Goyal L, DiToro D, Hollebecque A, Bridgewater J A, Shimura M, Kano A, Okamura S, Silhavy J L, Wacheck V, Halim A, Meric-Bernstam F
Department of Medicine, Stanford Cancer Center, Stanford University School of Medicine, Palo Alto, USA; Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
Brigham and Women's Hospital, Boston, USA.
Ann Oncol. 2025 Apr;36(4):414-425. doi: 10.1016/j.annonc.2024.11.017. Epub 2024 Dec 11.
Futibatinib is the only covalent inhibitor of FGFR1-4 to gain regulatory approval in oncology. In this article, we present genomic analyses of tissue biopsies and circulating tumor DNA (ctDNA) from patients with 1 of nearly 20 tumor types treated with futibatinib in the phase I/II FOENIX study.
Eligible patients included those with ctDNA samples collected per protocol at baseline and/or progression on futibatinib in the phase Ib portion of the study for FGF/FGFR-altered advanced solid tumors or the phase II portion of the study for FGFR2 fusion/rearrangement-positive cholangiocarcinoma. Assessments included analytical concordance between tumor and ctDNA analyses for detection of FGFR alterations, association of ctDNA-detected co-occurring genomic alterations with response to futibatinib, and determination of patterns of acquired resistance following progression on futibatinib.
Among 300 patients treated with futibatinib, 226 were eligible for this analysis, including 139 (62%) with cholangiocarcinoma. Among patients with known FGFR2 fusions/rearrangements, FGFR1 fusions, FGFR3 fusions, or FGFR2 amplifications per tissue analysis, detection rates in ctDNA for these aberrations were 84%, 0%, 11%, and 59%, respectively. Objective response rates on futibatinib were not significantly different between patients with TP53-altered versus -unaltered solid tumors; progression-free survival was reduced in patients with CDKN2B-altered versus -unaltered cholangiocarcinoma (median 4.8 versus 11.0 months; P = 0.03). Acquired resistance to futibatinib was frequently polyclonal and driven by an array of mutations within the relevant FGFR kinase domain, predominantly V565L, V565F, and N550K variants.
In this largest and most systematic analysis of acquired resistance to an FGFR inhibitor from prospective clinical trials, emergence of secondary FGFR2 kinase domain mutations was observed in most patients receiving clinical benefit to futibatinib. ctDNA analysis shows clinically relevant potential as a noninvasive method for assessing genomic profiles, identifying patients who may benefit from FGFR inhibitor treatment, and exploring acquired resistance mechanisms.
伏替巴替尼是唯一获得肿瘤学监管批准的FGFR1-4共价抑制剂。在本文中，我们展示了在I/II期FOENIX研究中接受伏替巴替尼治疗的近20种肿瘤类型之一的患者的组织活检和循环肿瘤DNA（ctDNA）的基因组分析。
符合条件的患者包括在研究的Ib期部分针对FGF/FGFR改变的晚期实体瘤或研究的II期部分针对FGFR2融合/重排阳性胆管癌，按照方案在基线和/或伏替巴替尼治疗进展时收集ctDNA样本的患者。评估包括肿瘤和ctDNA分析之间在检测FGFR改变方面的分析一致性、ctDNA检测到的共发生基因组改变与对伏替巴替尼反应的相关性，以及确定伏替巴替尼治疗进展后的获得性耐药模式。
在300例接受伏替巴替尼治疗的患者中，226例符合该分析条件，其中139例（62%）为胆管癌患者。在通过组织分析已知有FGFR2融合/重排、FGFR1融合、FGFR3融合或FGFR2扩增的患者中，这些畸变在ctDNA中的检测率分别为84%、0%、11%和59%。TP53改变与未改变的实体瘤患者对伏替巴替尼的客观缓解率无显著差异；CDKN2B改变与未改变的胆管癌患者的无进展生存期缩短（中位值分别为4.8个月和11.0个月；P = 0.03）。对伏替巴替尼的获得性耐药通常是多克隆的，由相关FGFR激酶结构域内的一系列突变驱动，主要是V565L、V565F和N550K变体。
在这项来自前瞻性临床试验的关于FGFR抑制剂获得性耐药的最大规模、最系统的分析中，在大多数从伏替巴替尼治疗中获得临床益处的患者中观察到了继发性FGFR2激酶结构域突变的出现。ctDNA分析作为一种评估基因组谱、识别可能从FGFR抑制剂治疗中获益的患者以及探索获得性耐药机制的非侵入性方法，显示出与临床相关的潜力。
