33 The Drug Rediscovery Protocol serves as their own control) might be able to overcome some of these challenges, but has its own limitations (as pre-study progression-free-survival data are collected retrospectively). Taken together, the DRUP shows the feasibility of performing precision medicine in multiple, parallel cohorts driven by tumour type and tumour profile. It provides a framework through which patients with all types of tumours are able to acquire access to existing targeted therapies and immunotherapies, and in which treatment outcomes are monitored and publicly reported. This improves on current practice, in which individual physicians obtain anticancer drugs ‘off label’ for their patients without subsequent public reporting of clinical outcomes. The public availability of these data is especially relevant given recent concerns that the increasingly widespread use of genetic profiling could escalate the demand for off-label treatment27. Furthermore, the importance of publicly reporting negative results cannot be underestimated, as it prevents patient exposure to ineffective agents with all their accompanying toxicities and financial costs. Another important advantage of the DRUP is that it enables the rapid incorporation of new drugs and scientific insights into clinical practice: matching rules can be adapted quickly, and cohorts based on new biomarkers may be opened almost instantaneously. In addition, our use of WGS identified many potentially actionable variants that were not identified by smaller gene panels, immunohistochemistry and/or in-situ hybridization. Eventually, WGS may thus identify more, or more-appropriate, treatment options for each patient. An integral part of our approach is a tiered review process that includes reviews of the literature and by multidisciplinary boards of experts, before patients are enrolled. This prevents the prescription of anticancer drugs when negative clinical data are available, or when the actionability of the variant is unknown or unlikely. Finally, our study design and informed consent both enable the sharing of data internationally. By combining cohorts from similar international studies, we will improve our knowledge of rare subsets of cancer, and the outcomes of their treatment. Most importantly, our approach shows that existing anticancer drugs may have value beyond their approved indications, which potentially expands the range of patients who may benefit from their use. METHODS The DRUP is a national, prospective, non-randomized multi-drug and multi-tumour study, designed and conducted on behalf of the Center for Personalized Cancer Treatment (CPCT) (clinicaltrials.gov: NCT02925234). The trial was approved by the Medical Ethical Committee of the Netherlands Cancer Institute in Amsterdam, and was conducted in accordance with good clinical practice guidelines and the Declaration of Helsinki’s ethical principles for medical research. Written informed consent was obtained from all study subjects. Patients were accrued at multiple hospitals throughout the Netherlands, and followed for 30 days after end of study treatment, or death, respectively, for toxicity and survival analyses. Figure 1 provides a schematic overview of the study design. 2
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