After the first project funded by the FFC Ricerca aimed to assess effectiveness and the safety of Kaftrio in patients with cystic fibrosis (pwCF) and advanced respiratory disease, that ends in the second half of 2023, a new multicentric study starts. This second observational, retrospective and prospective study, will be aimed to continue the assessment of effectiveness and safety in pwCF with advanced respiratory disease for overall 4 years (group A) and to enroll pwCF, in which Kaftrio has been supplied by the Italian Healthcare Service after July 2021 (group B). Real-world data will be obtained in patients of both groups, who will be 12 years of age or older and compound heterozygous for F508del and one minimal function mutation. Different effectiveness (lung function, body mass index, quality of life, sweat chloride) and safety (treatment-related adverse effects, interruption of the drug administration, increase in blood levels of hepatic enzymes and creatine phosphokinase) measurements will be evaluated for 2 years prior to and 2 or 4 years after Kaftrio was initiated. A secondary focus of the study will be directed toward pwCF who failed to obtain any beneficial improvement of lung function following treatment with Kaftrio (no responders). Considering different clinical characteristics and positive effects of the drug, these no responders will be compared to patients, which obtained a good increase in lung function (responders). Two sub-studies will be planned to compare the two groups for some relevant aspects of the responsiveness to the drug. The first sub-study will be mainly aimed to verify the correlation between ex vivo functional data of CFTR activity, obtained in nasal epithelia generated in vitro from responders and no responders, and their clinical response to the treatment with Kaftrio. The second sub-study will be mainly aimed to identify specific bacterial phenotypic and genetic characteristics of Pseudomonas aeruginosa, as markers of clinical response to treatment with the triple drug combination.