Effectiveness of ETI in people with Cystic Fibrosis and no F508del CFTR variant: a multicenter study in Greece

<bold>Introduction:</bold> In Europe, elexacaftor-tezacaftor-ivacaftor (ETI) has been approved for people with Cystic Fibrosis (PwCF) with at least one F508del variant, while FDA has also approved ETI for another 177 mutations. <bold>Aim:</bold> To evaluate the effectiveness of ETI in PwCF with no F508del CFTR variants. <bold>Method:</bold> Data from 3 CF centers on PwCF >12 years old were retrospectively collected. Initiation of ETI was based on reduced pulmonary function tests, frequent exacerbations or severe symptoms. <bold>Results:</bold> Twenty PwCF (10 males, 10 females, 8 with CFRD) aged 30.8±11.2 years were included in the study after 5.5±4.5 months on ETI. Nineteen PwCF had no FDA-approved mutations- 4 had one NK1303K variant. An improvement was observed in FEV1% (68.1±23.5 before vs 77.4±28.3 after, p=0.006), FVC% (81±20.7 vs 90.8±25.6, p=0.011) and sweat chloride concentration (103.8±20.6 vs 80.36±13.4 mmol/lt, p=0.003). The number of exacerbations decreased from 3.1±2.6 to 1.1±1.2 in the year after ETI initiation (p=0.001) and BMI increased (21.03±3.4 vs 21.7±3.5 Kg/m², p=0.009). The corresponding changes for the 4 PwCF with one NK1303K variant were: FEV1% 58±18.1 vs 85.3±31.6 (p=0.031), FVC% 79±20.5 vs 104.8±30.2 (ns), number of exacerbations 4±2.5 vs 0.5±1 (ns), BMI 21.2±2.8 vs 22.4±2.8 Kg/m² (p=0.003). Seven participants showed no improvement in FEV1%, while five patients showed improvement >20%, out of whom 3 had one NK1303K variant and one had an FDA-approved variant (G85E). Regarding symptoms, improvement was reported in dyspnea and exercise in 15 patients and cough in 19. <bold>Conclusions:</bold> Response to ETI in PwCF and no F508del CFTR variant is rather individualized and varies amongst different parameters.