Sutent® is a potent tyrosine kinase inhibitor of KIT, platelet-derived growth factor receptor alpha (PDGFRA), and other signaling proteins. It has properties similar to those of Gleevec.® Both drugs inhibit KIT protein, which is mutated in 75% to 80% of gastrointestinal stromal tumors (GISTs), and PDGRA protein, which is mutated in 5% to 8% of GISTs. Inhibition of the mutated protein, either KIT or PDGFRA, has a direct antitumor effect. In addition, KIT inhibition is beneficial in patients whose tumors lack KIT or PDGFRA mutations (wild-type GISTs).1
Sunitinib (Sutent) was previously called SU-11248. Its chemical name is sunitinib malate. Sunitinib is manufactured by Pfizer.2 On January 26, 2006, the Food and Drug Administration approved Sutent for the treatment of patients who have imatinib-resistant GISTs or who cannot tolerate imatinib.2 Sutent is available as 12.5-, 25-, and 50-mg capsules.1 The recommended dose is 50 mg orally per day for 4 weeks, followed by 2 drug-free weeks, then a repeated cycle. The drug is continued until disease progression or the development of unacceptable toxicity.3
Get detailed prescribing information on the Sutent monograph page at MPR.
Mechanism of Action
Sunitinib is a small-molecule, multitargeted receptor tyrosine kinase inhibitor4 with anti-angiogenic and anti-tumor properties. Sunitinib is particularly an inhibitor of PDGFRA and PDGFRAB, KIT, vascular endothelial growth factor receptor (VEGFR) types 1 through 3, glial cell line-derived neurotrophic factor receptor, fetal liver tyrosine kinase receptor 3, and colony-stimulating factor type 1.5
Maximum plasma concentrations (Cmax) of sunitinib are usually achieved between 6 and 12 hours (Tmax) after oral administration. The bioavailability of sunitinib is not affected by food. Therefore, it can be taken with or without food. Sunitinib is metabolized by the cytochrome P450 enzyme CYP3A4 to generate the primary active metabolite, which is then further metabolized by CYP3A4. Elimination is mainly through feces. In a human mass balance study of sunitinib, 61% of the dose was eliminated in feces, and 16% of the dose was eliminated renally. The clearance rate is 34 to 62 L/h, and the volume of distribution is 2230 L.4
Efficacy in Trials and Trial Results
A total of 97 patients in a Western population who had metastatic GIST that had progressed on imatinib or who could not tolerate it were enrolled in an open-label, single-arm, dose-escalation phase I/II trial. The patients received sunitinib at a dose of 25, 50, or 75 mg/d on 1 of 3 schedules. Clinical benefits were noted in 52 patients (54%): 7 with an objective partial response and 45 with stable disease lasting 6 months or longer. A reduction in tumor glycolytic activity, measured with [18F]fluoro-2-deoxy-d-glucose positron emission tomography, was observed in many patients within 7 days after they had started sunitinib. The treatment reduced tumor cell proliferation by more than 25% in 52% of cases analyzed and reduced levels of phospho-KIT in tumor biopsy specimens, suggesting target modulation. The recommended dose schedule was 50 mg/d for 4 weeks followed by 2 weeks off treatment. Adverse effects were mild to moderate.6
Another open-label, nonrandomized, dose-escalating phase I/II study evaluated the efficacy and safety of sunitinib in an Asian population. In phase I of the study, 12 patients received sunitinib doses of 25, 50, or 75 mg/d on a 4/2 schedule (4 weeks on, then 2 weeks off treatment). The administration of 50 mg/d on a 4/2 schedule until disease progression and/or unacceptable toxicity was the recommended phase II dosage. Many dose-limiting toxicities were noted in the cohort that received 75 mg/d on a 4/2 schedule.7
In phase II of the study, which comprised 36 patients, the clinical benefit rate was found to be 39% (95% CI, 23%-57%): partial response in 11% and stable disease (≥22 weeks) in 28% of patients. The treatment-related non-hematologic adverse effects observed were hand-foot syndrome in 86% and fatigue in 67% of patients. A correlation was noted between reduction from baseline in plasma soluble KIT levels and clinical benefit.7
After the phase I/II trial, the efficacy of sunitinib was evaluated in a multicenter, randomized, double-blind, placebo-controlled phase III trial (NCT00075218) of patients with imatinib resistance or intolerance.8 Sunitinib or placebo was administered orally once daily at a starting dose of 50 mg administered in 6-week cycles (4 weeks on, then 2 weeks off treatment). The primary endpoint was time to tumor progression. A total of 312 patients were randomized in a ratio of 2:1 to sunitinib (207 patients) or placebo (105 patients). Median time to tumor progression was 27.3 weeks (95% CI, 16.0-32.1) in the patients who received sunitinib and 6.4 weeks (95% CI, 4.4-10.0) in those who received placebo (hazard ratio, 0.33; P <0.0001). The therapy was tolerated very well. Treatment-related adverse side effects were nausea, diarrhea, fatigue, and skin discolorations. A significant clinical benefit, including disease control and superior survival, was observed for sunitinib in comparison with placebo in individuals who had advanced GISTs after imatinib treatment failure and discontinuation of imatinib.8
An expanded-access study was undertaken among patients ineligible for previous trials or for whom sunitinib was unavailable. This trial enrolled 1126 individuals, who received sunitinib at 50 mg/d on a 4/2 schedule until disease progression and/or unacceptable toxicity. The results were better than those in the pivotal trial. Median time to progression was 41.0 weeks (95% CI, 36-47), and overall survival (OS) was approximately 75.0 weeks (95% CI, 68-84). On subgroup analysis, factors favoring OS were age younger than 65 years, previous imatinib dose of 400 mg daily or less, and Eastern Cooperative Oncology Group performance status of 1 or lower.9
Warnings, Precautions and Adverse Reactions
Sutent can cause hepatotoxicity resulting in liver failure or death. Cases of liver failure have occurred in clinical trials.10 Liver function tests should be done before the start of treatment, between each cycle of treatment, and whenever clinically indicated. Sutent should not be restarted in patients with marked alterations in liver function tests or evidence of liver failure. Women of childbearing age must be informed about detrimental effects to the fetus, and pregnancy should be avoided. Cardiac toxicity, including a decline in left ventricular ejection fraction, cardiac failure, and death, has been noted. Patients should be monitored to detect clinical features of congestive heart failure and hypertension. Prolonged QT intervals and torsades de pointes have also been documented. Patients taking Sutent must undergo on-treatment electrocardiography and electrolyte monitoring. Hemorrhagic events and thyroid dysfunction have also been observed. Temporary interruption of Sutent is advised in patients undergoing major surgery. Patients’ adrenal function should be monitored in the case of stressors such as surgery, trauma, and severe infection because adrenal hemorrhage has been observed in animal studies.10
Adverse effects of Sutent are nausea, diarrhea, fatigue, mouth irritation, and skin and hair color changes. More serious effects include hypertension, increased bleeding risk, swelling, heart diseases, and fatal liver conditions.11
The CYP3A4 inducers that should be avoided or that require an increase in the dose of sunitinib are phenytoin, carbamazepine, dexamethasone, rifampin, rifabutin, rifapentine, St. John’s wort, and phenobarbital. The CYP3A4 Inhibitors that should be avoided or that require a decrease in the dose of sunitinib are ketoconazole, itraconazole, aprepitant, clarithromycin, erythromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole.2
- What Is Sutent – Gleevec resistant GIST medication. Accessed August 8, 2021.
- Sunitinib (Sutent) basics for GIST | GIST Support International. Accessed August 8, 2021.
- Sutent (sunitinib) dosing, indications, interactions, adverse effects, and more. Medscape. Accessed August 8, 2021.
- PubChem compound summary for CID 5329102, Sunitinib. National Library of Medicine. National Center for Biotechnology Information. Accessed August 8, 2021.
- Mulet-Margalef N, Garcia-Del-Muro X. Sunitinib in the treatment of gastrointestinal stromal tumor: patient selection and perspectives. Onco Targets Ther. 2016;9:7573-7582. doi:10.2147/OTT.S101385
- Demetri GD, Heinrich MC, Fletcher JA, et al. Molecular target modulation, imaging, and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure. Clin Cancer Res. 2009;15(18):5902-5909. doi:10.1158/1078-0432.CCR-09-0482
- Shirao K, Nishida T, Doi T, et al. Phase I/II study of sunitinib malate in Japanese patients with gastrointestinal stromal tumor after failure of prior treatment with imatinib mesylate. Invest New Drugs. 2010;28(6):866-875. doi:10.1007/s10637-009-9306-9
- Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368(9544):1329-1338. doi:10.1016/S0140-6736(06)69446-4
- Reichardt P, Kang Y, Ruka W, et al. Detailed analysis of survival and safety with sunitinib (SU) in a worldwide treatment-use trial of patients with advanced GIST. J Clin Oncol. 200820;26(15 Suppl):10548.
- Sutent (sunitinib). US Food and Drug Administration. Revised 5/2011. Reference ID: 2950085. Accessed August 8, 2021.
- Targeted drug therapy for gastrointestinal stromal tumors. American Cancer Society. Accessed August 8, 2021.
Reviewed by Debjyoti Talukdar, MD, on 8/16/221.