Two targets, one drug for new EGFR inhibitors. (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)q uinazolin-4-amine)

摘要

The new drug that garnered the most media attention at this year's American Society of Clinical Oncology meeting was lapatinib (Tykerb), a targeted agent that showed a tumor response in metastatic breast cancer resistant to trastuzumab (Herceptin). In an international phase III trial, lapatinib with capecitabine significantly improved the time to progression compared with capecitabine alone. The findings prompted early closing of the trial and put lapatinib on track for regulatory review later this year.But lapatinib drew attention for another reason as well: It was designed to hit two receptors at once-the epidermal growth factor receptor (EGFR) and HER2. Both receptors are important targets of already-approved drugs: Trastuzumab targets HER2, and cetuximab,gefitinib, and erlotinib aim at EGFR. But as the first successful agent designed to hit both receptors, lapatinib marks the coming of age of a new generation."We're moving now from the era of single-targeted agents to agents that are multitargeted," said Ronald Natale, M.D., director of the national lung cancer research program at Cedars-Sinai Medical Center in Los Angeles. Natale presented positive findings for another new drug that aims at two targets: ZD6474 (Zactima).Lapatinib and ZD6474 have many younger cousins in this second generation of dual-targeted drugs. At least eight agents that aim at EGFR and one or more other targets are in clinical trials (see box), and many others are in pre-clinical pipelines.As this new wave of multitargeted drugs moves into and through clinical trials, investigators are working through several key questions: Is hitting two targets better than one? If so, is one molecule with two targets superior to acombination of two separate drugs? And are there meaningful differences between drugs that have the same two or three targets?