背景:由于缺乏支持疗效的临床数据,无F508del变异的囊性纤维化(PwCF)患者获得elexacaftor/tezacaftor/ivacaftor(ETI)的途径有限。
方法:在本系统综述和荟萃分析中,我们检查了来自研究的患者水平数据,这些研究报告了非F508delCFTR变异的PwCF对ETI的临床反应.我们搜索了包括Embase在内的电子数据源,MEDLINE,中央从1月1日起,2019年5月14日2024.
结果:我们的搜索结果确定了4,795项研究,其中20项符合资格标准。164人中有120人(73%)对ETI有积极的临床反应,定义为汗液氯化物(SwCl)降低≥10mmol/L或预测的FEV1(ppFEV1)改善百分比≥5%。在这120个个体中代表了51个独特的ETI反应性变体,其中27个变体(53%)尚未获得美国FDA的批准。对于迄今为止至少有10个人接受ETI治疗的变体,对于N1303K和G85E,观察到一致的阳性临床应答.对于N1303K(n=48),ppFEV1的中位数增加为16%(IQR:8%,29%),SwCl的中值降低为-9(IQR:-4,-22)mmol/L。对于G85E(n=16),ppFEV1的中位数增加为13.5%(IQR:8%,19%),SwCl的中位数降低为-46(IQR:-39,-66)mmol/L。
结论:在对无F508del的PwCF中ETI临床应用进行全面审查后,发现了其他ETI反应性变体。CF社区可以使用此数据来扩展标记的适应症或帮助倡导标签外的ETI报销。
BACKGROUND: Access to elexacaftor/tezacaftor/ivacaftor (ETI) for people with cystic fibrosis (PwCF) without a F508del variant is limited due to lack of clinical data supporting efficacy.
METHODS: In this systematic review and meta-analysis, we examined patient-level data from studies reporting the clinical response to ETI for PwCF with non-F508del CFTR variants. We searched electronic data sources including Embase, MEDLINE, and CENTRAL from January 1st, 2019 to May 14th, 2024.
RESULTS: Our search results identified 4,795 studies and 20 met the eligibility criteria. 120 of 164 (73 %) individuals had a positive clinical response to ETI, defined by a sweat chloride (SwCl) decrease of ≥10 mmol/L or percent-predicted FEV1 (ppFEV1) improvement of ≥5 %. 51 unique ETI-responsive variants were represented across these 120 individuals and 27 of these variants (53 %) have not been previously approved by the U.S. FDA. For variants with at least 10 individuals treated with ETI to date, a consistent positive clinical response was observed for N1303K and G85E. For N1303K (n = 48), the median increase in ppFEV1 was 16 % (IQR: 8 %, 29 %), with a median decrease in SwCl of -9 (IQR: -4, -22) mmol/L. For G85E (n = 16), the median increase in ppFEV1 was 13.5 % (IQR: 8 %, 19 %) with a median decrease in SwCl of -46 (IQR: -39, -66) mmol/L.
CONCLUSIONS: Additional ETI-responsive variants were identified following a comprehensive review of ETI clinical use in PwCF without F508del. This data can be used by the CF community in efforts to expand the labelled indications or to help advocate for off-label ETI reimbursement.