Sunitinib

Last updated

Sunitinib
Sunitinib.svg
Sunitinib-3D-balls.png
Clinical data
Trade names Sutent, others
Other namesSU11248
AHFS/Drugs.com Monograph
MedlinePlus a607052
License data
Pregnancy
category
  • AU:D
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Unaffected by food
Protein binding 95%
Metabolism Liver (CYP3A4-mediated)
Elimination half-life 40 to 60 hours (sunitinib)
80 to 110 hours (metabolite)
Excretion Fecal (61%) and kidney (16%)
Identifiers
  • N-(2-Diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C22H27FN4O2
Molar mass 398.482 g·mol−1
3D model (JSmol)
  • CCN(CC)CCNC(=O)c1c(c([nH]c1C)/C=C\2/c3cc(ccc3NC2=O)F)C
  • InChI=1S/C22H27FN4O2/c1-5-27(6-2)10-9-24-22(29)20-13(3)19(25-14(20)4)12-17-16-11-15(23)7-8-18(16)26-21(17)28/h7-8,11-12,25H,5-6,9-10H2,1-4H3,(H,24,29)(H,26,28)/b17-12- Yes check.svgY
  • Key:WINHZLLDWRZWRT-ATVHPVEESA-N Yes check.svgY

  • as salt: InChI=1S/C22H27FN4O2.C4H6O5/c1-5-27(6-2)10-9-24-22(29)20-13(3)19(25-14(20)4)12-17-16-11-15(23)7-8-18(16)26-21(17)28;5-2(4(8)9)1-3(6)7/h7-8,11-12,25H,5-6,9-10H2,1-4H3,(H,24,29)(H,26,28);2,5H,1H2,(H,6,7)(H,8,9)/b17-12-;/t;2-/m.0/s1
  • Key:LBWFXVZLPYTWQI-IPOVEDGCSA-N
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Sunitinib, sold under the brand name Sutent, is an anti-cancer medication. [2] It is a 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) in January 2006. Sunitinib was the first cancer drug simultaneously approved for two different indications. [3]

Contents

As of August 2021, sunitinib is available as a generic medicine in the US. [4]

Medical uses

Gastrointestinal stromal tumor

Like renal cell carcinoma, gastrointestinal stromal tumor does not generally respond to standard chemotherapy or radiation. Imatinib was the first cancer agent proven effective for metastatic gastrointestinal stromal tumor 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. [5]

Sunitinib offers patients with imatinib-resistant gastrointestinal stromal tumor 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. [5]

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. [5]

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. [5] 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. [5]

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. [5]

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. [5]

Meningioma

Sunitinib is being studied for treatment of meningioma which is associated with neurofibromatosis. [6]

Pancreatic neuroendocrine tumors

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'. [7] In May 2011, the USFDA approved Sunitinib 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)'. [8]

Renal cell carcinoma

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

Renal cell carcinoma 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 III 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. [2] [9] 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. An update in 2008 showed that 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. [10] [11]

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

Hypertension (HTN) was found to be a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. [12] 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).

Mechanism of action

Sunitinib inhibits cellular signalling 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 reduces tumor vascularization and triggers cancer cell apoptosis and thus results in tumor shrinkage.

Sunitinib also inhibits CD117 (c-KIT), [13] the receptor tyrosine kinase that (when improperly activated by mutation) drives the majority of gastrointestinal stromal cell tumors. [14] It has been recommended as a second-line therapy for patients whose tumors develop mutations in c-KIT that make them resistant to imatinib, or who the cannot tolerate the drug. [15] [16]

In addition, sunitinib binds other receptors. [2] These include:

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.

History

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 and SU6668. The concept was of an ATP mimic that would compete with ATP for binding to the catalytic site of receptor tyrosine kinases. This concept led to the invention of many small-molecule tyrosine kinase inhibitors, including Gleevec, Sutent, Tarceva and many others. [ citation needed ]

Side effects

Sunitinib adverse events are considered somewhat manageable and the incidence of serious adverse events low. [5] [9]

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. [17] 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. [2] [5]

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. [2] [18]

A study done at MD Anderson Cancer Center compared the outcomes of metastatic renal cell cancer patients who received sunitinib on the standard schedule (50 mg/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. [19]

Interactions

Epigallocatechin-3-gallate, a major constituent of green tea, may reduce the bioavailability of sunitinib when they are taken together. [20]

Society and culture

Economics

Sunitinib is marketed by Pfizer as Sutent, and was subject to patents and market exclusivity as a new chemical entity until 15 February 2021. [21] [22] 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. [23] [24] Sutent is one of the most expensive drugs widely marketed.[ citation needed ] Doctors and editorials have criticized the high cost for a drug that does not cure cancer, but only prolongs life.

US

In the U.S., many insurance companies[ which? ] 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 Medicare Part D coverage gap. Patients have to spend thousands of dollars out-of-pocket during the gap in coverage. 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

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. [25] [26] This was overturned in February 2009 after pricing changes and public responses. [27] Therefore, sunitinib is recommended as a first-line treatment option for people with advanced and/or metastatic renal cell carcinoma who are suitable for immunotherapy and have an ECOG performance status of 0 or 1 (i.e. completely ambulatory). [28]

AU

Sunitinib is available in Australia and is subsidized 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). [29]

Research

Other solid tumors

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.

Leukemia

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. [34]

Unsuccessful trials

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. [35]

Related Research Articles

<span class="mw-page-title-main">Tyrosine kinase</span> Class hi residues

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.

<span class="mw-page-title-main">Everolimus</span> Chemical compound

Everolimus, sold under the brand name Afinitor among others, is a medication used as an immunosuppressant to prevent rejection of organ transplants and as a targeted therapy in the treatment of renal cell cancer and other tumours.

<span class="mw-page-title-main">Gastrointestinal stromal tumor</span> Human disease (cancer)

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs arise in the smooth muscle pacemaker interstitial cell of Cajal, or similar cells. They are defined as tumors whose behavior is driven by mutations in the KIT gene (85%), PDGFRA gene (10%), or BRAF kinase (rare). 95% of GISTs stain positively for KIT (CD117). Most (66%) occur in the stomach and gastric GISTs have a lower malignant potential than tumors found elsewhere in the GI tract.

<span class="mw-page-title-main">Targeted therapy</span> Type of therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

<span class="mw-page-title-main">Sorafenib</span> Chemical compound

Sorafenib, sold under the brand name Nexavar, is a kinase inhibitor drug approved for the treatment of primary kidney cancer, advanced primary liver cancer, FLT3-ITD positive AML and radioactive iodine resistant advanced thyroid carcinoma.

<span class="mw-page-title-main">Lapatinib</span> Cancer medication

Lapatinib (INN), used in the form of lapatinib ditosylate (USAN) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways. It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2).

Pazopanib, sold under the brand name Votrient, is an anti-cancer medication marketed worldwide by Novartis. It is a potent and selective multi-targeted receptor tyrosine kinase inhibitor that blocks tumour growth and inhibits angiogenesis. It has been approved for renal cell carcinoma and soft tissue sarcoma by numerous regulatory administrations worldwide.

<span class="mw-page-title-main">Axitinib</span> Chemical compound

Axitinib, sold under the brand name Inlyta, is a small molecule tyrosine kinase inhibitor developed by Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (xenograft) models and has shown partial responses in clinical trials with renal cell carcinoma (RCC) and several other tumour types.

<span class="mw-page-title-main">Platelet-derived growth factor receptor A</span>

Platelet-derived growth factor receptor A, also termed CD140a, is a receptor located on the surface of a wide range of cell types. The protein is encoded in the human by the PDGFRA gene. This receptor binds to certain isoforms of platelet-derived growth factors (PDGFs) and thereby becomes active in stimulating cell signaling pathways that elicit responses such as cellular growth and differentiation. The receptor is critical for the embryonic development of certain tissues and organs, and for their maintenance, particularly hematologic tissues, throughout life. Mutations in PDGFRA, are associated with an array of clinically significant neoplasms, notably ones of the clonal hypereosinophilia class of malignancies, as well as gastrointestinal stromal tumors (GISTs).

<span class="mw-page-title-main">Afatinib</span> Chemical compound

Afatinib, sold under the brand name Gilotrif among others, is a medication which is used to treat non-small cell lung carcinoma (NSCLC). It belongs to the tyrosine kinase inhibitor family of medications. It is taken by mouth.

Regorafenib, sold under the brand name Stivarga among others, is an oral multi-kinase inhibitor developed by Bayer which targets angiogenic, stromal and oncogenic receptor tyrosine kinase (RTK). Regorafenib shows anti-angiogenic activity due to its dual targeted VEGFR2-TIE2 tyrosine kinase inhibition. Since 2009 it was studied as a potential treatment option in multiple tumor types. By 2015 it had two US approvals for advanced cancers.

Angiokinase inhibitors are a new therapeutic target for the management of cancer. They inhibit tumour angiogenesis, one of the key processes leading to invasion and metastasis of solid tumours, by targeting receptor tyrosine kinases. Examples include nintedanib, afatinib and motesanib.

<span class="mw-page-title-main">Cabozantinib</span> Chemical compound

Cabozantinib, sold under the brand names Cometriq and Cabometyx among others, is an anti-cancer medication used to treat medullary thyroid cancer, renal cell carcinoma, and hepatocellular carcinoma. It is a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2, and also inhibits AXL and RET. It was discovered and developed by Exelixis Inc.

Onyx Pharmaceuticals Inc. has been a biopharmaceutical company headquartered in South San Francisco, California. The company developed and marketed medicines for the treatment of cancer. Onyx was founded in 1992 by Kevin J. Kinsella and Frank McCormick Ph.D., FRS. McCormick served as the chief scientific officer until 1998, while Kinsella was the firm's chairman. In 2009, the company acquired Proteolix, Inc., a private biotechnology company, for $276 million in cash plus additional milestone payments. In January 2012, the company was named "the top biotechnology takeover target in 2012" through an industry survey. Onyx president and chief executive officer (CEO) Tony Coles had said that Onyx liked its prospects as an independent company and was focused on bringing new therapies to patients. However, at the end of August 2013, Amgen announced it was acquiring Onyx in an agreed $10.4 billion deal.

<span class="mw-page-title-main">Atezolizumab</span> Monoclonal anti-PD-L1 antibody

Atezolizumab, sold under the brand name Tecentriq, is a monoclonal antibody medication used to treat urothelial carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma and alveolar soft part sarcoma, but discontinued for use in triple-negative breast cancer (TNBC). It is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1).

Avelumab, sold under the brand name Bavencio, is a fully human monoclonal antibody medication for the treatment of Merkel cell carcinoma, urothelial carcinoma, and renal cell carcinoma.

<span class="mw-page-title-main">Abemaciclib</span> Anti-breast cancer medication

Abemaciclib, sold under the brand name Verzenio among others, is a medication for the treatment of advanced or metastatic breast cancers. It was developed by Eli Lilly and it acts as a CDK inhibitor selective for CDK4 and CDK6.

VEGFR-2 inhibitor, also known as kinase insert domain receptor(KDR) inhibitor, are tyrosine kinase receptor inhibitors that reduce angiogenesis or lymphangiogenesis, leading to anticancer activity. Generally they are small, synthesised molecules that bind competitively to the ATP-site of the tyrosine kinase domain. VEGFR-2 selective inhibitor can interrupt multiple signaling pathways involved in tumor, including proliferation, metastasis and angiogenesis.

<span class="mw-page-title-main">Avapritinib</span> Chemical compound

Avapritinib, sold under the brand name Ayvakit among others, is a medication used for the treatment of advanced systemic mastocytosis and for the treatment of tumors due to one specific rare mutation: it is specifically intended for adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) that harbor a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation. Avapritinib is a kinase inhibitor.

<span class="mw-page-title-main">Ripretinib</span> Chemical compound

Ripretinib, sold under the brand name Qinlock, is a medication for the treatment of adults with advanced gastrointestinal stromal tumor (GIST), a type of tumor that originates in the gastrointestinal tract. It is taken by mouth. Ripretinib inhibits the activity of the kinases KIT and PDGFRA, which helps keep cancer cells from growing.

References

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  29. ↑ "Pharmaceutical Benefits Scheme (PBS)". Australian Government Department of Health and Aged Care. Archived from the original on 19 April 2023. Retrieved 19 April 2023– via www.pbs.gov.au.
  30. ↑ 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.
  31. ↑ 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 (20 June suppl)). Available at: http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=40&abstractID=34252.
  32. ↑ 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.
  33. ↑ Guti E, Regdon Z, Sturniolo I, Kiss A, Kovács K, Demény M, et al. (September 2022). "The multitargeted receptor tyrosine kinase inhibitor sunitinib induces resistance of HER2 positive breast cancer cells to trastuzumab-mediated ADCC". Cancer Immunology, Immunotherapy. 71 (9): 2151–2168. doi:10.1007/s00262-022-03146-z. PMC   9374626 . PMID   35066605.
  34. ↑ Kolata G (7 July 2012). "In Gene Sequencing Treatment for Leukemia, Glimpses of the Future". The New York Times. Archived from the original on 28 April 2021. Retrieved 28 February 2017.
  35. ↑ GEN Staff Writer (23 May 2011). "FDA Expands Sutent Label to Include Pancreatic Neuroendocrine Tumors". GEN - Genetic Engineering and Biotechnology News. Archived from the original on 19 April 2023. Retrieved 19 April 2023.
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