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  • Review Article
  • Published:

Safety and feasibility of targeted agent combinations in solid tumours

Nature Reviews Clinical Oncology volume 10, pages 154–168 (2013)Cite this article

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Abstract

The plethora of novel molecular-targeted agents (MTAs) has provided an opportunity to selectively target pathways involved in carcinogenesis and tumour progression. Combination strategies of MTAs are being used to inhibit multiple aberrant pathways in the hope of optimizing antitumour efficacy and to prevent development of resistance. While the selection of specific agents in a given combination has been based on biological considerations (including the role of the putative targets in cancer) and the interactions of the agents used in combination, there has been little exploration of the possible enhanced toxicity of combinations resulting from alterations in multiple signalling pathways in normal cell biology. Owing to the complex networks and crosstalk that govern normal and tumour cell proliferation, inhibiting multiple pathways with MTA combinations can result in unpredictable disturbances in normal physiology. This Review focuses on the main toxicities and the lack of tolerability of some common MTA combinations, particularly where evidence of enhanced toxicity compared to either agent alone is documented or there is development of unexpected toxicity. Toxicities caused by MTA combinations highlight the need to introduce new preclinical testing paradigms early in the drug development process for the assessment of chronic toxicities resulting from such combinations.

Key Points

  • There is increasing interest in combining molecular-targeted agents (MTAs) because of the growing understanding of the complexity and heterogeneity of the signalling networks controlling solid tumour growth

  • While numerous combination trials of MTAs that target select dysregulated pathways have been conducted, there has been little exploration of the molecular vulnerability of normal tissues to these combinations

  • For combinations using inhibitors of VEGF, EGFR, mTOR, and HER2 pathways, effective tolerable doses have been difficult to deliver owing to overlapping toxicities, enhanced single-agent toxicity, and/or unexpected toxicities

  • There is an urgent need for strategies to evaluate the consequences of multitarget inhibition in tumours and normal tissues

  • Development of biomarkers of efficacy and toxicity of MTA combinations, and for preclinical pharmacokinetic and pharmacodynamic modelling to guide schedules and dose adjustments are needed

  • Such biomarkers will help determine the recommended phase II doses based on acute and chronic toxicities associated with the use of MTA combinations

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Authors and Affiliations

  1. Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 31, Room 3A44, 31 Center Drive, Bethesda, 20892, MD, USA

    Sook Ryun Park, Myrtle Davis, James H. Doroshow & Shivaani Kummar

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  1. Sook Ryun Park
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  2. Myrtle Davis
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  3. James H. Doroshow
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  4. Shivaani Kummar
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S. R. Park and S. Kummar made substantial contributions to researching the data, discussion of content, and writing, reviewing and editing of the manuscript before submission. M. Davis contributed to researching the data and writing the article. J. H. Doroshow contributed to writing, reviewing and editing of the manuscript and discussion of the content.

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Correspondence to Shivaani Kummar.

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Park, S., Davis, M., Doroshow, J. et al. Safety and feasibility of targeted agent combinations in solid tumours. Nat Rev Clin Oncol 10, 154–168 (2013). https://doi.org/10.1038/nrclinonc.2012.245

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