Independent Drug Action in Combination Therapy: Implications for Precision Oncology

Combination therapies are superior to monotherapy for many cancers. This advan-tage was historically ascribed to the ability of combinations to address tumor heterogeneity, but synergistic interaction is now a common explanation as well as a design criterion for new combinations. We review evidence that independent drug action, described in 1961, explains the efficacy of many practice-changing combination therapies: it provides populations of patients with heterogeneous drug sensitivities multiple chances of benefit from at least one drug. Understanding response heterogeneity could reveal predictive or pharmacodynamic biomarkers for more precise use of existing drugs and realize the benefits of additivity or synergy. Significance: The model of independent drug action represents an effective means to predict the mag-nitude of benefi t likely to be observed in new clinical trials for combination therapies. The "bet-hedging" strategy implicit in independent action suggests that individual patients often benefi t from only a subset-sometimes one-of the drugs in a combination. Personalized, targeted combination therapy, consisting of agents likely to be active in a particular patient, will increase, perhaps substantially, the magnitude of therapeutic benefi t. Precision approaches of this type will require a better understand-ing of variability in drug response and new biomarkers, which will entail preclinical research on diverse panels of cancer models rather than studying drug synergy in unusually sensitive models.