Bridging the Gap Between Preclinical and Clinical Evaluation of Therapeutic Candidates

Session 6

Kinase Inhibitors for the Treatment of Cancer

Mark J. Ratain, M.D.
Department of Medicine
Committee on Clinical Pharmacology and Pharmacogenomics
Cancer Research Center
The University of Chicago
Chicago, IL 60637

As of July 10, 2007, there are seven small molecule kinase inhibitors approved by the US Food and Drug Administration for the treatment of cancer (including leukemia). In addition, there are four monoclonal antibodies targeted against either kinase receptors or their cognate ligands. The first approved monoclonal antibody was trastuzumab, approved for the treatment of breast cancer in 1998, and the first approved small molecule was imatinib, approved for the treatment of chronic myelogenous leukemia in 2001. The nine subsequent approvals have been for a diverse set of malignancies, including lung, colorectal, and kidney cancers, as well as chronic myelogenous leukemia and gastrointestinal stromal tumors. Two agents, sunitinib and dasatinib, represent second-generation drugs, in that they are indicated for patients refractory to imatinib. Scores, if not hundreds, of kinase inhibitors are in late preclinical and clinical development, with a wide range of targets. Successful development of kinase inhibitors requires careful attention to clinical pharmacology and trial design, and in some cases codevelopment of a predictive diagnostic test. Several examples of successful development will be discussed in detail.

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