Abstract

ABSTRACT:

Phase I clinical trials in unselected patient populations have typically produced low response rates of 4% to11%. Therefore, for many decades, phase I clinical trials have been viewed as merely dose-finding studies with, at best, a modest impact on patient outcome. It has become clear that the traditionally low response rate historically seen in early-phase trials can be increased substantially if patient selection has been driven by molecular matching. Several recent early-phase clinical trials using targeted therapies based upon molecular matching demonstrated response rates of 39% to 81% (Table). Novel technologies, including next-generation sequencing, can yield further insight into the underlying molecular pathology of cancers and concordant sensitivity/resistance mechanisms in response to targeted therapies. It is plausible that druggable molecular abnormalities occur in small subset of patients across different histologic types. Therefore, testing one molecular abnormality at a time is neither practical nor sustainable. Novel technologies such as next-generation sequencing are capable of testing myriad of molecular abnormalities in the whole cancer genome. This provides an unparalleled opportunity to create umbrella protocols to match these molecular abnormalities with appropriately selected targeted therapies. Moving from dose-finding studies to better designed clinical trials based on molecular technologies provides a greater chance of therapeutic benefit and may significantly shorten the drug development timeline.