34 CHAPTER 2 PATIENT POPULATION Patients who were eligible for the study had an advanced or metastatic solid tumour, multiple myeloma or B cell non-Hodgkin lymphoma, and had exhausted standard-treatment options. A tumour genetic or protein-expression test (CPCT or regular diagnostics) had to have revealed a potentially actionable variant, for which FDA- and/or EMA-approved targeted therapy was available—but not for the tumour type in question. In addition, patients were required to be ≥18 years of age, with acceptable organ function and performance status (Eastern Cooperative Oncology Group (ECOG) score ≤ 2), and to have objectively evaluable disease of which a fresh baseline tumour biopsy could safely be obtained. For every study drug, further drug-specific selection criteria applied. MATCHING RULES Upon case submission, the study team attempted to match each patient to the appropriate study treatment (Extended Data Figure 1), according to pre-defined matching rules (Extended Data Table 1). For matching purposes, a potentially actionable molecular variant was defined following a previous publication28, as either one of the following options: (1) the variant is the target of an approved drug for any cancer indication, or is known to predict sensitivity to an approved drug for any cancer indication; (2) the variant is in the same molecular pathway, but located upstream of the target of an approved drug for any cancer indication, and has been reported as an oncogenic or pathogenic mutation; (3) mutations that result in unique susceptibility to a specific molecular intervention (such as BRCA1 and BRCA2 mutations and PARP inhibitors, or MSI and PD-1 inhibitors); and (4) other variants that have appropriate justification for selection on the basis of published scientific evidence regarding their susceptibility to specific targeted therapies. If multiple variant–drug matches could be made for one patient, the drug with the highest level of evidence was selected unless there was a rationale (such as drug intolerance) that justified selecting an agent with a lower level of evidence. Levels of evidence were adapted from a previous publication28 and were defined as: the drug met a clinical endpoint (objective response, PFS or overall survival) in a prospective trial, in patients with the same variant and tumour type, and has not yet received regulatory approval for use in the tumour type of the patient (level 1); clinical studies have demonstrated an association between presence of the variant and drug activity against the tumour type of the patient (level 2); the drug is commercially available in the US and/or European Union (EU) for use in another tumour type that contains the same variant (level 3); and preclinical evidence of anti-tumour activity and target inhibition in model systems of the tumour type of the patient (level 4). STUDY TREATMENT AND ASSESSMENTS If a slot for a matching study treatment was available (to which the patient consented) the patient could be enrolled, if all drug-specific selection criteria were met. Once a fresh baseline tumour biopsy for biomarker analyses was obtained, the study treatment could be initiated. Treatment and follow-up were conducted according to the approved indication. All treat-
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