Long-term outcomes in people with CF lacking FEV1 response to elexacaftor/tezacaftor/ivacaftor therapy.

Background: Real-world data demonstrate variability in the response to elexacaftor/tezacaftor/ivacaftor (ETI) treatment among people with CF (pwCF). The aim of this study was to evaluate long-term outcomes in pwCF that had not shown early improvement in the percentage of predicted FEV1 (ppFEV1) following ETI treatment.

Methods: A single-center prospective study in pwCF who initiated ETI. Patients were categorized as 'early responders' if showing an improvement of at least 10 % in ppFEV1 within three months of treatment or 'non-early responders' if not. Patients with pretreatment ppFEV1 of above 99 % predicted were excluded. Respiratory and non-respiratory outcomes 18 to 24 months after ETI initiation were evaluated.

Results: A total of 52 pwCF (median age 30 (22-34), 22 (42 %) female) were included, of whom 21 (40 %) were 'non-early responders'. In a multivariable analysis, previous CFTR modulator therapy (p = 0.002), higher pretreatment ppFEV1 (p = 0.002), and higher pretreatment BMI (p = 0.018), were negatively associated with early change in ppFEV1. After 18 to 24 months of ETI therapy, ppFEV1 did not significantly improve in the 'non-early responders' group (p = 0.29). However, rates of ppFEV1 decline (p < 0.001), BMI (p < 0.005), number of pulmonary exacerbations (p < 0.02), days of intravenous antibiotic treatment (p < 0.01), and chest CT scores (p < 0.05), all significantly improved in both patient groups.

Conclusions: This study provides evidence for the long-term clinical benefits of ETI in pwCF lacking an early ppFEV1 response. The data suggest that a lack of early improvement should not deter clinicians from treatment continuation.