FGFR2b作为胃癌治疗性生物标志物：来自Bemarituzumab的经验教训及对下一代靶向治疗的启示。
完整摘要 · 中文译文
综述目的：FGFR2b是胃腺癌和胃食管交界处腺癌中一个有吸引力的治疗生物标志物，但尽管FORTITUDE-101主要总生存期分析结果在统计学上呈阳性，一线贝马里珠单抗的研发仍然终止。本综述借助贝马里珠单抗项目，探讨临床上有用的FGFR2b生物标志物必须涵盖哪些内容，以及这些要求在不同治疗模式下如何变化。 近期发现：FGFR2b蛋白过表达与FGFR2基因组改变识别的是相关但不等同的人群。检测阈值、标本年龄和空间异质性会影响表观表达水平。在FIGHT和FORTITUDE-101两项研究中，总生存期风险比估计值在后来的数据截止时间点均趋向于无效值，但不应将不同试验的结果解读为单一趋势。一项基于纳武利尤单抗联合方案的三期试验根据申办方通报，因疗效不足而终止。两项三期研究均尚未在同行评审出版物中完整发表。新兴的靶向FGFR2的药物可能需要超越原始贝马里珠单抗染色阈值的模式特异性生物标志物。前瞻性开发应评估与治疗模式相匹配的生物标志物：抗体对应可及表面蛋白和空间分布，激酶抑制剂对应激活型基因组改变，抗体药物偶联物对应抗原密度、内化、转运和载荷敏感性。这些仍是研究优先事项，而非经过验证的患者层面的治疗规则。
完整摘要 · 英文原文
PURPOSE OF REVIEW: FGFR2b is an appealing therapeutic biomarker in gastric and gastroesophageal junction adenocarcinoma, but first-line bemarituzumab development ended despite a statistically positive FORTITUDE-101 primary overall-survival analysis. This review uses the bemarituzumab programme to examine what a clinically useful FGFR2b biomarker must capture and how those requirements change across therapeutic modalities. RECENT FINDINGS: FGFR2b protein overexpression and FGFR2 genomic alteration identify related but non-equivalent populations. Assay threshold, specimen age and spatial heterogeneity affect apparent expression. Within both FIGHT and FORTITUDE-101, OS hazard-ratio estimates moved toward the null at later data cutoffs, although results should not be interpreted across trials as a single trend. A phase 3 trial on a nivolumab-containing backbone was stopped for inadequate efficacy according to sponsor communications. Neither phase 3 study has yet been fully reported in a peer-reviewed publication. Emerging FGFR2-directed agents may require modality-specific biomarkers beyond the original bemarituzumab staining threshold. Prospective development should evaluate modality-matched biomarkers: accessible surface protein and spatial distribution for antibodies, activating genomic changes for kinase inhibitors, and antigen density, internalisation, trafficking and payload sensitivity for antibody-drug conjugates. These remain research priorities rather than validated patient-level treatment rules.