Safety of targeted agent combinations in solid tumours
Little progress in bringing effective, tolerable targeted agent combinations to clinical practice
- Date : 14 Feb 2013
- Topic : Anticancer agents & Biologic therapy
There is increasing interest in combining targeted agents because of the growing understanding of the complexity and heterogeneity of the signalling networks controlling solid tumour growth. Such combination strategies are being used to inhibit multiple aberrant pathways in the hope of optimising anti-tumour efficacy, but also 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 targeted agent combinations can result in unpredictable disturbances in normal physiology. While numerous combination trials of targeted agents that target dysregulated pathways have been conducted, there has been little exploration of the molecular vulnerability of normal tissues to these combinations.
The review article published as advance online publication on 29 January 2013 in the Nature Reviews Clinical Oncologyby Sook Park and colleagues from the USA NCI, focuses on the main toxicities and the lack of tolerability of some common targeted agent combinations. They obtained information by searching the PubMed database for articles published in English before 23 January 2012 and updated after peer review. The search terms were “targeted therapy”, “targeted anticancer agent”, “monoclonal antibody”, “tyrosine kinase inhibitor”, “small molecule”, “combination”, “solid tumours” and “cancer”, limited by publication type “clinical trial”. Abstracts from ASCO Annual Meetings were also searched for relevant trial data. A total of 68 clinical trials (28 different targeted agent regimens) were included in the review: 20 phase I, 10 phase I/II, 26 single-arm studies and 10 randomised phase II, and 2 phase III studies.
In their article, the authors discuss on and cover by examples, combining VEGF pathway inhibitors, dual VEGF and EGFR pathway inhibition, dual mTOR and VEGF pathway inhibition, dual mTOR and EGFR pathway inhibition, combining EGFR pathway inhibitors, combining HER2 pathway inhibitors, and dual EGFR and HER2 pathway inhibition.
Although targeted agents are considered less toxic than conventional cytotoxic chemotherapies this is not always the case. Importantly, the effects on normal cell physiology can lead to chronic and sometimes unpredictable toxicities. In general, mild toxicities were encountered in the first cycle of trials where targeted agents were used as single agents. Although a plethora of trials of targeted agent combinations have been conducted, the majority of these have failed to deliver tolerable combinations that improve patient outcome.
Development of rational combination strategies suffers from an incomplete understanding of the on-target and off-target effects of targeted agents on normal tissues, highlighting the need to evaluate the effect of targeted agent combinations on normal tissues as well as the tumour in preclinical models to inform clinical development.
For majority of 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. Decisions regarding further development of such combinations should be based on the observed efficacy and assessments regarding the potential clinical benefit compared to the toxicities of a given regimen, according to the study authors.
The authors concluded that there is an urgent need for strategies to evaluate the consequences of multi-targeted inhibition in tumours and normal tissues. A reassessment of clinical trial methodology to specifically address considerations surrounding the development of targeted agent combinations is warranted. Development of biomarkers of efficacy and toxicity of molecular-targeted agent 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 targeted agent combinations.
The full article you can read through the ESMO Scientific Journal Access programme.
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