32 CHAPTER 2 The EMA has not yet approved checkpoint inhibitors for the MSI indication. However, on the basis of these DRUP data, the Dutch Health Care Institute and insurance agencies have now embraced a pay-for-performance model for this and future successful cohorts from the DRUP. This not only creates access to these drugs for patients with rare tumour profiles, but also allows further confirmation of clinical benefit in a larger cohort of patients20. Another immunotherapy cohort—pembrolizumab treatment for patients with microsatellite-stable colorectal cancer, with a tumour mutational load of between 140 and 290 (which corresponds to 11–22 mutations per megabase)—showed limited clinical benefit in stage I, and was therefore closed (Extended Data Table 6). Together, these two cohorts illustrate the potential for the DRUP to identify subgroups of patients who may benefit from a broader use of approved drugs, and to prevent unnecessary treatment in other subgroups. Upon enrolment, the DRUP mandated a fresh baseline tumour biopsy for WGS. Baseline WGS results were used for the confirmation of previously identified variants, and for exploratory biomarker analyses. In the first 215 patients, baseline WGS was successfully performed in 131 patients (61%); the main reason for failure was insufficient tumour cells in the baseline biopsy (Extended Data Figure 3). The variant on the basis of which patients were included was confirmed in 121 patients (92%) with successful baseline WGS. Notably, in 112 patients (85%) with baseline WGS, potentially relevant additional information was revealed (Supplementary Table 1). This information included high mutational load, variants associated with therapy response or resistance, and variants that were potentially actionable with experimental or off-label agents (other than the current treatment that the patient was receiving in the DRUP). The latter may lead to re-enrolment upon failure of the first treatment administered to the patient in the DRUP. Some limitations of the DRUP should be taken into account. One important caveat is the absence of comparator groups, owing to the non-randomized trial design. With the increasing availability of large, clinically and molecularly annotated databases, this may be addressed by methodologies such as trials within cohorts. Another concern is that, in a heterogeneous study population such as that of the DRUP, the correct interpretation of molecular aberrations is challenging. Fortunately, we were able to draw upon previous experiences with a much larger cohort21: we combined three large repositories of knowledge—‘Clinical Interpretation of Variants in Cancer’ (CIViC)22, ‘Precision Oncology Knowledge Base’ (OncoKB)23 and ‘Cancer Genome Interpreter’ (CGI)24. We also followed the ‘European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets’ ESCAT)25 wherever possible. The efficacy endpoints bear additional, inherent limitations26: the objective response rate can detect tumour growth (or reductions in size) but cannot detect reductions in the rate of growth. By contrast, survival statistics cannot differentiate between a true effect of the treatment and a naturally slow growth rate. The progression-free-survival ratio (in which each patient
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