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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02934-7

摘要内容如下：

成纤维细胞生长因子受体（FGFR）的改变驱动多种肿瘤类型的肿瘤发生。在FGFR改变的晚期实体瘤的2期FIGT-207研究中，我们研究了培米加替尼，一种选择性、强效、口服FGFR1-FGFR3抑制剂。主要终点是队列A（融合/重排）和队列B（激活非激酶结构域突变）的客观缓解率（ORR）。次要终点是队列A和B的无进展生存期、缓解持续时间和总生存期，以及安全性。探索性终点包括队列C的ORR（激酶结构域突变，具有未知意义的潜在致病变异）和与耐药和应答相关的共改变分析。队列A、B和C的ORR分别为26.5%、9.4%和3.8%。没有批准的FGFR抑制剂的肿瘤或那些以前没有证实对FGFR抑制敏感的改变的肿瘤具有客观反应。在队列A和B中，中位无进展生存期分别为4.5个月和3.7个月，中位缓解期分别为7.8个月和6.9个月，中位总生存期分别为17.5个月和11.4个月。安全性与之前的报告一致。最常见的任何级别治疗中出现的不良事件是高磷血症（84%）和口腔炎（53%）。TP53共突变与缺乏应答相关，BAP1改变与较高应答率相关。FGFR1-FGFR3看门人和分子制动突变导致获得性耐药。FGFR抑制和药物失效机制的新治疗领域在不同肿瘤类型中得到确认。ClinicalTrials.gov标识符：NCT03822117。

英文原文如下：

Abstracts

Fibroblast growth factor receptor (FGFR) alterations drive oncogenesis in multiple tumor types. Here we studied pemigatinib, a selective, potent, oral FGFR1-FGFR3 inhibitor, in the phase 2 FIGHT-207 basket study of FGFR-altered advanced solid tumors. Primary end points were objective response rate (ORR) in cohorts A (fusions/rearrangements) and B (activating non-kinase domain mutations). Secondary end points were progression-free survival, duration of response and overall survival in cohorts A and B, and safety. Exploratory end points included ORR of cohort C (kinase domain mutations, potentially pathogenic variants of unknown significance) and analysis of co-alterations associated with resistance and response. ORRs for cohorts A, B and C were 26.5%, 9.4% and 3.8%, respectively. Tumors with no approved FGFR inhibitors or those with alterations not previously confirmed to be sensitive to FGFR inhibition had objective responses. In cohorts A and B, the median progression-free survival was 4.5 and 3.7 months, median duration of response was 7.8 and 6.9 months and median overall survival was 17.5 and 11.4 months, respectively. Safety was consistent with previous reports. The most common any-grade treatment-emergent adverse events were hyperphosphatemia (84%) and stomatitis (53%). TP53 co-mutations were associated with lack of response and BAP1 alterations with higher response rates. FGFR1-FGFR3 gatekeeper and molecular brake mutations led to acquired resistance. New therapeutic areas for FGFR inhibition and drug failure mechanisms were identified across tumor types. ClinicalTrials.gov identifier: NCT03822117 .

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