WS07.04Baseline variability in percent predicted forced expiratory volume in one second predicts short-term lung function response to elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis

Abstract

Objectives

Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a highly effective drug, improving Percent Predicted Forced Expiratory Volume in One Second (PPFEV₁) in People With Cystic Fibrosis (PWCF). Lung function response to ETI varies but limited research exists on predictors of PPFEV₁ response. This study examined how pre-ETI PPFEV₁ variability influences short-term (≤12 months) PPFEV₁ response to ETI. We hypothesised that greater pre-ETI PPFEV₁ variability predicts larger PPFEV₁ changes, reflecting reversible airflow obstruction from airway inflammation and mucus plugging.

Methods

Observational study with 1,619 PWCF starting ETI, followed in the CF Canada Registry. Eligibility criteria: ≥4 PPFEV₁ measurements within 2 years before ETI initiation (baseline period) and ≥1 PPFEV₁ value within 12 months post-ETI. Wilcoxon matched-pairs sign-rank test was used to evaluate ETI's effect on PPFEV₁. Pre-ETI variability was assessed via median deviation from the highest PPFEV₁ in the baseline period, consistent with previously described methodologies. Correlation between pre-ETI variability and maximum PPFEV₁ change from baseline to 1 year post-ETI was analysed using Spearman's correlation (ρ).

Results

The median for the maximum post-ETI PPFEV₁ change from baseline was 11.6 (IQR:5.4 – 19.2; p<0.001). Median baseline age was 26.6 years and PPFEV₁ 67.6%. Pre-ETI PPFEV₁ variability correlated with maximum post-ETI PPFEV₁ change but was weak (ρ=0.11; p<0.001). Correlation strength varied by lung disease severity: PPFEV₁<40% (n=281, ρ=0.35; p<0.001), 40%≤PPFEV₁<70% (n=572, ρ=0.14; p<0.001), 70%≤PPFEV₁<90% (n=423, ρ=0.14; p=0.005), and PPFEV₁≥90% (n=343, ρ=0.02; p=0.66).

Conclusion

Increased pre-ETI PPFEV₁ variability correlated with greater 1 year PPFEV₁ response post-ETI, with stronger correlations at lower baseline PPFEV₁. This suggests variable airflow obstruction predicts short-term lung function response to ETI, particularly in PWCF with lower baseline lung function.