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

<bold>Introduction:</bold> Real-life observations indicate variability in response to elexacaftor/tezacaftor/ivacaftor (ETI) treatment among people with CF (pwCF). <bold>Aims and objectives:</bold> To evaluate long-term outcomes in pwCF who did not show early improvement in percentage of predicted FEV1 (ppFEV1) following ETI treatment. <bold>Methods:</bold> A single-center prospective study in all pwCF who initiated ETI. Early spirometry response was defined as an improvement of at least 10% in ppFEV1 three months after ETI initiation. Patients with pretreatment ppFEV1 of above 99% predicted were excluded. Respiratory and non-respiratory outcomes 18 to 24 months after ETI initiation were evaluated. <bold>Results:</bold> A total of 52 pwCF (median age 30 (22-34), 30 (58%) male) were included, of which 21 (40%) lacked an early spirometry response. Previous CFTR modulator therapy (p=0.011), higher pretreatment ppFEV1 (p=0.002) and lower rates of ppFEV1 decline (p=0.014) were associated with lack of early spirometry response in a multivariable analysis. After 18 to 24 months of ETI therapy, ppFEV1 did not significantly improve in patients without early spirometry response (p=0.29). However, sweat chloride levels (p<0.02), annual rates of ppFEV1 decline (p<0.001), BMI (p<0.005), number of pulmonary exacerbations (p<0.02) and days of intravenous antibiotic treatment (p<0.01) all significantly improved in both patient groups, with and without early spirometry response. <bold>Conclusion:</bold> This study provides evidence for long-term clinical benefits in pwCF lacking an early improvement in ppFEV1 after ETI treatment initiation. The data suggest that lack of an early improvement should not deter clinicians from treatment continuation.