Long-term outcomes in people with CF lacking FEV1 response to elexacaftor/tezacaftor/ivacaftor therapy

Mohamad Hadhud; Dan Halevy; Joel Reiter; Elad Ben Meir; Alex Gileles-Hillel; Ido Sadras; Eitan Kerem; Malena Cohen-Cymberknoh; Oded Breuer

doi:10.1016/j.jcf.2025.05.005

Long-term outcomes in people with CF lacking FEV₁ response to elexacaftor/tezacaftor/ivacaftor therapy

J Cyst Fibros. 2025 Jun 2:S1569-1993(25)01486-9. doi: 10.1016/j.jcf.2025.05.005. Online ahead of print.

Authors

Mohamad Hadhud¹, Dan Halevy², Joel Reiter³, Elad Ben Meir³, Alex Gileles-Hillel³, Ido Sadras³, Eitan Kerem³, Malena Cohen-Cymberknoh³, Oded Breuer³

Affiliations

¹ Pediatric Pulmonary Unit and Cystic fibrosis Center, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Israel. Electronic address: Hadhod.m@gmail.com.
² Department of Radiology, Hadassah University Hospital, Jerusalem, Israel.
³ Pediatric Pulmonary Unit and Cystic fibrosis Center, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Israel.

PMID: 40461393
DOI: 10.1016/j.jcf.2025.05.005

Abstract

Background: Real-world data demonstrate variability in the response to elexacaftor/tezacaftor/ivacaftor (ETI) treatment among people with CF (pwCF). The aim of this study was to evaluate long-term outcomes in pwCF that had not shown early improvement in the percentage of predicted FEV₁ (ppFEV₁) following ETI treatment.

Methods: A single-center prospective study in pwCF who initiated ETI. Patients were categorized as 'early responders' if showing an improvement of at least 10 % in ppFEV₁ within three months of treatment or 'non-early responders' if not. Patients with pretreatment ppFEV₁ of above 99 % predicted were excluded. Respiratory and non-respiratory outcomes 18 to 24 months after ETI initiation were evaluated.

Results: A total of 52 pwCF (median age 30 (22-34), 22 (42 %) female) were included, of whom 21 (40 %) were 'non-early responders'. In a multivariable analysis, previous CFTR modulator therapy (p = 0.002), higher pretreatment ppFEV₁ (p = 0.002), and higher pretreatment BMI (p = 0.018), were negatively associated with early change in ppFEV₁. After 18 to 24 months of ETI therapy, ppFEV₁ did not significantly improve in the 'non-early responders' group (p = 0.29). However, rates of ppFEV₁ decline (p < 0.001), BMI (p < 0.005), number of pulmonary exacerbations (p < 0.02), days of intravenous antibiotic treatment (p < 0.01), and chest CT scores (p < 0.05), all significantly improved in both patient groups.

Conclusions: This study provides evidence for the long-term clinical benefits of ETI in pwCF lacking an early ppFEV₁ response. The data suggest that a lack of early improvement should not deter clinicians from treatment continuation.

Keywords: Cystic fibrosis; Drug response; Elexacaftor/tezacaftor/ivacaftor; Variation in treatment response.