Opportunities and pitfalls of targeted therapeutic combinations in solid tumors

Recent advances in cancer biology have led to the discovery and development of chemical compounds and drugs that target specific cellular receptors, mediators, or effectors that are central to oncogenic survival, growth, and invasion. However, the complexity of tumor biology makes it is unrealistic to expect an antitumor therapeutic to be successful based on the inhibition of a single target or even a lone signaling pathway. Therefore, the potential success of such "targeted therapies" is likely to require the development of multiagent combinations. Combination strategies have a greater likelihood of addressing issues with genetically complex tumors, potentially avoiding drug resistance mechanisms through the inhibition of escape signaling pathways and slowing the development of newly resistant tumor cells. Combination regimes also have the potential of enhancing target inhibition through synergistic antitumor effects and minimizing drug-related toxicities to patients. However, numerous challenges to developing these combinations exist. This review will focus on the opportunities and pitfalls of developing novel targeted drug combinations, with a particular focus on early-phase drug development, where the greatest challenges exist, analyzing key points for the design and development of clinical trials for combinations of targeted agents.