On November 16, 2017, sunitinib malate (Sutent) was approved for the adjuvant treatment of adult patients at high risk of recurrent renal cell carcinoma following nephrectomy.1,2
Supporting Efficacy Data
Approval was based on the findings of the double-blind phase III S-TRAC trial in which 615 patients with a high risk of recurrent renal cell carcinoma following nephrectomy were randomized 1:1 to receive sunitinib malate at 50 mg once daily for 4 weeks on treatment followed by 2 weeks off or placebo.2,3 Patients were treated for nine cycles (approximately 1 year) or until disease recurrence, unacceptable toxicity, or withdrawal of consent.
Sunitinib carries warnings/precautions for hepatotoxicity, cardiovascular events, hypertension, hemorrhagic events, tumor-lysis syndrome, thrombotic microangiopathy, thyroid dysfunction, hypoglycemia, osteonecrosis of the jaw, impaired wound healing, and embryofetal toxicity.
Overall, the median age of patients was 58 years, 73% were male, 84% were white and 12% Asian, and all but one patient had an Eastern Cooperative Oncology Group performance status of 0 or 1.
The median duration of treatment was 12.4 months in the sunitinib group and 12.4 months in the placebo group. The median disease-free survival was 6.8 years (95% confidence interval [CI] = 5.8 years to not reached) in the sunitinib group vs 5.6 years (95% CI = 3.8–6.6 years) in the placebo group (hazard ratio = 0.76, P = .03). Five-year disease-free survival was 59.3% vs 51.3%. Overall survival data were not mature at the time of this analysis.
How It Works
Sunitinib is a small-molecule inhibitor of multiple receptor tyrosine kinases, some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. The agent inhibits platelet-derived growth factor receptors -(PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2, and VEGFR3), stem cell factor receptor (KIT), FMS-like tyrosine kinase 3, colony-stimulating factor receptor type 1, and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib inhibition of the activity and function of these receptor tyrosine kinases has been demonstrated in biochemical and cellular assays and cell proliferation assays. The primary metabolite of sunitinib exhibits potency similar to the parent compound in biochemical and cellular assays.
Sunitinib inhibits phosphorylation of multiple receptor tyrosine kinases (PDGFRβ, VEGFR2, KIT) in tumor xenografts expressing receptor tyrosine kinase targets in vivo and inhibits tumor growth and metastasis in some experimental models. The agent inhibits growth of tumor cells expressing dysregulated target receptor tyrosine kinases (PDGFR, RET, or KIT) in vitro and PDGFRβ-and VEGFR2-dependent tumor angiogenesis in vivo.
How It Is Used
The recommended dose of sunitinib as adjuvant treatment of renal cell carcinoma is 50 mg once daily on a schedule of 4 weeks on treatment followed by 2 weeks off for nine 6-week cycles.
Dose interruption and/or dose modification in 12.5-mg increments or decrements is recommended based on individual safety and tolerability. The maximum dose administered in a study of the agent in patients with pancreatic neuroendocrine tumors was 50 mg daily. In the adjuvant renal cell carcinoma study, the minimum dose given was 37.5 mg.
Treatment should be interrupted for grade 3 or 4 drug-related hepatic adverse reactions and discontinued if there is no resolution. Treatment should not be restarted if patients experience severe changes in liver function tests or have signs and symptoms of liver failure. Treatment should be discontinued in patients with clinical manifestations of congestive heart failure. Treatment should be discontinued in patients developing thrombotic microangiopathy. Treatment should be interrupted in patients with 24-hour urine protein ≥ 3 g and discontinued for repeat episodes of protein ≥ 3 g despite dose reductions or for nephrotic syndrome.
If concomitant use of sunitinib with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir) cannot be avoided, a sunitinib dose reduction to a minimum of 37.5 mg/d should be considered. If concomitant use of sunitinib with a CYP3A4 inducer (eg, dexamethasone, phenytoin, carbamazepine, rifampin) cannot be avoided, a dose increase to a maximum of 87.5 mg/d should be considered. Sunitinib should not be coadministered with the CYP3A4 inducer St John’s wort. Patients with dose increases should be monitored carefully for toxicity.
In the phase III trial of adjuvant therapy in renal cell carcinoma, the most common adverse events of any grade in the sunitinib group occurring more commonly than in the placebo group were mucositis/stomatitis (61% vs 15%), fatigue/asthenia (57% vs 34%), diarrhea (57% vs 22%), hand-foot syndrome (50% vs 10%), hypertension (39%vs 14%), dysgeusia/altered taste (38% vs 6%), and nausea (34% vs 15%). Grade 3 or 4 adverse events occurred in 60% vs 15% of patients, with the most common including hand-foot syndrome (16% vs < 1%), fatigue/asthenia (8% vs 2%), hypertension (8% vs 1%), and mucositis/stomatitis (6% vs 0%). The most common grade 3 or 4 laboratory abnormalities in the sunitinib group were neutropenia (13%), thrombocytopenia (5%), leukopenia (3%), and lymphopenia (3%). Adverse events led to dose interruption in 54% vs 28% of patients, dose reduction in 46% vs 5%, and permanent treatment discontinuation in 28% vs 6%.
Sunitinib has a boxed warning for hepatotoxicity, including severe and fatal cases. It also carries warnings/precautions for hepatotoxicity, including fatal liver failure; cardiovascular events including myocardial ischemia, myocardial infarction, left-ventricular ejection fraction declines to below the lower limit of normal and cardiac failure including death; prolonged QT intervals and torsade de pointes; hypertension; hemorrhagic events, including tumor-related hemorrhage and viscus perforation (both with fatalities); tumor-lysis syndrome (including fatalities); thrombotic microangiopathy, including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure or a fatal outcome; proteinuria; necrotizing fasciitis, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis (including fatalities); thyroid dysfunction; hypoglycemia; osteonecrosis of the jaw; impaired wound healing; and embryofetal toxicity.
Patients should be regularly monitored for liver function, blood pressure, urine protein, complete blood cell counts, and blood glucose. Electrocardiographic and electrolyte monitoring should be considered. Patients with a high tumor burden should be monitored closely for tumor-lysis syndrome. ■
1. U.S. Food and Drug Administration: FDA approves sunitinib malate for adjuvant treatment of renal cell carcinoma. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm585686.htm. Accessed December 12, 2017.
2. Sutent (sunitinib malate) capsules prescribing information, Pfizer, Inc, November 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021938s033lbl.pdf. Accessed December 12, 2017.
3. Ravaud A, Motzer RJ, Pandha HS, et al: Adjuvant sunitinib in high-risk -renal-cell carcinoma after nephrectomy. N Engl J Med 375:2246-2254, 2016.
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).