Limited data is available on the real-life long-term effect of elexacaftor/tezacaftor/ivacaftor (ETI) treatment on respiratory disease in people with CF (pwCF).

A single-center observational study was conducted in pwCF to evaluate predictors for a sustained respiratory improvement. A sustained respiratory improvement was defined as an improvement of at least 10% from baseline in percentage of predicted FEV1 (ppFEV1) after 18-24 months of ETI treatment. Early respiratory improvement was defined as an increase in ppFEV1 of 10% or more within 30 days of ETI treatment initiation.

A total of 61 pwCF (median age 27.28(14.5-33.8)) were included in the study. An overall improvement in nutritional status, measured by body mass index (BMI)(p<0.001) and pulmonary exacerbations (p=0.004) were observed. Thirty-six pwCF (59%) met the definition of a sustained respiratory improvement. Factors that predicted a sustained respiratory improvement were lack of prior modulator therapy(p=0.022), higher pre-ETI treatment lung clearance index(p<0.001), lower pre-ETI treatment ppFEV1(p<0.001), and Early respiratory improvement(p<0.001). Patient-reported adherence to airway clearance therapy was not associated with sustained respiratory improvement.

Our results describe the long-term effect of ETI therapy. Patients with worse baseline pulmonary disease were more likely to have a sustained respiratory improvement. Spirometry may not be sensitive enough to detect ETI treatment-related improvement in pwCF with milder baseline respiratory disease and those who received prior modulator therapies. More sensitive outcome measures are required to ensure the appropriate validation of next-generation CFTR modulators.