Background: Elexacaftor/tezacator/ivacaftor (ETI) is highly effective in people with cystic fibrosis (pwCF) with at least one F508del mutation. This prospective cohort study aims to characterize the variety in responses to ETI and to identify patients who respond best.

Methods: After 6 months of ETI we evaluated change in sweat chloride concentration (SCC), ppFEV1 and sex- and age-specific standard deviation scores of body mass index (BMISDS). K-means clustering analysis was performed to group patients according to their response. Baseline characteristics and treatment responses were compared.

Results: We enrolled 164 pwCF who received ETI in two CF centres in Milan. At 6 months from ETI start, SCC declined by a mean of -53 mmol/L (95% CI: -57; -50); ppFEV1 rose by 16.4 points (14.6; 18.1) and BMISDS by 0.41 (0.34; 0.49). SCC did not improve in 2 (1.2%) patients; 18 (11.0%) patients had changes in ppFEV1<3 points; BMISDS did not increase in 32 (19.5%) patients. Cluster analysis identified two groups of patients. Those in group1 had a lower reduction in SCC (mean changes: -48 vs -61 mmol/L, p<0.001) and lower increases in ppFEV1 (+9.2 vs +25.2, p<0.001) and BMISDS (+0.16 vs +0.81, p<0.001) compared to patients in group 2. Patients in group 1 had a milder clinical phenotype, with better pulmonary function, less airway resistance, better nutritional status, lower P. aeruginosa infections and lower rates of diabetes.

Conclusions. Most pwCF had remarkable benefits from ETI, however a part of them had suboptimal responses. Further research is needed to better identify the causes of poor response to ETI.