PT - JOURNAL ARTICLE AU - Burgel, Pierre-Régis AU - Sermet-Gaudelus, Isabelle AU - Durieu, Isabelle AU - Kanaan, Reem AU - Macey, Julie AU - Grenet, Dominique AU - Porzio, Michele AU - Coolen-Allou, Nathalie AU - Chiron, Raphael AU - Marguet, Christophe AU - Douvry, Benoit AU - Dufeu, Nadine AU - Danner-Boucher, Isabelle AU - Foucaud, Pierre AU - Lemonnier, Lydie AU - Girodon, Emmanuelle AU - Da Silva, Jennifer AU - Martin, Clémence ED - , TI - The French Compassionate Program of elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis with advanced lung disease and no F508del <em>CFTR</em> variant AID - 10.1183/13993003.02437-2022 DP - 2023 Jan 01 TA - European Respiratory Journal PG - 2202437 4099 - http://erj.ersjournals.com/content/early/2023/02/09/13993003.02437-2022.short 4100 - http://erj.ersjournals.com/content/early/2023/02/09/13993003.02437-2022.full AB - Background The European Medicines Agency has approved the cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination elexacaftor-tezacaftor-ivacaftor (ETI) for people with cystic fibrosis (pwCF) carrying at least one F508del variant. The United States Food and Drug Administration (FDA) also approved ETI for pwCF carrying one of 177 rare variants.Methods An observational study was conducted to evaluate the effectiveness of ETI in pwCF with advanced lung disease that were not eligible to ETI in Europe. All patients with no F508del variant and advanced lung disease (defined as having a percent predicted forced expiratory volume (ppFEV1)&lt;40 and/or being under evaluation for lung transplantation) and enrolled in the French Compassionate Program initiated ETI at recommended doses. Effectiveness was evaluated by a centralized adjudication committee at 4–6 weeks in terms of clinical manifestations, sweat chloride concentration and ppFEV1.Results Among the first 84 pwCF included in the program, ETI was effective in 45 (54%) and 39 (46%) were considered to be non-responders. Among the responders 22/45 (49%) carried a CFTR variant that is not currently approved by FDA for ETI eligibility. Important clinical benefits, including suspending the indication for lung transplantation, a significant decrease in sweat chloride concentration by a median [IQR] −30 [-14;-43]mmol·l−1 (n=42; p&lt;0.0001) and an improvement in ppFEV1 by+10.0 [6.0; 20.5] (n=44, p&lt;0.0001), were observed in those for whom treatment was effective.Conclusion Clinical benefits were observed in a large subset of pwCF with advanced lung disease and CFTR variants not currently approved for ETI.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of Interest: Pierre-Régis Burgel reports support for the present work from Vaincre la Mucoviscidose. Pierre-Régis Burgel reports grants from Boehringer Ingelheim, GSK, Vertex; consulting fees and lecture honoraria from Boehringer Ingelheim, GSK, AstraZeneca, Vertex, Chiesi, Pfizer, Novartis, Zambon, Insmed; outside the submitted work.Conflict of Interest: Isabelle Sermet-Gaudelus reports support from the present manuscript from French CF association for primary nasal cell generation and Institut Necker Enfants Malades. Isabelle Sermet-Gaudelus reports grants from Institut Necker Enfants Malades; member of scientific advisory board and innovation award from Vertex; travel support from North American Cystic Fibrosis Conference, Société Francais de Mucoviscidose; outside the submitted work.Conflict of Interest: Christophe Marguet reports payment for expert testimony from Vertex; travel support from Sanofi; advisory board participation with Vertex, Zambon, Viatris, Sanofi; leadership role with French paediatric pulmonology and allergy society; outside the submitted work.Conflict of Interest: Benoit Douvry reports grants and payment for expert testimony from Vertex, outside the submitted work.Conflict of Interest: Clémence Martin reports lecture honoraria from AstraZeneca, Chiesi, Zambon; travel support from Zambon, Sanofi; advisory board membership from Vertex, Zambon, GSK; outside the submitted work.Conflict of Interest: All other authors have nothing to disclose.