosis produced by the tyrosine kinase inhibitors sunitinib and sorafenib". Journal of Clinical Oncology 26 (24): 4047–8. doi:10.1200/jco.2008.18.3525. 
  22. ^ Atkinson BJ, Kalra S, Wang X, Bathala T, Corn P, Tannir NM, Jonasch E (March 2014). "Clinical Outcomes in Patients with Metastatic Renal Cell Carcinoma Treated with Alternative Sunitinib Schedules.". J Urol 191 (3): 611–618. doi:10.1016/j.juro.2013.08.090. 
  23. ^ Ge J, Tan BX, Chen Y, Yang L, Peng XC, Li HZ, Lin HJ, Zhao Y, Wei M et al. (Jun 2011). "Interaction of green tea polyphenol epigallocatechin-3-gallate with sunitinib: potential risk of diminished sunitinib bioavailability". J Mol Med (Berl) 89 (6): 595–602. doi:10.1007/s00109-011-0737-3. 
  24. ^ "Patent and Exclusivity Search Results from query on Appl No 021938 Product 003 in the OB_Rx list". U.S. FDA. Retrieved 2009-06-05.  Sutent is subject to US patent 7211600 (expires Dec 22 2020), 7125905 and 6573293 (expire Feb 15 2021). Note that this information does not include or predict patent extensions.
  25. ^ "Details for Generic 'SUNITINIB MALATE'". DrugPatentWatch. 
  26. ^ Jamie Dlugosch (2009-03-13). "Will biologics and Sutent save Pfizer?". InvestorPlace. 
  27. ^ Zacks Investment Research (2007-03-22). "Pfizer's a Sell: Shrinking Top Line, No Blockbusters In the Pipeline". SeekingAlpha. 
  28. ^ BMJ 31-Jan-2009 "NICE and the challenge of cancer drugs" p271
  29. ^ BBC news - Aug 2008 - 'We'll sell our house for this drug'
  30. ^ Daily Telegraph, Feb 4, 2009
  31. ^ Australian Pharmaceutical Benefits Scheme - Sutent[1]
  32. ^ See Patent Lens - Free Full-Text Patent Search (compound 80), with relevant sections reproduced in the original figures below
  33. ^ see e.g. http://www.manusaktteva.in/Details/2/130/62/View/86770-31-2.html

External links[edit]

  • Sutent.com — Manufacturer's site
  • The Life Raft Group-The Life Raft Group (LRG) is an organization that provides support, information and assistance to patients and families with a rare cancer called Gastrointestinal Stromal Tumor (GIST).
  • 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.
  • 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.
  • [2] Cancer veteran's blog with two years experience with Sutent, Nexavar and chemo.
  • Cancer Management Handbook: Principles of Oncologic Pharmacotherapy