**Background:** Cystic fibrosis (CF) is a progressive autosomal recessive disease affecting over 100,000 people worldwide, caused by mutations in the CFTR gene. The F508del mutation is the most prevalent, occurring in 80-85% of CF cases. CFTR modulator drugs target the underlying defect: potentiators (ivacaftor) enhance channel open probability, while correctors (lumacaftor, tezacaftor, elexacaftor) improve protein folding and trafficking. The triple combination elexacaftor-tezacaftor-ivacaftor (ETI), approved by the FDA in 2019 and EMA in 2020, represents the most effective CFTR modulator therapy to date.
**Methods:** This review aggregates data from clinical trials, observational studies, case reports, and real-world evidence examining ETI therapy in PwCF. Key phase 3 trials include a 4-week active-controlled trial in F508del homozygotes (n=107) showing ETI superiority over TEZA-IVA, and a 24-week placebo-controlled trial in F508del/MF genotypes (n=403) demonstrating significant ppFEV1 improvement and a 63% lower annualized rate of pulmonary exacerbations. Additional studies examined children aged 6-11 years, PwCF with advanced lung disease (ppFEV1 ≤40%), transplant recipients, and rare genotypes.
**Key Results:** In phase 3 trials, ETI therapy produced rapid and sustained improvements: ppFEV1 increased by 10-14 percentage points in F508del/MF genotypes and 10 percentage points in F508del homozygotes compared to controls. Sweat chloride concentration decreased by approximately 40-50 mmol/L, with many patients achieving values near or within normal range. BMI improved by 1.5-2.1 kg/m², and CFQ-R respiratory domain scores increased by 20-32 points. In advanced lung disease cohorts (mean ppFEV1 ~29-34%), absolute ppFEV1 improvements of 10-15 percentage points were observed, with 50% reduction in oxygen therapy, 30% reduction in non-invasive ventilation, and many patients removed from lung transplant lists. Long-term follow-up (up to 2 years) demonstrated sustained benefits, with ETI therapy increasing lung function by 0.39 percentage points versus a 1.92-point decline in untreated controls. In children aged 6-11 years, ETI improved LCI2.5, ppFEV1, and CFQ-R scores with similar safety profiles. Gastrointestinal studies showed reduced intestinal inflammation (decreased fecal calprotectin) but no improvement in pancreatic elastase-1 or steatocrit, indicating persistent exocrine pancreatic dysfunction. Glycemic control improved in patients with CFRD, though findings were mixed. Adverse effects included elevated liver enzymes (AST, ALT, bilirubin) in the first 3 months, skin manifestations (rash, Malassezia folliculitis, acne exacerbation) in up to 10% of patients, and mental health concerns including depression, anxiety, and sleep disturbances. Drug-drug interactions with immunosuppressants (tacrolimus, sirolimus) required dose adjustments in transplant recipients. Pregnancy outcomes were generally favorable, with ETI crossing the placenta and appearing in breast milk at therapeutic concentrations.
**Clinical Implications:** ETI therapy has fundamentally altered the CF treatment landscape, with estimated life expectancy increases to above 50 years in the US and UK. The therapy enables reduction or discontinuation of ancillary treatments including hypertonic saline, dornase alpha, oxygen therapy, and enteral feeding. However, less than 15% of eligible PwCF worldwide currently receive ETI due to excessive cost and regulatory barriers. Close multidisciplinary monitoring is essential for managing adverse effects, particularly hepatotoxicity, mental health symptoms, and drug interactions. Early initiation of therapy may prevent irreversible tissue damage including bronchiectasis and olfactory dysfunction. Novel preclinical models using patient-derived nasal epithelial cells and intestinal organoids enable personalized prediction of therapeutic response, supporting label expansion to rare CFTR mutations. Emerging therapies including vanzacaftor-tezacaftor-deutivacaftor show potential for similar or greater efficacy in ongoing phase 3 trials.