Systematic survey of therapeutic trials for metastatic colorectal cancer.

Abstract

523 Background: The FDA’s 2004 “Critical Path Initiative” encouraged novel clinical trials and incorporation of biomarker-based enrichment studies to improve drug development. A survey of metastatic colorectal cancer (mCRC) trials from 2006 (Kopetz et al. JCO) demonstrated a very low utilization of novel therapies and minimal biomarker integration. The extent of change of mCRC clinical trials 5 years later is unknown. Methods: The NIH clinical trials database was searched for enrolling phase II or III treatment trials in mCRC, using previously published search strategies. Enrichment studies were defined by the presence of a tumor-based biomarker in the eligibility criteria. Trials were categorized according to FDA approval status and mechanism of action of the included agents, with novel agents being defined as ones not targeting the same protein or cellular mechanism as an existing agent that is FDA-approved for mCRC. Results: 162 trials were identified for mCRC pts with planned enrollment of 31,050 mCRC patients, representing a 58% and 45% increase from the 2006 survey, respectively. Fewer studies used only agents already FDA-approved for mCRC in 2011 compared to 2006 (39% vs 54%, respectively, P=0.02), with a substantial increase in the number of trials that included agents against novel therapeutic targets (n=49 vs 13, P=0.001). Enrichment trial designs were identified in 64 studies, compared with 13 in 2006 (P=0.0001). While the majority of these designs were for KRAS-wild type tumors and EGFR monoclonal antibodies, there has been a 5-fold increase in novel biomarker-directed trials (n=3 vs 15). However, 101 trials (62%) with an anticipated enrollment of over 21,000 mCRC pts, neither incorporate a novel agent nor biomarker in their trial design. Conclusions: Compared with trial in 2006, current mCRC trials are more likely to evaluate novel agents and incorporate enrichment designs with tumor-based biomarkers. Yet despite the rapid development of biomarker technology for pt enrichment and wider acceptance of innovative trial designs, most clinical trials are empiric in design and fail to integrate recommendations from the FDA Critical Path Initiative.