Sunitinib

Sunitinib (marketed as Sutent, and previously known as SU11248) is an oral, 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. ^[1] Sunitinib has become the standard of care for both of these cancers, and is currently being studied for the treatment of many others.

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Mechanism of action

Sunitinib inhibits cellular signaling by targeting multiple RTKs. These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R), which play a role in both tumor angiogenesis and tumor cell proliferation. The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularization and cancer cell death, and ultimately tumor shrinkage. Sunitinib also inhibits KIT (CD117), the RTK that drives the majority of GISTs. In addition, sunitinib inhibits other RTKs including RET, CSF-1R, and flt3. ^[2]

Indications

Renal cell carcinoma

Sunitinib has become the new standard of care in the first-line treatment of metastatic RCC.

RCC is generally resistant to chemotherapy or radiation. Prior to RTKs, metastatic disease could only be treated with the cytokines interferon alpha (IFNa) or Interleukin 2 (IL-2). However, these agents demonstrated low rates of efficacy (5%-20%) and are associated with severe infusion-related adverse events. ^[3]

In two separate Phase II studies, sunitinib demonstrated consistent response rates of approximately 40% in patients who had already failed cytokine therapy. ^[3] Although these were Phase II studies, these results were impressive enough for the FDA to approve sunitinib for first-line use even before Phase III data were available.

The results of the Phase III study, published in the New England Journal of Medicine in 2007, proved that sunitinib offers superior efficacy compared with IFNa. Progression-free survival (primary endpoint) was more than doubled: 11 months for sunitinib compared with 5 months for IFNa (P<.000001). ^[2] The benefit for sunitinib was significant across all major patient subgroups, including those with a poor prognosis at baseline. ^[3]

Secondary endpoints also favored sunitinib. 28% of sunitinib patients had significant tumor shrinkage (objective response) compared with only 5% of patients who received IFNa (P<.001). Although overall survival data are not yet mature, there is a clear trend toward improved survival with sunitinib. Patients receiving sunitinib also reported a significantly better quality of life than those treated with IFNa (P<.001). ^[3]

Sunitinib was generally better tolerated than IFNa. Significantly more patients discontinued IFN due to adverse events (P=.05), withdrawal of consent (P<.001), or disease progression (P<.001). Serious fatigue was significantly more common with IFNa (P<.05), while diarrhea was reported more commonly with sunitinib. ^[3]

Based on these results, lead investigator Dr. Robert Motzer announced at ASCO 2006 that “Sunitinib is the new reference standard for the first-line treatment of mRCC.” ^[4]

Gastrointestinal stromal tumor

Like RCC, GIST does not generally 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 2 years. Prior to sunitinib, patients had no therapeutic option once they became resistant to imatinib. ^[5]

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 proven in a large, Phase III clinical trial 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. ^[5]

The study was unblinded early, at the very first interim analysis, due to the clearly emerging benefit of sunitinib. At that time, patients receiving placebo were offered to switch over to sunitinib. In the primary endpoint of this study, median time to tumor progression (TTP) was more than 4-fold longer with sunitinib (27 weeks) compared with placebo (6 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, including: ^[5]

• Prior dose of imatinib
• Prior duration of imatinib therapy
• ECOG Performance status
• Age
• Weight
• Race
• Pain score
• Time since initial diagnosis
• Study location
• ITT vs PP analysis
• Investigator vs independent radiology lab assessment

Among the secondary endpoints, the difference in PFS was similar to that in TTP (24 weeks vs 6 weeks, P<.0001). 7% 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. ^[5] 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 by the fact that placebo patients crossed over to sunitinib upon disease progression, and most of these patients subsequently responded to sunitinib. ^[5]

Sunitinib was relatively well tolerated. 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. 9% of sunitinib patients and 8% of placebo patients discontinued therapy due to an adverse event. ^[5]

Fatigue is the adverse event most commonly associated with sunitinib therapy. In this study, 34% of sunitinib patients reported any grade of fatigue, compared with 22% for placebo. The incidence of grade 3 (severe) fatigue was similar between the two groups, and there was no grade 4 fatigue reported. ^[5]

Other solid tumors

The efficacy of sunitinib is currently being evaluated in a broad range of solid tumors, including breast, lung, and colorectal cancers. Early studies have shown single-agent efficacy in a number of different areas.

• A Phase II study in previously-treated patients with metastatic breast cancer found that sunitinib “has significant single agent activity” ^[6]
• A Phase II study of refractory non-small-cell lung cancer found that “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.” ^[7]
• In a Phase II study of patients with nonresectable neuroendocrine tumors (NET), 91% of patients responded to sunitinib (9% partial response + 82% stable disease) ^[8]

Safety

An oral agent, sunitinib is generally well tolerated. Adverse events are manageable and the incidence of serious adverse events is low. ^{[3] [5]}

The most common adverse events associated with sunitinib therapy include fatigue, diarrhea, nausea, anorexia, hypertension, and skin discoloration. 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] [5]}

Serious (grade 3 or 4) adverse events occur in ≤10% of patients and include hypertension, fatigue, asthenia, diarrhea, and hand-foot syndrome. Lab abnormalities associated with sunitinib therapy include lipase, amylase, neutrophils, lymphocytes, and platelets. Hypothyroidism has also been associated with sunitinib. ^[2]

Most adverse events can be managed through supportive care, dose interruption, or dose reduction. ^{[3] [5]}

References