Molecularly targeted therapy for receptor tyrosine kinases (RTKs) has faced limitations in gastric and gastroesophageal junction (G/GEJ) cancer except for HER2-targeted agents, possibly due to inappropriate assay selection that has hindered identification of sensitive patients, in addition to coexisting genetic abnormalities as well as intratumoral heterogeneity. Immunohistochemistry of RTKs has, thus, proved largely unsuccessful for patient selection, and detection of RTK gene amplification as a true oncogenic driver is problematic given the small numbers of affected individuals. FGFR2 amplification is associated with poor prognosis in G/GEJ cancer, and immunohistochemistry of the FGFR2b protein isoform has proved effective for the detection of such FGFR2-dependent tumors. Phase III and Ib/III trials of the FGFR2-targeted antibody bemarituzumab for G/GEJ cancer overexpressing FGFR2b are ongoing based on the promising result in a phase II trial, especially in cases with an FGFR2b positivity of ≥ 10%. Challenges to EGFR- and MET-targeted therapies are being tackled with antibody–drug conjugates (ADCs) and bispecific antibodies. CLDN18.2 is expressed in some G/GEJ tumors but lacks oncogenic driver potential, and the CLDN18.2-targeted antibody zolbetuximab prolonged the survival of CLDN18.2-positive G/GEJ cancer patients in phase III trials. Antibody–drug conjugates and ADCs that target CLDN18.2 are also being pursued for treatment of such patients. Similarly, targeting of nondriver molecules such as DKK1, TROP2, and CEACAM5 is under investigation in early-stage clinical trials. This shift in focus from target molecules with driver potential to markers for precise drug delivery should increase the number of possible targets in G/GEJ cancer.

除 HER2 靶向药物外，受体酪氨酸激酶 (RTK) 的分子靶向治疗在胃和胃食管交界处 (G/GEJ) 癌症中面临局限性，这可能是由于不适当的检测选择阻碍了敏感患者的识别，此外还有共存的遗传因素。异常以及瘤内异质性。因此，事实证明，RTK 的免疫组织化学对于患者选择来说在很大程度上是不成功的，并且考虑到受影响个体的数量较少，检测 RTK 基因扩增作为真正的致癌驱动因素是有问题的。FGFR2扩增与 G/GEJ 癌的不良预后相关，FGFR2b 蛋白亚型的免疫组织化学已证明可有效检测此类 FGFR2 依赖性肿瘤。 FGFR2 靶向抗体 bemarituzumab 用于治疗过度表达 FGFR2b 的 G/GEJ 癌的 III 期和 Ib/III 期试验正在进行中，基于 II 期试验的有希望的结果，特别是在 FGFR2b 阳性≥ 10% 的病例中。 EGFR 和 MET 靶向治疗面临的挑战正在通过抗体药物偶联物 (ADC) 和双特异性抗体来解决。 CLDN18.2在一些G/GEJ肿瘤中表达，但缺乏致癌驱动潜力，并且CLDN18.2靶向抗体zolbetuximab在III期试验中延长了CLDN18.2阳性G/GEJ癌症患者的生存期。靶向 CLDN18.2 的抗体药物偶联物和 ADC 也正在被用于治疗此类患者。同样，针对 DKK1、TROP2 和 CEACAM5 等非驱动分子的靶向治疗正在早期临床试验中进行研究。这种焦点从具有驱动潜力的目标分子转向用于精确药物递送的标记物应该会增加 G/GEJ 癌症中可能目标的数量。