XL281 ¹
Stage
Phase 1
Status
A phase 1 trial of XL281 in patients with advanced solid tumors is ongoing.
Studies
Advanced Solid Tumors
Principal Targets
Cell growth: B-RAF, C-RAF
- RAF kinases act downstream of RAS and are key components of the RAS/RAF/MEK/ERK kinase signaling pathway.
- Genetic lesions that activate this pathway are common in human tumors, with activating mutations in K-RAS occurring in 30 percent of tumors and activating mutations in B-RAF occurring in approximately 60 percent of melanomas.
Preclinical Data
XL281 specifically targets RAF, a cytoplasmic serine/threonine kinase that lies immediately downstream of RAS and a key component of the RAS/RAF/MEK/ERK pathway that is frequently activated in human tumors. Activating mutations in B-RAF occur in approximately 60 percent of melanoma patients indicating a potentially pivotal role for deregulation of this kinase in the progression of melanoma. XL281 is a potent and highly selective inhibitor of RAF kinases, is orally bioavailable and showed efficacy in tumor xenograft models.
About Melanoma
Melanoma is a form of skin cancer that begins in pigment-producing melanocytes. The American Cancer Society estimated that there would be 59,940 new cases of melanoma and 8,110 melanoma deaths in 2007. Although melanoma accounts for only 3% of all skin cancers, it accounts for the greatest number of skin cancer deaths. Treatment and prognosis vary significantly with the stage of disease at the time of diagnosis. Five-year survival in patients with Stage 0 or Stage I disease is greater than 90%; however, it is only 18% for patients with Stage IV disease.
Recent studies demonstrate that activating mutations of B-RAF kinase are a common occurrence in melanoma, and such mutations have been identified in 60% of melanoma cell lines and biopsies of primary melanoma tumors. RAF kinases act downstream of RAS and are key components of the RAS/RAF/MEK/ERK kinase signaling pathway. Inappropriate activation of this pathway is a prevalent feature of tumor cells and drives tumor growth and survival.
Surgery, the primary treatment for melanoma, may be curative for early stage disease. However, once melanoma has metastasized to distant organs, surgery is no longer considered a curative approach. Chemotherapy or interferon-alpha may also be used to treat late-stage melanoma. However, chemotherapy is less effective in treating this disease than in other cancers.
Additionally, many patients find it difficult to tolerate the high doses of interferon used in a standard treatment regimen. Radiation may be used to treat recurrent melanoma that is not amenable to surgical excision. Chemotherapy and radiation may also be used to treat the symptoms of metastatic melanoma, but such regimens do not cure the disease. The low success rate of standard treatments for late-stage melanoma is reflected in five-year survival rates less than 20%.
Information on Clinical Trials
Information about ongoing clinical trials of Exelixis' investigational product candidates is available at ClinicalTrials.gov, a service of the U.S. National Institutes of Health. General information about clinical trials and issues related to participating in clinical trials also is available at ClinicalTrials.gov.
Related Publications
For publication information related to this compound, please see the Related Publications page.
Footnotes:
1 Pursuant to a product development and commercialization agreement between Exelixis and GlaxoSmithKline, GlaxoSmithKline has the option, after completion of proof-of-concept by Exelixis, to elect to develop up to three compounds in the Exelixis pipeline including XL820, XL184, XL844, XL281 and XL228.
