XL888 is a highly potent and orally bioavailable ATP-competitive inhibitor of HSP90, a molecular chaperone protein that regulates the activity and stability of a range of key regulatory proteins, including a number of kinases implicated in cancer cell growth and survival. In preclinical studies, XL888 has been shown to inhibit the proliferation of a broad panel of human tumor cell lines, and to induce marked degradation of HSP90 client proteins, including BRAF, MET, and HER2. XL888 was discovered by Exelixis and is wholly owned by the company.

Clinical Development

Exelixis Internal Development

In 2008 Exelixis conducted a phase 1 study evaluating the safety and tolerability of XL888 in subjects with solid tumors. In order to focus the company’s resources on its lead compound, cabozantinib, Exelixis elected to deprioritize XL888 as well as its other pipeline assets.

Moffitt Cancer Center Investigator-Sponsored Trial (IST)

In 2012, Exelixis granted permission for researchers at Moffitt Cancer Center to initiate a phase 1 IST evaluating the combination of XL888 with vemurafenib in malignant melanoma. The researchers’ preclinical work showed that vemurafenib resistance can arise in melanoma cells as a result of the upregulation of HSP90 client proteins, and that these proteins are effectively downregulated by XL888 treatment. These findings led to the hypothesis that co-treating melanomas with vemurafenib and XL888 may delay the development of resistance and improve duration of response. Data from the phase 1 clinical trial were presented in a late-breaking oral presentation at the 2014 Society for Melanoma Research Congress. Investigators reported that the combination was generally well tolerated, and the objective response rate in 12 response-evaluable patients was 92 percent.

Future Development

Based on the phase 1 results, as well as the successful outcome of coBRIM, the phase 3 pivotal trial of vemurafenib and cobimetinib, the Moffitt Cancer Center plans to initiate a phase 1b triple combination of vemurafenib, cobimetinib and XL888 in patients with metastatic melanoma.

XL888 is an investigational compound; its safety and efficacy profile has not yet been established.