Small Molecule Tyrosine Kinase Inhibitors with VEGFR as a Target
Sunitinib and Sorafenib
Tumor cells, like normal cells, need an adequate blood supply in order to perform vital cellular functions. In fact, as cells multiply and grow in number and size, access to nutrients and blood supply becomes increasingly critical for their continued survival. Actively dividing tumors secrete special proteins that signal the surrounding area to sprout new blood vessels. This new blood vessel formation is called angiogenesis, and the proteins that trigger this process are called pro-angiogenic factors. The main pro-angiogenic factor is VEGF, which stands for vascular endothelial growth factor. In essence, by secreting VEGF and other related proteins to stimulate new blood vessel growth, tumors support and feed themselves, allowing them to grow. The concept behind angiogenesis inhibition is to thwart this process and thereby fight tumor progression. The appeal of VEGF as a target for anticancer agents is obvious – if you can block the signals needed for the creation of new blood vessels for tumor cells, you can theoretically "starve" the tumor and perhaps arrest progression or cause tumor death. As we will discuss in further detail in the following section on antibody targeted therapies, the first FDA approved anti-VEGF treatment was an antibody against VEGF known as bevacizumab (Avastin) whose first indication was for the first-line treatment of patients with metastatic carcinoma of the colon or rectum, when used in combination with intravenous 5-fluorouracil -based chemotherapy (more on this in the next section).
Interestingly, since the VEGF receptor (VEGFR) is very similar to many other receptor TKIs, small molecules directed against this receptor have some activity at other receptors (see table in the introduction to Part One). The similarity of the VEGF receptor to these receptors predicts that agents developed against the VEGF target may have activity at other receptor TKs, including PDGFRα, PDGFRβ, c-Kit, Flt-3 and CSFR-1, some of which are oncologically important. This is critical because developed drugs may have the benefit of not only affecting angiogenesis, but the downstream targets of these TKIs as well. As we have touched on, c-Kit is important in gastrointestinal stromal tumors (GIST), as are PDGFR and Flt-3, which are implicated in the pathogenesis of acute myelogenous leukemia (AML).
To date, there are two VEGFR TKIs that have been FDA approved for use in cancer patients. They are sunitinib maleate (SU11248, Sutent) and sorafenib (BAY 43-9006, Nexavar). We will begin by discussing sunitinib before moving onto the indications and uses of sorafenib. In the laboratory, sunitinib inhibits the activation of VEGF, Flt-3, c-kit, and PDGFRβ in human cancer cells in mice, resulting in arrested tumor growth and regression of tumor. It was first approved by the FDA for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST) on January 26, 2006, making it the first cancer drug simultaneously approved for two different indications. The latter indication is based on sunitinibâ€™s ability to inhibit c-KIT (CD117), which is the receptor tyrosine kinase mutated in the majority of GISTs.
Gastrointestinal Stromal Tumors
The clinical effectiveness of sunitinib compared to placebo was established in a phase III study published in The Lancet in October of 2006, in which patients with advanced GIST who were intolerant of imatinib, or who progressed during imatinib therapy were randomized to either sunitinib or placebo. Prior to sunitinib, patients had no therapeutic option once they became resistant to imatinib. Compared with placebo, median time to tumor progression (the primary study endpoint) was more than four times as long with sunitinib (27.3 versus 6.4 weeks). Furthermore, the difference in survival benefit may even have been greater, but there were many patients on the placebo arm who crossed over to the sunitinib arm at disease progression, and most of these patients subsequently responded to sunitinib. These results prompted an early unblinding of this study. The side effects, precautions and suggested monitoring tests can be found in summary table in the introduction to this section. Although sunitinib targets the same c-Kit pathway as imatinib, cancer cells may not be as able to find resistance commonly seen with imatinib, which may explain its effectiveness in patients no longer responding to first line therapy.
Renal Cell Carcinoma
The efficacy of sunitinib is currently being evaluated in a broad range of solid tumors, including: colorectal, breast, lung and prostate cancers. However, the other malignancy for which sunitinib has FDA approval for use in is renal cell carcinomas, which is a type of kidney cancer. There are two main types of kidney cancers: 1) renal cell carcinomas (RCC), which arise in the renal cortex and comprises 80-85% of total kidney cancers, and transitional cell carcinomas, which arise in the renal pelvis and represent the remainder of cases. The incidence of kidney and renal pelvis malignancies has increased over the past three decades, although they still only account for about 2% of all cancers. For the discussion regarding sunitinib and sorafenib, our discussion will be limited to renal cell carcinomas.
Although surgical removal of these tumors is the standard of care for patients without advanced or locally metastatic disease, many patients unfortunately present with more advanced disease or subsequently develop metastases following removal of the primary tumor. Prior to the approval of TKIs for metastatic renal cell carcinoma (mRCC), the only option was cytokine treatment with interleukin-2 (IL-2) or interferon alpha (IFNα), both of which are associated with significant side effects. In one large study looking at sunitinib from the New England Journal of Medicine published in January 2007, progression-free survival (the studyâ€™s primary endpoint) more than doubled: 11 months for sunitinib versus 5 months for IFNα. This result held up in their update at the 2008 ASCO meeting.
Now we will switch gears and discuss sorafenib, which is a potent small molecule TKI of multiple receptors, including: BRAF, VEGFR, EGFR, and PDGFR. Sorafenib was approved by the U.S. Food and Drug Administration (FDA) in December 2005 and received European Commission marketing authorization in July 2006 for use in the treatment of advanced renal cell cancers. The clinical efficacy of sorafenib was demonstrated in a randomized phase III trial published in 2007 in the New England Journal of Medicine in which patients with advanced RCC who had received one prior systemic therapy were randomized to receive either sorafenib or placebo. The progression-free survival for patients receiving sorafenib was 167 days compared with 84 days for patients receiving placebo.
Sorafenib has also been demonstrated to possess activity against hepatocellular carcinoma, an aggressive cancer often occurring in the setting of chronic liver disease and cirrhosis. This disease is the third cause of cancer death globally with most deaths occurring within 1 year of diagnosis: median survival ranges from 6-20 months. In a trial first reported at the 2007 ASCO meeting, the multicenter European randomized SHARP trial of 602 patients demonstrated a modest but statistically significant survival benefit, with 3 month improvement in overall survival and time to progression.
Sunitinib and Sorafenib and Toxicities
Sunitinib has been generally well tolerated with a low incidence of serious adverse events, the most common of which are fatigue, diarrhea, nausea, anorexia, high blood pressure, a yellow skin discoloration, rash, and inflammation of the oral mucosa. Most sunitinib-related toxicities can be managed symptomatically or with temporary withdrawal or dose reduction. Side effects with sorafenib are generally similar; however, sorafenib has also been implicated in the development of a neurological condition known as reversible posterior leukoencephalopathy syndrome.
In summary, here are the current FDA approved indications for sunitinib:
- GIST after disease progression on or intolerance to imatinib mesylate.
- Advanced renal cell carcinoma.
Dosing recommendations for sunitinib: 50 mg/day orally, with or without food, 4 weeks on treatment followed by 2 weeks off.
Here are the following current FDA approved indications for sorafenib:
- Advanced renal cell carcinoma.
- Treatment of patients with unresectable hepatocellular carcinoma.
- Dosing recommendations for sorafenib: 400 mg twice daily without food (800 mg/day).