Enzastaurin is an oral, serine threonine kinase inhibitor which selectively targets the PKC-ß and PI3K/AKT signaling pathways. By blocking these key pathways frequently over-expressed in a wide variety of cancers, enzastaurin suppresses tumor cell proliferation, induces tumor cell death and inhibits tumor-induced angiogenesis. Enzastaurin is being evaluated as a maintenance therapy for the treatment of diffuse large B-cell lymphoma (DLBCL), as well as being evaluated in several studies across a variety of more common tumor types including: breast, colon, lung, ovarian and prostate cancers.
For breast cancer, Lily is sponsoring several comparative trials. There is phase II randomized studies: “A Double-Blind, Randomized, Phase 2 Trial of Capecitabine Plus Enzastaurin Versus Capecitabine Plus Placebo in Patients With Metastatic or Recurrent Breast Cancer Previously Treated With an Anthracycline and a Taxane” and NCT00536939, to determine efficacy and safety of paclitaxel, bevacizumab and enzastaurin versus paclitaxel, bevacizumab, and placebo in patients who are diagnosed with locally recurrent or metastatic breast cancer. A Randomized, Double-Blind, Phase II Trial of Fulvestrant Plus Enzastaurin Versus Fulvestrant Plus Placebo in Aromatase Inhibitor-Resistant Metastatic Breast Cancer, NCT00451555, is also recruting.
It is not clear how the NCT00536939 would be affeted by new developments in the Avastin story in breast cancer. Genetech has filed for the FDA approval for the breast cancer indication in May 2006. However, on Dec. 17th or 2007, ODAC has recoemmended that Avastin not be FDA approved. This was based on the newer analysis that revealed excess mortalitya nd no increase in survival in the Avastin arm, although there was a small progression free survival advantage. While the application for aproval of Avastin is in the process of the FDA approval, and the ODAC has recommended against approval, we cannot act based on this fact until the FDA reacts. The data reported to the FDA had not been fully released for analysis and it is not know whether FDA will follow experts’ recommendations. FDA had on ooccasion disregarded this nonbinding recommendation. The recommendations was made based on the publicly available and released information that has gone through sufficient peer-review and discussion.
Pearce HL, et al, The evolution of cancer research and drug discovery at Lilly Research Laboratories. Adv Enzyme Regul. 2005;45:229-55. Epub 2005 Sep 6.
Antiangiogenic Therapy for Breast Cancer: One Step Forward, Two Steps Back?. JWatch Oncology and Hematology 2008: 1-1