Contributors to the heterogeneity of response to CFTR modulators.

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have transformed the management of cystic fibrosis; however, substantial interindividual variability in clinical response persists, even among people with identical CFTR genotypes. This variability challenges clinicians, regulators, and researchers in defining treatment success and optimising long-term outcomes. We synthesise evidence from clinical trials, real-world cohorts, and mechanistic studies to examine the contributors to heterogeneity in response to CFTR modulators, with a focus on triple therapy (elexacaftor-tezacaftor-ivacaftor). Treatment response varies across lung function, pulmonary exacerbations, sweat chloride, nutritional status, and quality of life, and is influenced by different factors, including disease stage, CFTR genotype and complex alleles, pharmacokinetic variability, adherence, side-effects, environmental exposures, and host modifiers. No single metric adequately captures individual response. Binary classifications of responder and non-responder are therefore overly reductive. A multidimensional and longitudinal approach integrating clinical outcomes with biomarkers and selected functional assessments is required to maximise benefit and guide future therapeutic strategies.