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.
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 tumors do not generally respond to standard chemotherapy or radiation. Imatinib was the first chemotherapeutic agent proven effective for metastatic gastrointestinal stromal tumors and represented a significant 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. Before sunitinib, patients had no therapeutic option once they became resistant to imatinib.
Sunitinib offers patients with imatinib-resistant gastrointestinal stromal tumors 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 or secondary resistance or intolerance) were treated in a randomized and blinded fashion with either sunitinib or placebo.
The study was unblinded early—at the first interim analysis—due to the clearly emerging benefit of sunitinib. Patients receiving a placebo were offered to switch to sunitinib at that time. In the primary endpoint of the study, the median time to tumor progression (TTP) was more than four-fold longer with sunitinib (27 weeks) compared with placebo (six weeks, P<.0001), based on an independent radiological assessment. The benefit of sunitinib remained statistically significant when stratified by many prespecified baseline variables.
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), the receptor tyrosine kinase that (when improperly activated by mutation) drives the majority of gastrointestinal stromal cell tumors.[10] 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.[11][12]
In addition, sunitinib binds other receptors.
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.
Side effects
Sunitinib adverse events are considered somewhat manageable and the incidence of serious adverse events low.
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. 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]
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][13]
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.
Interactions
Epigallocatechin-3-gallate, a major constituent of green tea, may reduce the bioavailability of sunitinib when they are taken together.[15]
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. 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. 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.
US
In the U.S., many 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 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
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.
- A Phase II study in previously treated patients with metastatic breast cancer found sunitinib “has significant single agent activity”.
- 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.”
- In a phase II study of patients with nonresectable neuroendocrine tumors, 91% of patients responded to sunitinib (9% partial response + 82% stable disease).
- 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.[21]
External links
References
- Sunitinib MSN sunitinib (as malate) 50 mg hard capsule bottle (Accelagen Pty Ltd) Therapeutic Goods Administration (TGA), 28 September 2022, retrieved 19 April 2023^
- Sutent- sunitinib malate capsule DailyMed, retrieved 7 April 2021^
- Sutent EPAR