L3.3 Role of Biomarkers in the Development of Targeted Cancer Therapeutics

Abstract

ABSTRACT Success rates in oncology drug development have been challenging for a number of reasons, including issues with drugability and target validation, determination of the appropriate dose and schedule, tumor and patient heterogeneity, and drug resistance mechanisms. With an increased understanding of the genetic basis of cancer, the identification of specific biomarkers that help predict drug response in specific patient populations has become of critical importance. Drug development efforts are focusing on both pharmacodynamic markers to determine the ability of drugs to inhibit their specific target and predictive biomarkers to define subpopulations of patients who will respond to specific targeted agents. Predictive markers, including HER2 amplification in breast cancer, EGFR mutation and EML4-ALK translocation in lung cancer, BRAF V600E mutation in melanoma, and K-ras mutations in colorectal cancer, have been critical to the development of agents that target these genetic changes in tumors. A better understanding of cancer biology, specifically tumor heterogeneity coupled with novel technologies, will help facilitate the identification of patient populations more likely to respond to targeted therapeutics. Improving the application and utility of this detailed understanding of disease will increase both the success rate in cancer clinical development and the benefit to specific patients. This presentation will review efforts to better understand tumor heterogeneity and the development of novel cancer therapeutics and associated biomarkers. One example of this is the Asian Cancer Research Group (ACRG) which is a pre-competitive consortium comprised of Lilly, Merck and Pfizer that was initiated in 2009 to study genomic profiling and clinical outcomes of prevalent cancers in Asia, including HCC, NSCLC and gastric cancer. The recent results of an ACRG HCC analysis, and the potential impact on drug development, will be presented. Next, the development of biomarkers for cancer therapeutics will be discussed, with a focus on targets involved in the regulation of the tumor microenvironment and tumor invasion, including cMET and TGFb. This discussion will include Lilly Oncology's approach to biomarker co-development with specific therapeutics against these targets.