ABSTRACT
Molecularly targeted agents (MTAs) are developed to modulate specific aberrant pathways in cancer cells while sparing normal tissue. Combining traditional cytotoxic agents with novel MTAs provides an important approach to treating cancer and achieving better patient outcomes. Since cytotoxic agents and MTAs work via different mechanisms, combining them can induce a synergistic treatment effect, target tumor cells with differing drug susceptibilities, and achieve a higher intensity of dose with non-overlapping toxicities. As more MTAs become available, it has become commonplace to combine multiple MTAs that target different elements of a genomic pathway or multiple pathways, to overcome treatment resistance and achieve synergistic treatment effects. For MTAs, the dose-Efficacy curve often is non-monotonic. For example, in immunotherapy trials, the dose-Efficacy relationship could be umbrella-shaped, so the most effective dose is in the middle of the therapeutic dose range. In some cases, Efficacy of the MTA may even decrease at higher dose levels, showing an umbrella-shaped dose-Efficacy curve.
