Fig. 3: Development pathway for anti-metastatic agents.

The general process for development of anti-metastatic agents has the same fundamental basis as that used in the development of drugs with a direct antitumour mechanism of action, with some special considerations as highlighted in the figure and described as follows. In target identification and preclinical development, special consideration must be given to the functional relevance of the models being used, which should reflect human metastatic disease as much as possible; the role of the immune system in metastasis is a critical factor. The experimental conditions should also mimic those of the clinical setting. Drug discovery and subsequent preclinical testing strategies need to be designed to account for the fact that, in most cases, the anti-metastatic therapy under development will be given chronically in a healthier population of patients, such as those that have been cured of their primary disease but are at high risk of developing secondary tumours, necessitating oral administration and a risk–benefit profile lacking key toxicity liabilities. Other considerations, such as activity in several different preclinical models, an optimized pharmacokinetic (PK) profile and development of pharmacodynamic (PD) markers suitable for use in the clinic, are common to all cancer drug discovery and development programmes. Given the favourable risk–benefit profile necessary for anti-metastatic agents, an accelerated development approach can be taken by conducting initial phase I studies in healthy volunteers rather than the classical populations with advanced-stage cancer. The key aims of these studies are to determine the safety, PK profile and PD characteristics (ensuring the putative biomarkers developed can be measured in non-malignant tissues) in order to provide an early go or no-go decision point and ensure that the drug has the intended biological effects. To gain rapid biological proof of concept in patients with cancer, window-of-opportunity studies, in which a dose of the anti-metastatic agent is given before surgery to examine PD effects, can be considered. If validated surrogate end points of clinical efficacy are available, these can be used to substantially reduce development timelines and, provided agreement has been reached with appropriate regulatory bodies, support provisional approval. If successfully executed, this regulatory strategy will avoid the protracted clinical development timelines that are one of the greatest barriers to the development of anti-metastatic drugs. Provided that provisional approval is given, regulatory bodies will require further in-use continuous assessment, typically in confirmatory phase IV studies that can be funded using ongoing sales revenue. The aim of these larger-cohort and much longer duration clinical trials is to confirm that a pre-defined level of clinical benefit is achieved according to more traditional outcomes, such as overall survival. If provisional approval has not been given by regulators, then costly (in terms of both finance and time) randomized controlled phase III studies in large cohorts will be necessary to gain approval on the basis of standard clinical outcome measures. CE, Conformité Européene.