Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Patients With Severe Lung Disease Carrying Previously Ineligible CFTR Mutations.

INTRODUCTION

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have transformed cystic fibrosis (CF) treatment. Elexacaftor/tezacaftor/ivacaftor (ETI) is approved for patients with F508del, but individuals with rare mutations or uncharacterized genotypes often lack therapeutic options. We evaluated ETI efficacy over 12 months in this population at a time when CFTR modulator therapy was not approved for use in these mutations, although some variants have since been included in updated clinical indications.

MATERIAL AND

METHODS

Prospective multicenter real-world study including 13 patients from 6 Spanish CF units treated under a compassionate use program. Inclusion criteria were age ≥12 years, rare CFTR mutations or inconclusive sweat test with single F508del mutation, and advanced lung disease. ETI was administered at standard doses with quarterly follow-up over 12 months. Outcomes included percent predicted forced expiratory volume in 1 s (ppFEV1), sweat chloride (SWCl), exacerbations, sputum microbiology, body mass index (BMI), and concomitant therapies.

RESULTS

Mean age was 34 years; 53.8% were female; baseline ppFEV1 was 42.3% and SWCl 92.5 mmol/l; 61.5% had chronic Pseudomonas aeruginosa infection. After 12 months, SWCl decreased in most patients except those carrying N1303K. ppFEV1 improved by 13% (95% CI, 5.5-32), with fewer exacerbations and hospitalizations. Pathogen prevalence decreased from 84.6% to 53.8%. Antibiotic and inhaled therapy use decreased, while BMI increased and respiratory symptoms improved.

CONCLUSION

ETI therapy in CF patients with rare mutations showed clinical, functional, and microbiological benefits. These findings support the potential benefit of ETI in selected patients with severe disease carrying previously ineligible CFTR variants. The safety profile was consistent with that previously described for ETI.