Personalized Predictive Medicine and Genomic Clinical Trials Richard Simon, D.Sc. Chief, Biometric Research Branch National Cancer Institute http://brb.nci.nih.gov brb.nci.nih.gov „ Powerpoint presentations „ Reprints „ BRB-ArrayTools software „ Web based Sample Size Planning Personalized Oncology is Here Today and Rapidly Advancing „ Key information is generally in the tumor genome, not in inherited genetics „ Personalization is based on limited stratification of traditional diagnostic categories, not on individual genomes (so far) Personalized Oncology is Here Today „ Estrogen receptor over-expression in breast cancer „ tamoxifen, aromatase inhibitors „ HER2 amplification in breast cancer „ Trastuzumab, Lapatinib „ OncotypeDx in breast cancer „ Low score for ER+ node - = hormonal rx „ KRAS in colorectal cancer „ WT KRAS = cetuximab or panitumumab „ EGFR mutation or amplification in NSCLC „ EGFR inhibitor These Diagnostics Have Medical Utility „ They are actionable; they inform therapeutic decision-making leading to improved patient outcome „ Tests with medical utility help patients and can reduce medical costs „ Although the randomized clinical trial remains of fundamental importance for predictive genomic medicine, some of the conventional wisdom of how to design and analyze rct’s requires re-examination „ The concept of doing an rct of thousands of patients to answer a single question about average treatment effect for a target population presumed homogeneous with regard to the direction of treatment efficacy in many cases no longer has an adequate scientific basis „ Cancers of a primary site often represent a heterogeneous group of diverse molecular diseases which vary fundamentally with regard to „ the oncogenic mutations that cause them „ their responsiveness to specific drugs „ How can we develop new drugs in a manner more consistent with modern tumor biology and obtain reliable information about what regimens work for what kinds of patients?