Peter van Mourik

132 Chapter 6 assuming a nominal type I error of 0.05 and a power of 0.8 suggested a sample size of 20 patients to detect a correlation between FIS and in vivo CFTR biomarkers with a correlation coefficient of 0.6. However, in a relatively homogeneous group such as F508del-homozygous individuals with limited response to lumacaftor-ivacaftor, sensitivity may be limited due to measurement variability in both FIS and in vivo CFTR biomarkers. Neither FIS nor any of the in vivo CFTR biomarkers correlated with changes in ppFEV 1 observed after 8-16 weeks of lumacaftor-ivacaftor therapy (Figure 1). Of note, the magnitude of CFTR function detected by FIS and other CFTR biomarkers under lumacaftor-ivacaftor treatment has been associated with milder CF multi-organ disease including pancreatic sufficiency (3, 8). Moreover, biomarkers of CFTR function are probably less dependent on the severity of structural lung damage and rate of decline before the start of lumacaftor-ivacaftor treatment, as well as environmental factors, while these factors can have a substantial impact on ppFEV 1 responsiveness. Further, this study did not detect improvement in ppFEV1 at the group level, which may in part be related to the sample size, as well as a larger range in baseline ppFEV1 and shorter duration of this real world observational study compared to the pivotal phase 3 trials (10). Taken together, these findings support that the effects of lumacaftor-ivacaftor detected by FIS and the other CFTR biomarkers are clinically relevant, and that more sensitive outcomes of lung function and structure or longer clinical follow-up may be necessary to unequivocally determine individual benefit of lumacaftor-ivacaftor on clinical outcomes (1, 2). In summary, our data suggest that FIS of intestinal organoids and in vivo biomarkers of CFTR function are sensitive tools for detection and quantification of restoration of CFTR function in response to CFTR-directed therapeutics. However, we did not observe a correlation at the low levels of functional rescue of lumacaftor-ivacaftor in F508del homozygous patients. We conclude future studies in a larger group of patients with a spectrum of responsive CFTR mutations and more effective CFTR modulators (1, 2, 11) will be required to determine the exact role of patient-derived organoids and in vivo biomarkers of CFTR function in predicting clinical efficacy of different CFTR modulators in individual patients to enhance precision medicine for CF.