XL518  ³

Stage

Phase 1

Status

A phase 1 trial of XL518 in patients with advanced solid tumors is ongoing.

Studies

Advanced Solid Tumors

Principal Targets

Cell growth: MEK

• MEK is a component 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

Preclinical data were presented most recently at the 2007 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2007.

• In vitro analyses indicate that XL518 is a potent and selective non-competitive inhibitor of MEK1, a component of the RAS/RAF/MEK/ERK signaling pathway. Dysregulation of this pathway contributes to many of the hallmarks of cancer cells: uncontrolled proliferation, invasion, metastasis, angiogenesis, and evasion of apoptosis.
• Inhibition of MEK activity by XL518 prevents phosphorylation and activation of ERK, thus inhibiting downstream signaling activity. Administration of XL518 results in sustained inhibition of pERK in multiple preclinical tumor models. Notably, pERK inhibition in Colo-205 xenograft tumors is substantially more durable than other MEK inhibitors currently in clinical trials.
• XL518 shows dose-dependent tumor growth inhibition and regression at well-tolerated doses in multiple preclinical human tumor xenograft models.

Based on these data, a phase 1 trial of XL518 was initiated. This trial is currently enrolling patients with advanced solid malignancies in order to define the maximum tolerated dose as well as pharmacokinetic and pharmacodynamic effects of XL518.

View the poster

About Melanoma

Melanoma is a form of skin cancer that begins in pigment-producing melanocytes. The American Cancer Society estimates that there will 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%.

About Colorectal Cancer

Colorectal cancer comprises cancers that occur in the colon or the rectum, both of which are components of the gastrointestinal system. The American Cancer Society estimates that there will be 153,760 new cases of colorectal cancer and 51,280 deaths from colorectal cancer in 2007, making it the third most common cancer in both men and women (excluding skin cancer). The five-year survival rate varies widely based on disease stage at time of diagnosis, ranging from 93% for Stage I disease to only 8% for Stage IV.

Recent studies demonstrate that activating mutations of B-RAF kinase are present in 15% of colon cancers. 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.

The primary treatment for colorectal cancer is surgery to remove the malignant tissue and nearby lymph nodes. Radiation, chemotherapy and monoclonal antibodies also may be used alone or in combination after surgery to kill remaining cancer cells.

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:
3 XL518 is the subject of a co-development collaboration between Genentech and Exelixis.