Sunitinib

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Sunitinib

Systematic (IUPAC) name
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2- dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4- dimethyl-1H-pyrrole-3-carboxamide
Identifiers
CAS number	341031-54-7
ATC code	L01XE04
PubChem	5329102
Chemical data
Formula	C22H27FN4O2
Mol. mass	398.474 g/mol 532.561 g/mol (malate)
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%)
Therapeutic considerations
Licence data	EU EMEA:link, US FDA:link
Pregnancy cat.	D(AU) D(US)
Legal status	℞-only(US)
Routes	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. ^[1] Sunitinib has become a standard of care for both of these cancers, and is currently being studied for the treatment of many others.

Contents 1 Mechanism of action 2 Indications 2.1 Renal cell carcinoma 2.1.1 RCC: update 2.2 Gastrointestinal stromal tumor 2.3 Other solid tumors 3 Side effects 4 Costs 4.1 US 4.2 UK 5 Synthesis 6 References 7 External links

[edit] Mechanism of action

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:

• RET
• CSF-1R
• flt3

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.

[edit] Indications

[edit] Renal cell carcinoma

Sunitinib is a standard of care in the first-line treatment of metastatic RCC, other therapeutic options in this setting are sorafenib (Nexavar), temsirolimus (Torisel) and interleukin-2 (Proleukin).

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%).

In two separate Phase II studies, sunitinib demonstrated consistent response rates of approximately 40% in patients who had already failed cytokine therapy. ^[7] 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). ^[6] The benefit for sunitinib was significant across all major patient subgroups, including those with a poor prognosis at baseline. ^[7]

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). ^[7]

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.” ^[8]

[edit] RCC: update

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. ^[9][10]

Sunitinib was associated with somewhat 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 is 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.
• Also worth noting in this presentation was the fact that the updated percentage of patients that had to discontinue sunitinib due to adverse events was 19%. This is a clinically meaningful number.

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.” ^[9]

[edit] Gastrointestinal stromal tumor

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 2 years. Prior to sunitinib, patients had no therapeutic option once they became resistant to imatinib. ^[11]

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. ^[11]

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: ^[11]

• Prior dose of imatinib
• Prior duration of imatinib therapy
• ECOG Performance status
• Age
• Weight
• Race
• 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. ^[11] 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. ^[11]

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. ^[11]

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. ^[11]

[edit] 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. In addition to blocking angiogenesis, Sutent® also inhibits additional enzymes that are involved in the development of tumours. The discovery of the drug and clarification of the multi-specific mechanism of action is based on discoveries of Axel Ullrich and his team at the Max Planck Institute of Biochemistry in the 1980s in Munich. Medical and pharmaceutical development as well as clinical testing of the drug was carried out by Sugen, a company founded in 1991 by Ullrich and his American colleague Joseph Schlessinger (the S in Sugen stands for Schlessinger, the U for Ullrich), also involving New York University and the Max Planck Society.The concept was of a ATP analogue that would compete with ATP for binding to the catalytic site of receptor tyrosine kinases. This concept led to the invention of an important small-molecule tyrosine kinase inhibitor called Sunitinib.

• A Phase II study in previously-treated patients with metastatic breast cancer found that sunitinib “has significant single agent activity” ^[12]
• 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.” ^[13]
• In a Phase II study of patients with nonresectable neuroendocrine tumors (NET), 91% of patients responded to sunitinib (9% partial response + 82% stable disease) ^[14]

[edit] Side effects

Sunitinib has been generally well tolerated. Adverse events were 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.^[15] 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][11]

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 hand-foot syndrome. Lab abnormalities associated with sunitinib therapy include lipase, amylase, neutrophils, lymphocytes, and platelets. Hypothyroidism and reversible erythrocytosis have also been associated with sunitinib.^{[6] [16]}

Most adverse events can be managed through supportive care, dose interruption, or dose reduction.^[7][11]

The efficacy of the dose reduced sub-group has never been published.

[edit] Costs

Sunitinib is marketed by Pfizer as Sutent, and is subject to patents and market exclusivity as a new chemical entity until February 15, 2021.^[17][18] 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.^[19][20] Sutent is one of the most expensive drugs widely marketed. Doctors and editorials have criticized the high cost, for a drug that doesn't cure cancer but only prolongs life.

[edit] US

In the U.S., insurance companies have refused to pay for all or part of the costs of Sutent. Because Sutent is an oral therapy, the "co-pay" 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.

[edit] UK

In the UK NICE refused (late 2008) to recommend suntinib 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.^[21] It was also refused by NICE in 2008 for the treatment of kidney cancer.^[22] This refusal/guidance was updated Feb 2009 after negotiations on price for the first course of treatment.^{[citation needed]}

[edit] Synthesis

The organic synthesis for this chemical from commercially available precursors is disclosed in US patent 6573293^[23], together with nuclear magnetic resonance and mass spectrometry data to assist in characterizing intermediates. It proceeds in the following conceptual steps:

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.

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.^[24] 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.

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)

[edit] References

[edit] External links

• 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

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