Chapter 1 - Preclinical Drug Development: Translating Basic Research into Clinical Work
The high failure rate observed in late clinical trials of many “promising” new anti-cancer agents has motivated efforts to define alternative strategies of drug development and evaluation of anti-tumour activity of new agents, both in the clinical as well as in the preclinical settings. Up to now, only few predictive biomarkers are used in routine clinical practise and most have been established retrospectively. The emergence of the so-called companion diagnostics would potentially help expedite the drug development process by identifying predictive biomarkers early in the preclinical setting and carrying out analytical and clinical validation during drug development. Companion diagnostics are assays performed starting from the preclinical stage to help elucidate the efficacy and/or safety of a new drug for a target patient population, based on specific genotype and biological characteristics of the tumour.
Spigel and colleagues reported recently the results of a randomised phase II trial of erlotinib in combination with MetMab (a monoclonal antibody targeting MET) versus erlotinib plus placebo in patients with previously treated non-small cell lung cancer. The study included evaluation of the expression of cMET in tumoural tissue through both fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC). They showed that the addition of MetMab to erlotinib resulted in significant improvement in progression-free and overall survival only in patients who had high expression levels of cMET and that expression by IHC was the most sensitive predictor of benefit from MetMab. Conversely, patients with low cMET expression did not benefit from MetMab. In fact, those treated with the combination had significantly worse outcomes that those treated with erlotinib alone. This study represents an example of prospective evaluation of a predictive biomarker and underlines the importance of companion diagnostics in the evaluation of experimental treatments.
To support drug development toward a tumour-specific focus after early clinical trials, preclinical studies should be performed to allow the discovery of biomarkers and the development of assays to evaluate them. This will lead to the development of a diagnostic predictive signature to be clinically evaluated in early clinical trials and prospectively validated in randomised phase II and III studies.