Sunitinib
This article includes improve this article by correcting them. (June 2019) ) |
Clinical data | |
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Trade names | Sutent, others |
Other names | SU11248 |
AHFS/Drugs.com | Monograph |
MedlinePlus | a607052 |
License data | |
Pregnancy category |
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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 | |
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Sunitinib, sold under the brand name Sutent, is an
As of August 2021, sunitinib is available as a
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
Among the
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
Renal cell carcinoma is generally resistant to chemotherapy or radiation. Prior to RTKs, metastatic disease could only be treated with the cytokines
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.
- Median overall survivability 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.[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
Sunitinib also inhibits
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
History
The drug was discovered at
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
Society and culture
Economics
Sunitinib is marketed by
US
In the U.S., many insurance companies[
UK
In the UK,
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
- A Phase II study in previously treated patients with metastatic breast cancer found sunitinib “has significant single agent activity”.[30]
- 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.” [31]
- In a phase II study of patients with nonresectable neuroendocrine tumors, 91% of patients responded to sunitinib (9% partial response + 82% stable disease).[32]
- Sunitinib was found to protect JIMT-1 breast cancer cells against natural killer cell-mediated cytotoxicity, which was claimed to block the anticancer immune response. If sunitinib were to be paired with anticancer immunotherapies, this finding might need to be taken into account.[33]
Leukemia
Sunitinib was used to treat the
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]
References
- ^ "SUNITINIB MSN sunitinib (as malate) 50 mg hard capsule bottle (Accelagen Pty Ltd)". Therapeutic Goods Administration (TGA). 28 September 2022. Archived from the original on 16 October 2022. Retrieved 19 April 2023.
- ^ a b c d e f "Sutent- sunitinib malate capsule". DailyMed. Archived from the original on 23 March 2021. Retrieved 7 April 2021.
- ^ "FDA approves new treatment for gastrointestinal and kidney cancer". U.S. Food and Drug Administration (FDA). 2006. Archived from the original on 3 February 2006.
- ^ "Sunitinib malate: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Archived from the original on 25 September 2021. Retrieved 24 September 2021.
- ^ S2CID 25931515.
- ^ "Phase II Trial of Sunitinib (SU011248) in Patients With Recurrent or Inoperable Meningioma". 21 December 2015. Archived from the original on 19 April 2023. Retrieved 19 April 2023 – via clinicaltrials.gov.
- ^ "Pfizer Scores New Approval for Sutent in Europe". 2 December 2010. Archived from the original on 24 September 2015. Retrieved 4 December 2010.
- ^ "FDA approves Sutent for rare type of pancreatic cancer". U.S. Food and Drug Administration (FDA) (Press release). 20 May 2011. Archived from the original on 23 May 2011. Retrieved 23 April 2023.
- ^ PMID 17215529.
- ^ 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.
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- ^ "Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. | CureHunter". www.curehunter.com. Archived from the original on 19 April 2023. Retrieved 19 April 2023.
- PMID 19015436. Archived from the originalon 25 July 2011.
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- patent extensions.
- ^ "Details for Generic 'SUNITINIB MALATE'". DrugPatentWatch. Archived from the original on 10 April 2021. Retrieved 27 April 2016.
- ^ Jamie Dlugosch (13 March 2009). "Will biologics and Sutent save Pfizer?". InvestorPlace. Archived from the original on 4 March 2016. Retrieved 27 April 2013.
- ^ Zacks Investment Research (22 March 2007). "Pfizer's a Sell: Shrinking Top Line, No Blockbusters In the Pipeline". Seeking Alpha. SeekingAlpha. Archived from the original on 3 March 2016. Retrieved 7 June 2009.
- ^ BMJ 31 January 2009 "NICE and the challenge of cancer drugs" p271
- ^ "'We'll sell our house for this drug'". 7 August 2008. Archived from the original on 19 April 2023. Retrieved 19 April 2023 – via news.bbc.co.uk.
- ^ "Kidney cancer patients should get Sutent on the NHS, says NICE - Telegraph". 24 May 2010. Archived from the original on 30 December 2010. Retrieved 6 July 2021.
- ^ "Renal cancer - NICE Pathways". pathways.nice.org.uk. Archived from the original on 15 March 2017. Retrieved 14 March 2017.
- ^ "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.
- ^ 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.
- ^ 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.
- ^ 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.
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- ^ 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.
- ^ 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.
External links
- "Sunitinib". National Cancer Institute.