RATIONAL DESIGN AND DEVELOPMENT OF MOLECULAR TARGETED THERAPIES: TARCEVATM FROM THE BENCH TO THE BEDSIDE AND

Patients with non-small cell lung carcinoma (NSCLC) and pancreatic carcinomas have among the poorest prognosis of all malignancies. Erlotinib hydrochloride (erlotinib, Tarceva™, OSI-774) is an orally active small molecule antitumor agent designed to specifically inhibit the kinase activity of human epidermal growth factor receptor (EGFR/HER1), which is one of the factors influencing the formation and growth a number of cancers. In mid-2004 Tarceva ™ became the first and only targeted therapy clinically proven to produce an increase in survival for NSCLC patients. Recently, it also became the first drug shown in a Phase III trial to prolong survival when added to the standard of care (gemcitabine) in the treatment of patients with previously untreated locally-advanced or metastatic pancreatic cancer. The pre-clinical and clinical experiences with this highly specific EGFR inhibitor have afforded valuable lessons for the rational discovery and development of other targeted therapies and some of these will be elaborated in more detail below. Tarceva ™ acts through direct and reversible inhibition of the epidermal growth factor receptor tyrosine kinase. It emerged as a result of the lead optimization of a high