Combination development

Abstract

In recent years, the pharmaceutical industry has focused its efforts towards the development of novel combination targeted therapies for the treatment of cancer. In the battle against the most complex and heterogeneous disease, researchers have been increasing their understanding on cell signaling pathways and tumor biology. This knowledge supports the increasing interest in combinatorial approaches to overcome challenges such as drug resistance, or sub-optimal efficacy. The development of combination therapy faces several challenges: characterization of the synergy between the two chemical entities, definition of the appropriate doses and schedule to maximize efficacy without increasing the level of adverse events, which increased significantly its level of complexity. To address these obstacles several tools are made available. In vitro, the number of cell lines validated for pre-clinical testing and the availability of high throughput screening methods has increased significantly. The characterization of cells at a genomic and protein level have improved the predictability of effects in vivo and enabled the identification of synergistic, additive, or antagonistic effects of combination therapies. In vivo, xenograft models are frequently used to optimize combination therapies and understand mechanisms of drug resistance. Moreover, in silico approaches such as multi-scale mathematical models are gaining interest to integrate knowledge on cellular pathways, cellular environment, and tumor growth in order to optimize dosing strategies. The clinical development of combination therapies has prompted the need to reassess how clinical studies are designed in order to identify the right dose and the right schedule of administration for drugs in combination. Several strategies can be used for dose escalation in phase I combination studies but the use of pharmacokinetic properties of individual drugs and the collection of pharmacodynamics endpoints early in development has proven to be essential in optimizing combination therapies across the various phases of clinical development. Finally, an increased collaboration across the pharmaceutical industry is needed for the development of combination therapies for the successful treatment of cancer.