Sunitinib (brand name Sutent) is a medication used to treat cancer. 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) on January 26, 2006.

Sunitinib was the first cancer drug simultaneously approved for two different indications.

Gastrointestinal Stromal Tumor

Like RCC, gastrointestinal stromal tumor does not typically respond to standard chemotherapy or radiation. Imatinib was the first cancer agent proven effective for metastatic GIST 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.

Sunitinib offers patients with imatinib-resistant GIST 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 trial1 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.

In the primary endpoint of this study, median time to tumor progression (TTP) was more than four-fold longer with sunitinib (27 weeks) compared with placebo (six weeks, P<.0001). These are based on the assessments of an independent radiology lab assessment. The benefit of sunitinib remained statistically significant when stratified for a multitude of prespecified baseline factors.

Among the secondary endpoints, the difference in progression-free survival (PFS) was similar to that in TTP (24 weeks vs six weeks, P<.0001). Seven percent of sunitinib patients had significant tumor shrinkage (objective response) compared with 0% of placebo patients (P=.006).

Another 58% of sunitinib patients had disease stabilization vs. 48% of patients receiving placebo. The median time to response with sunitinib was 10.4 weeks. Sunitinib reduced the relative risk of disease progression or death by 67%, and the risk of death alone by 51%.

The difference in survival benefit may be diluted because placebo patients crossed over to sunitinib upon disease progression, and most of these patients subsequently responded to sunitinib.

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.

Renal Cell Carcinoma

Sunitinib is approved for treatment of metastatic RCC. Other therapeutic options in this setting are pazopanib (Votrient), sorafenib (Nexavar), temsirolimus (Torisel), interleukin-2 (Proleukin), everolimus (Afinitor), bevacizumab (Avastin), and aldesleukin.

Renal cell carcinoma is generally resistant to chemotherapy or radiation. Prior to RTKs, metastatic disease could only be treated with the cytokines interferon alpha (IFNα) or interleukin-2. However, these agents demonstrated low rates of efficacy (5%-20%).

In a phase III clinical trial, median progression-free survival was significantly longer in the sunitinib group (11 months) than in the IFNα group (five months), a hazard ratio of 0.422. 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 2009 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.

Sunitinib treatment trended towards a slightly longer overall survival, although this was not statistically significant.

Hypertension (HTN) was found to be a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib3. 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).

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.

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).

Sunitinib Side Effects

The most common adverse events associated with sunitinib therapy are fatigue, diarrhea, nausea, anorexia, hypertension, a yellow skin discoloration4, 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.

Dose reductions were required in 50% of the patients studied in RCC in order to manage the significant toxicities of this agent.

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.

  1. Demetri GD, et al. (2006). Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 368 (9544): 1329–1338 ↩︎

  2. Motzer RJ, et al. (2007). Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 356 (2): 115–124. ↩︎

  3. Brian I. Rini, Darrel P. Cohen, Dongrui R. Lu, Isan Chen, Subramanian Hariharan, Martin E. Gore, Robert A. Figlin, Michael S. Baum, Robert J. Motzer. Hypertension as a Biomarker of Efficacy in Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib JNCI: Journal of the National Cancer Institute, Volume 103, Issue 9, 4 May 2011, Pages 763–773. ↩︎

  4. Dasanu CA, et al. (2007) Yellow Skin Discoloration Associated with Sorafenib Use for Treatment of Metastatic Renal Cell Carcinoma. Southern Medical Journal. 100 (3): 328–330. ↩︎

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