Eli Lilly and Company's enzastaurin, an investigational, multi-targeted therapy that is currently the focus of two global Phase III clinical trials, one for the treatment of glioblastoma and one in non-Hodgkin's lymphoma, is the subject of several abstracts presented at the annual meeting of the American Society of Clinical Oncology (ASCO).
New pre-clinical data provided support for the oral agent's activity in a number of difficult to treat and chemo resistant tumor types. Clinical results also highlighted enzastaurin's potential to enhance the benefit of standard-of-care chemotherapies such as Gemzar) (gemcitabine HCl), Alimta) (pemetrexed) and Xeloda) (capecitabine) with manageable side effects.
"Pre-clinical data showing enzastaurin's synergistic activity with standard-of-care chemotherapies like Gemzar and Alimta, suggest this oral agent is a book containing many chapters, and we look forward to understanding all of enzastaurin's promising applications," said Richard Gaynor, M.D., vice president, cancer research and global oncology platform leader for Eli Lilly and Company.
Three presentations were made highlighting enzastaurin's potential for additive or synergistic anticancer effects without excessive toxicity in advanced solid tumors including lung, breast, pancreas, and head/neck cancers. The data were gathered from three Phase I studies that combined enzastaurin with Gemzar/cisplatin (abstract #2046), Alimta (abstract #2047) and capecitabine (abstract #2048). Each study showed similar results, concluding in each case the enzastaurin combination was generally well tolerated across all dose levels; and there were no observations of significant alterations in pharmacokinetics (the process by which a medication is absorbed, distributed, metabolized, and eliminated by the body). Further data on enzastaurin's safety (abstract #13077) were published from a review of data gathered from three Phase I and II studies, suggesting that enzastaurin is generally well tolerated across all doses and for extended durations. According to this analysis and given the severity of the disease and absence of controlled studies for comparisons, no event other than chromaturia or fecal discoloration (due to reddish-orange color of the active ingredient) appears to be definitively attributable to enzastaurin.
Additional pre-clinical studies presented point toward enzastaurin's in-vitro activity in certain non-small cell (NSCLC) and small cell cancer (SCLC) cell lines, as well as in chemo resistant ovarian cancer cells types. In the lung cancer study, (abstract #13138) researchers concluded enzastaurin produced in-vitro growth inhibition of SCLC and NSCLC cell lines accompanied by modulation of GSK3-b (glycogen synthase kinase 3 beta), a protein involved in energy metabolism and neuronal cell development. This study also showed enzastaurin had synergistic growth inhibition when combined with Alimta in these cell lines. The ovarian cancer study (abstract #20037) corroborated the use of GSK3-beta phosphorylation as a marker for PKC-beta activity in ovarian cancer models. This further indicates that taxane-resistant cells seemed to respond to enzastaurin treatment in low concentrations and further supported the study of enzastaurin to evaluate the benefit for women with taxane-resistant ovarian cancer.
"Studies across tumor types continue to generate encouraging data on the utility of enzastaurin's multi-pronged mechanism of action," continued Dr. Gaynor. "The studies presented today specifically support further evaluation of enzastaurin in non-small cell and small cell lung cancers, as well as ovarian cancer. The findings are particularly important in directing further clinical development utilizing biomarker technology to provide patients with right therapy."
Enzastaurin is an oral serine-threonine kinase inhibitor that is designed to suppress tumor growth through multiple mechanisms. Pre-clinical data suggest it may reduce the cell's ability to divide (cell proliferation), increase the natural death of the tumor cells (apoptosis), and inhibit tumor-induced blood supply (angiogenesis). Data have suggested enzastaurin inhibits signaling through the PKC-beta and PI3K/AKT pathways. These pathways have been shown to be activated in a wide variety of cancers. In addition to glioblastoma and non-Hodgkin's lymphoma, enzastaurin is also being studied in other multiple tumor types, including colorectal cancer, non-small cell lung cancer, pancreatic cancer, and mantle cell lymphoma.