Managing Director of The Cancer Drug Development Forum, Prof. H. Zwierzina reveals his opinions on the current and future challenges of personalised cancer therapy, including the need for biomarkers
Traditionally, the efficacy of new anti-cancer agents is investigated in large patient populations with histologically defined tumours in randomised phase III clinical trials where the investigational drug is compared with standard-of-care treatment. This process is time-consuming, costly and has a considerable attrition rate. The results of these trials are used to obtain approval from regulatory agencies, such as US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to bring the agent on the market.
During the last two decades, progress and a better understanding of cancer biology broadened this approach from one size fits oncology drug development, into smaller studies with novel agents. Advances in technologies, such as next-generation sequencing enable fast and efficient molecular profiling to detect genetic aberrations in tumours. In combination with the clinical development of agents inhibiting the function of driver genes or their products, personalised therapy with targetable tumour aberrations has become possible in selected patients.
However, this approach does not allow large-scale randomised clinical trials, but only smaller studies where the clinical benefit of a drug may be predicted by signatures of target dependence and host genetic makeup. At the same time, it is becoming evident that the more we know, the more complex drug development becomes. Histopathologically well-defined tumour entities become multiple different diseases classified by genetic alterations. These may differ from one cancer type to another and the ones we commonly see in, for example, lung cancer aren’t always the ones we see in breast or colorectal cancer.
Furthermore, in the vast majority of cases, we do not have the drugs to target them. Another issue is that usually there is only a very small number of patients with a particular mutation. Thus, we will need to adapt the way we design trials to show whether a specifically targeted drug is effective in a very small patient population.
To accelerate drug development, reduce costs, increase efficacy and bring new and effective agents to patients as rapidly as possible, innovative trial designs are one way to tackle the problem. The Cancer Drug Development Forum (CDDF) recognises the complex issues of innovative oncology drug development. It organises and encourages multi-stakeholder meetings and workshops among academia, the pharmaceutical industry, regulatory authorities, health technology assessors, patient organisations, as well as payers to address these challenges.
Despite the progress in molecular phenotyping, a huge clinical need remains for minimally invasive tests to determine subgroups of patients with a high probability for (non-) response to therapy. Biomarkers that predict clinical outcome and can easily be measured in the serum hold major promises. Although small compared to the costs of oncology drug development, the development, validation and commercialisation of biomarker assays are expensive.
In many instances, a single marker (i.e., assessment of a single biochemical variable) cannot offer the necessary sensitivity and specificity; instead, a panel of multiple markers is required given the complexity of the neoplastic process. Consequently, many investigations now focus on the development of multiplexed assays that screen multiple genes and proteins in the same specimen at the same time. Proteins, the downstream products of genes, are central to the process of carcinogenesis and the targets of almost all drugs. Because of a plethora of co- and post-translational modifications, the nature and quantity of each unique protein cannot be predicted from DNA or mRNA analysis alone. In other words, genomic and transcriptomic approaches can only provide information up-stream of the proteins and their modifications.
In summary, omic biomarker technologies (for example, genomics, proteomics and metabolomics) are ideal tools for multivariate biomarker discovery, because they markedly increase the number of analytes that can be measured in a single clinical sample and therefore, the range of interpretive options available.
The future will see the widespread use of biomarkers. The regulatory challenges and the hurdles such as finances, access to clinical data and reimbursement will be addressed at the CDDF workshop ‘Biomarkers and Patients’ Access to Personalized Oncology Drugs in Europe’ (Brussels, September 24/25, 2018).
Prof. H. Zwierzina
Managing Director, The Cancer Drug Development Forum – CDDF
Professor of Internal Medicine, Innsbruck University, Austria
Tel: +32 2 775 02 15