Real-World Safety and Effectiveness of Elexacaftor, Tezacaftor, and Ivacaftor in People with Cystic Fibrosis and Advanced Lung Disease: A Two-Year Multicenter Cohort Study

Elexacaftor/tezacaftor/ivacaftor (ETI) is a cystic fibrosis (CF) transmembrane conductance regulator modulator, which has shown efficacy in people with CF (pwCF) carrying the F508del (F) variant, both in homozygosity and heterozygosity with a minimal function (MF) variant. Limited data exist on the effects of ETI in pwCF with advanced lung disease. Our aim was to investigate ETI safety and effectiveness in this patient group in a real-life setting over 2 years. A multicenter observational cohort study was designed to gather real-world information on the effect of ETI treatment on CF patients (aged >12 years, genotype: F/MF mutation) with advanced lung disease as defined by a FEV1 < 40% predicted. Retrospective demographic and clinical data were recorded for the two years preceding and the two years following ETI initiation. The following outcomes were investigated: treatment-associated adverse events (AEs), drug interruptions (temporary or permanent), variations in percent predicted FEV1 (ppFEV1), sweat chloride concentration (SwCl), antibiotic use, body mass index (BMI), and quality of life. A total of 124 (51.6% males) pwCF were treated with ETI over 2 years. The median (IQR) age and ppFEV₁ were 34 (26, 43) years and 34 (29, 41) percentage points, respectively. ETI was discontinued in two pwCF due to lung transplantation, and temporarily interrupted in two because of skin rash, and in three following elevated levels of aminotransferase. Most AEs were mild and short-lasting. In 12.1% pwCF, we registered an increase greater than twice the upper limit of the normal range in alanine aminotransferase, and in 16% we registered an increase in conjugated bilirubin with no increase in aminotransferase. Both increases were recurrent in about half of the subjects. The mean differences (95% CI) for ppFEV₁ and SwCl, assessed as mean values in the pre-ETI and ETI treatment periods, were +11.8 (11.1 to 12.6) and -43.7 (-47.6 to -39.9) mmol/L. A modest increase in ppFEV₁ persisted during the second year of treatment. Number of oral and IV antibiotic cycles/year, as well as hospitalizations/year, decreased significantly from 3.6 to 1.2, from 2.4 to 0.6, and from 2.1 to 0.5 during ETI treatment. A total of 8 of 16 (50%) pwCF were taken off the waiting list for lung transplantation, and significant reductions in the percentages of pwCF using long-term oxygen therapy and non-invasive ventilation were observed. A poor concordance between ppFEV1 and SwCl was found. In only 3/82 (3.7%), subjects with chronic airway infection by <i>Pseudomonas aeruginosa</i> cultures were always negative during ETI treatment. In CF patients with advanced lung disease on ETI treatment, we observed an improvement in a number of clinically significant outcomes over a 2-year study period. However, several additional observations, such as liver dysfunction, variable degrees of lung function improvement, and limited impact on chronic airway infection, underscore the fact that the benefit-risk profile of ETI treatment in cystic fibrosis patients with advanced lung disease has not been fully elucidated and warrants prolonged-term monitoring.