Sunitinib (Sutent)

Oral inhibitor of vascular endothelial growth factor (VEGF) tyrosine kinase.

It inhibits cellular signalling by targeting multiple receptor tyrosine kinases (RTKs): including 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.

An ATP competitive inhibitor of the catalytic activity of related receptor tyrosine kinases, including VEGFR-1,-2,-3, PDGFR-α and ß, c-KIT, FLT-3, CSF-1R, and RET.

Small molecule inhibitor with high affinity to bind to VEGF and PDGF receptors.

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.

Has benefit as second line treatment for Gastrointestinal stromal tumors.

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.

Each of receptor tyrosine kinases inhibited by sunitinib implicated in processes critical to tumor progression.

In a study of 63 patients treated with second line treatment there was a response rate greater than 40% in metastastic renal cell cancer, 27% had stable disease lasting greater than 3 months and median time to progression was 8.7 months.

Trial of sunitinib vs alfa-interferon as first line treatment in patients with favorable and intermediate profiles renal cell cancer: sunitinib response rate 39% vs 8% for alfa-interferon, median progression free time 11 vs. 5 months, respectively and quality of life favored sunitinib (Motzer).

Dose response and dose survival documented for renal cell carcinoma, indicating the importance of maintaining the maximum dose of drug.

Continuous treatment with only short breaks is important because tumor progression in renal cell carcinoma may occur during periods of treatment interruption.

Approved for use in gastrointestinal stromal tumors, and neuroendocrine tumors.

Use after failure of first time cytokine therapy in metastatic renal cancer associated with a median survival of 16.4 months.

In a pancreatic neuroendocrine tumor study 171 patients were randomly assigned best supportive care with sunitinib or placebo: median progression free survival 11.4 months in the sunitinib group compared to 5.5 monthsin the placebo group, the objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group ( Raymond E et al).

Used 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.

In a Phase II study of patients with nonresectable neuroendocrine tumors, 91% of patients responded to sunitinib (9% partial response + 82% stable disease).

Approved for treatment of metastatic renal cell carcinoma.

Objective response rate also remained superior: 39-47% for sunitinib versus 8-12% with IFN.

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.

Trial in patients with recurrent or metastatic squamous cell carcinoma of the head and neck demonstrated modest activity, but may be associated with bleeding, worsening tumor skin ulceration or tumor fistula formation (Machiels JP).

In patients with imatinib refractory GIST tumor there is a 4 fold increase in time to progression versus placebo with sunitinb, with an overall response rate of 6.8%.

Toxicities include fatigue, nausea, diarrhea, dermatitis, skin discoloration, myalgia, dyspnea and myelosuppression.

Sunitinib binds other receptors:




Most common adverse events: fatigue, diarrhea, nausea, anorexia, hypertension, a yellow skin discoloration, hand-foot skin reaction, and stomatitis.

Fatigue is the adverse event most commonly associated with sunitinib therapy.

Dose reductions were required in 50% of the patients studied in RCC.

Lab abnormalities associated with sunitinib therapy include lipase, amylase, neutrophils, lymphocytes, and platelets.

Hypothyroidism and reversible erythrocytosis have also been reported.

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

Associated with increase in lipase, amylase levels, stomatitis and hand-foot syndrome.

Hepatotoxicity, cardiovascular events including heart failure, myocardial disorders and cardiomyopathy have been reported.

4-8% of patients receiving ≥50 mg per day manifest grade ¾ hypertension.

Rarely associated with reversible posterior leukoencephalopathy syndrome.

Has been reported to occur with tumor lysis syndrome.

Occasionally associated with decreased cardiac ejection fraction.

Proteinuria in nephrotic syndrome and renal insufficiency have been reported.

Associated with changes in hair color.

The combination with zoledronic acid increases the risk of osteonecrosis of the jaw.

Approximately 50-75% of treated patients complained about fatigue.

Studies suggesting that 32% of patients will require a dose with interruption, and 32% required dose reduction secondary to adverse reactions.

One or more thyroid function abnormalities develop in treated patients, suggesting regular surveillance of thyroid infection is needed.

Hypothyroidism associated with increased survival in malignancies.

Hypoglycemia occurs in about 2% ofpatients.

Hand-foot syndrome is the most significant skin toxicity.

Approximately 30% of patients develop hand-foot syndrome.

Hand-foot syndrome may present as painful erythematous, edematous palms, soles, with paresthesias, tingling or numbness.

Skin toxicity typically occurs after three or four weeks of treatment.

Dose 50mg once daily orally, 4 weeks on and 2 weeks off.

Newer scheduling to reduce toxicity is 2 weeks on and 1 week off which maintains efficacy and reduces severity of adverse effects.

No dose adjustments for age, body weight, renal function race or gender.

Pregnancy category AU: D

Routes ofadministration oral

Protein binding 95%

Metabolism Liver (CYP3A4-mediated)

Elimination half-life 40 to 60 hours

80 to 110 hours (metabolite)


Fecal (61%) and Kidney (16%)

Patients should avoid St John’s Wort, and grapefruit products.

Dose should be decreased with coadministration of a strong CYP3A4 inhibitor and increased with a coadministered CYP3A4 inducer.

Most adverse events can be managed through supportive care, dose interruption, or dose reduction.

A study comparing 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): overall survival, progression free survival and drug adherence were significantly higher in the patients who received Sunitinib on the alternative schedule. 

Patients on the alternative schedule had a better tolerance and lower severity of adverse events which frequently lead to discontinuation of treatment of metastatic renal cell cancer patients.

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 that it 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).

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