P154 Cluster Analysis Explains Heterogeneity in Treatment Response to Elexacaftor/tezacator/ivacaftor in People with Cystic Fibrosis

Elexacaftor/tezacaftor/ivacaftor (ETI) has proven highly effective in people with cystic fibrosis (pwCF) carrying at least one F508del mutation. This prospective cohort study aims to better characterize the heterogeneity in responses to ETI and to identify patients who better respond to the treatment. We evaluated treatment response after 6 months into ETI therapy, in terms of changes in sweat chloride concentration, ppFEV1 and sex- and age-specific standard deviation scores of body mass index (BMISDS). K-means clustering analysis was carried out to group patients according to their patterns of response. Baseline characteristics and treatment responses were compared between the identified clusters. The study included 164 pwCF who received ETI at the paediatric and adult CF centres of Milan. At 6 months from treatment initiation, sweat chloride concentration decreased by a mean value of –53 mmol/L (95% CI: –57; –50); ppFEV1 increased by 16.4 points (14.6; 18.1) and BMISDS by 0.41 (0.34; 0.49). Sweat chloride concentration 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: group 1 and group 2. Patients in group1 had a lower reduction in sweat chloride concentration (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) as compared to patients in group 2. Patients in group 1 had a milder clinical phenotype, characterized by better respiratory function, less airways resistance, better nutritional status, lower P. aeruginosa infection rate and lower prevalence of diabetes. Most pwCF had remarkable clinical benefit from ETI, however a non-negligible share of them showed suboptimal responses. Further research is needed to better characterize the determinants of poor response to ETI.