Chapter 11: Combination Agents Versus Multi-Targeted Agents – Pros and Cons

Cancer, in all its various forms, is perhaps the archetypical multi-factorial disease and it is therefore not surprising that single-target drugs are rarely useful as anti-cancer agents when used on their own. Traditional cancer therapy has relied on effective drug combinations and the more recent emergence of compounds that simultaneously modulate multiple targets has added to the oncology armoury and raised the question as to which approach, drug combinations or single compound multi-targeted drug, is to be preferred. This chapter reviews the basis for combining existing drugs and how these combinations are selected, and compares these with multi-targeted drugs (MTDs) such as sunitinib, a broad-spectrum kinase inhibitor that inhibits a range of growth factors. Whether using physical combinations or MTDs, or indeed combinations of MTDs, the choice of which targets and which pathways to attack is crucial and the rationale for selecting these is discussed in detail. The NCI Cancer Therapy Evaluation Program, designed to facilitate trials of novel combinations, will aid in the rational selection of targets and pathways to combine in future MTDs. The pros and cons of combinations and MTDs in terms of the relative challenges in clinical development are examined, and the systematic use of biomarkers, better approaches to patient selection, and improved design of trials to take account of the heightened potential for acute and delayed on- and off-target toxicities are highlighted.