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.

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。在这里，我们在FGFR改变的晚期实体瘤的 2 期 FIGHT-207 篮子研究中研究了 pemigatinib，一种选择性、有效的口服 FGFR1-FGFR3 抑制剂。主要终点是队列 A（融合/重排）和 B（激活非激酶结构域突变）的客观缓解率 (ORR)。次要终点是 A 组和 B 组的无进展生存期、缓解持续时间和总生存期以及安全性。探索性终点包括 C 组的 ORR（激酶结构域突变、意义不明的潜在致病变异）以及与耐药性和反应相关的共同改变的分析。 A、B 和 C 组的 ORR 分别为 26.5%、9.4% 和 3.8%。没有批准的 FGFR 抑制剂的肿瘤或之前未确认对 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 和 3.7 个月，中位缓解持续时间分别为 7.8 和 6.9 个月，中位总生存期分别为 17.5 和 11.4 个月。安全性与之前的报告一致。最常见的任何级别的治疗引起的不良事件是高磷血症（84%）和口腔炎（53%）。TP53共突变与缺乏反应相关，而BAP1改变与较高的反应率相关。FGFR1 – FGFR3看门人和分子制动突变导致获得性耐药。跨肿瘤类型确定了 FGFR 抑制和药物失效机制的新治疗领域。 ClinicalTrials.gov 标识符：NCT03822117。