36 CHAPTER 2 mutation, translocation, amplification, overexpression or homozygous deletion; for example, the EGFR mutant that was defined as the variant for purposes of cohort definition included all detected EGFR mutations. The rate of clinical benefit for each treatment was analysed per cohort. Clinical benefit was defined as objective response, or absence of disease progression for ≥16 weeks (counted from treatment initiation until end of treatment or measurement of progressive disease, whichever came first), measured 2 or more times and ≥28 days apart (defined as a confirmed response). Per cohort, a rate of clinical benefit of <10% was considered to be of no clinical interest. A rate of clinical benefit of ≥30% was considered relevant and of sufficient interest to warrant further investigation. A Simon-like two-stage ‘admissible’ design15 was used for each cohort: in stage I, eight patients were enrolled. If no clinical benefit was observed in these first eight patients, the cohort was closed. Otherwise, 16 additional patients were enrolled. Cohorts with clinical benefit in ≤4 out of 24 patients were considered ineffective, whereas cohorts with clinical benefit in ≥5 patients were considered effective. This monitoring rule has 85% power and an α error rate of 7.8%. These operating characteristics were selected to represent a reasonable compromise between high power, low false-positive rates and a desire for small sample sizes, especially in stage I. STUDY ENDPOINTS The main study endpoints included (i) the percentage of submitted patients that started study treatment, and the main reasons for non-enrolment; (ii) the efficacy, including best overall response, response duration and rate of clinical benefit; and (iii) toxicity, including all treatment-related adverse events of grade 3 or higher. The sequencing-success rate of pre-treatment biopsies, and comparison of ‘historic’ and baseline tumour profiles formed an exploratory endpoint (endpoint iv). All endpoints were prospectively decided. For endpoint (i), all cases that were submitted for review were considered evaluable, and the reasons for non-enrolment were classified by two reviewers independently. For endpoint (ii), the best overall response was considered evaluable in patients who received at least one cycle of oral study medication or two cycles of intravenous study medication, and for whom response was radiologically or clinically evaluable (at the discretion of the treating physician). Clinical-benefit calculations included all enrolled patients, regardless of evaluability of the best overall response. All patients without clinical benefit had been followed for at least 16 weeks at the time of the analysis, so no censoring was necessary. All patients who received study treatment were considered evaluable for endpoint (iii), and all patients who were formally enrolled were considered evaluable for endpoint (iv). STATISTICS All statistical analyses were performed using R version 3.5.0 (http://www.R-project.org/). This trial was not randomized and investigators were not blinded to treatment allocation or outcome assessments. Patient characteristics, adverse events and tumour responses were summarized using descriptive statistics. In addition, a waterfall plot was used to illustrate
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