159 Discussion and future perspectives In chapter 2, we described the design and feasibility of the Drug Rediscovery Protocol (DRUP) and the results of the first 215 patients enrolled in this multicenter clinical trial, including the results of the first completed cohort. DRUP is an ongoing national prospective multi-drug and pan-cancer phase II clinical trial that started in 2016. Patients with advanced solid tumors, who have exhausted standard-treatment options, are treated with existing targeted anti-cancer drugs (small molecules, monoclonal antibodies and immune checkpoint inhibitors) based on their tumor molecular profile, but outside their labelled indications. The analysis of the first 215 patients included in the DRUP trial showed that overall, 34% had clinical benefit, defined as a confirmed objective response or disease control of at least 16 weeks. The overall clinical benefit rate indicates that the efficacy of the DRUP approach to therapy selection is higher than the disease control rate of 11% in other phase 1 trials9. Chapter 2 also describes the results of the first completed cohort within DRUP. In this cohort, 30 patients with various tumor types with mismatch repair deficiency (dMMR) and microsatellite instability (MSI) were enrolled and treated with nivolumab, an anti-PD-1 monoclonal antibody. The clinical benefit rate in this particular cohort was 63% and the median progression free survival (PFS) was not reached after 16.5 months of follow-up. This impressive result warranted confirmation in an independent cohort, and a “third stage” expansion cohort was created within DRUP and based on the positive outcome of this validation cohort, registration of nivolumab was obtained for patients with dMMR and MSI cancer without standard treatment options. There is a growing need for a learning health care model which enables early access to potentially effective therapies, where no other established treatment options are available, without overestimating the findings that are based on small cohorts of patients. To this end, we developed a performance-based, personalized reimbursement model10 that enables access to precision medicine in rare biomarker-defined subgroups. Patients are treated with study medication within the DRUP trial stage 3 cohort, and good performance of the regimen (objective response or stable disease for at least 16 weeks) leads to reimbursement by the health insurance. This model allows risk-sharing between the manufacturer of the drugs and payers. The benefit of genomics-based therapy selection may seem evident today, but that has not always been the case. In the French SHIVA trial, patients with molecular alterations in one of three pathways (hormone receptors, PI3K/AKT/mTOR pathway or RAS/RAF/MEK/ERK pathway) were randomized between one of ten molecular matched therapy regimens or physicians’ choice of treatment. The outcome was not significantly different for both groups (p=0.41, HR 0.88) and the authors concluded that off-label use of molecularly targeted agents should be discouraged. However, the study was criticized for lumping genetic profiles without consideration of the tissue context or relative importance of genetic aberrations11. In the WINTHER trial, patients were screened for molecular targets for treatment by DNA and RNA sequencing. An expert panel recommended matched therapies based on the sequencing results, after which the treating physician determined the therapy given. Among other clinical aspects, the eventual choice of therapy depended on drug availability and reimbursement. This trial 6
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