Sunitinib ( CAS: 557795-19-4 )

Sunitinib (marketed as Sutent by Pfizer, 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.

Mechanism of action

Sunitinib inhibits cellular signaling by targeting multiple receptor tyrosine kinases (RTKs).

These include 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. 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 (when improperly activated by mutation)

drives the majority of gastrointestinal stromal cell tumors. It has been recommended as a

second-line therapy for patients whose tumors develop mutations in KIT that make them

resistant to imatinib, or who become intolerant to the drug.

In addition, sunitinib inhibits other RTKs. These include the following:

• • RET
  • CSF-1R
  • flt3

The fact that sunitinib targets many different receptors, leads to many of its side effects

such as the classic hand-foot syndrome, stomatitis, and other dermatologic toxicities.

Indications

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 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 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.

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 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.

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 no grade 4 fatigue was reported.