A multi-center retrospective analysis of the clinical efficacy of elexacaftortezacaftor-ivacaftor in patients with advanced lung disease

Introduction: The CFTR modulators elexacaftor-tezacaftor-ivacaftor form a triple combination (TC) therapy that has been shown to improve clinical outcomes in cystic fibrosis (CF) patients including increased FEV1, decreased exacerbation frequency, and increased body mass index (BMI). Prior phase III clinical trials excluded patients with FEV1<40% predicted, excluding patients with advanced lung disease (ALD). In clinical practice patients with ALD are currently receiving TC therapy however the clinical efficacy and safety profile in this patient population is unknown. If effective, TC therapy could delay the need for lung transplant referral. The objective of this study was to characterize the short-term clinical efficacy and safety of TC therapy in eligible patients who have pre-existing ALD. Methods: We conducted a retrospective cohort study of adult patients with FEV1<40% and/or other high-risk features as defined by the 2019 CF Foundation lung transplant guidelines started on TC therapy between Sept 2019 and Feb 2020 from three academic centers located in the southeastern United States. Response to therapy was assessed with spirometry measuring FEV1 percent predicted (FEV1pp) and BMI measured between 2 to 12 weeks following initiation of therapy. Drug-related adverse events and drug toxicity monitoring was obtained from the medical record. Results: A total of 64 patients from 3 sites were identified and 31 (48%) were female. Mean age was 31.5 years and 53% of patients were homozygous for the F508del CFTR mutation. Colonization by Pseudomonas aeruginosa was present in 75% of cases, and high-risk features as defined by the 2019 CF lung transplant guidelines were identified in 42.1% of cases. Mean FEV1pp increased 8.2% (pre-TC 31.7% ± 6.0 vs 39.9% ± 10.2 post-TC, p=<0.0001). Pre-TC measurements in FEV1pp were measured outside of an acute exacerbation. Mean BMI improved by 0.65 kg/m2 (pre-TC 21.48 ±3.36 kg/m2 vs 22.13 ±3.17 kg/m2, p<0.0001). Adverse events were reported in 14 (18%) patients including transaminitis, constipation, and rash, and none of these were considered severe. Conclusions: Patients from three large academic centers with ALD demonstrated improved lung function and BMI after treatment with TC therapy. Adverse events requiring prolonged discontinuation of therapy were uncommon. The absolute change in FEV1pp was less in this cohort than was reported from prior phase III studies, likely due to greater pre-existing structural lung disease. Further registry studies are needed to elucidate the long-term effects of TC therapy on patients with pre-existing ALD including alterations to disease trajectory and timing of lung transplant referral.