Division of Medical Oncology, Department of Medicine, University of Kansas Medical Center, 2330 Shawnee Mission Pkwy, Suite 210, Westwood, Kansas City, KS, 66205, USA.
MetroWest Medical Center/Tufts University School of Medicine, Framingham, MA, USA.
J Hematol Oncol. 2021 Jan 12;14(1):13. doi: 10.1186/s13045-021-01034-0.
Several targeted therapies have shown efficacy in patients with advanced gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJC), including anti-angiogenic agents and immune checkpoint inhibitors. Ramucirumab, an anti-VEGFR2 antibody, has shown efficacy in GC, but the benefits are limited, in part due to MET-mediated resistance. Other VEGF targeted agents like VEGF tyrosine kinase inhibitors (TKIs) with broad multi-kinase inhibitory spectrum like regorafenib and cabozantinib have also shown modest single agent activity in early phase trials. For immune checkpoint inhibitors, pembrolizumab (anti-PD-1) monotherapy confers survival advantage as 3rd line therapy for the PD-L1 expressing GC and GEJC population and has been approved for use in this setting. Extensive tumor microenvironment immune modulatory effects from antiangiogenic agents have been demonstrated from preclinical data which support the clinical study rationale of dual blockade of VEGF and immune checkpoint. In addition, FDA has approved combinations of anti-VEGF/VEGFR with anti-PD-1/PD-L1 agents in hepatocellular carcinoma and renal cell carcinoma. Promising clinical activity has been demonstrated in patients with refractory GC/GEJC when treated with dual blockade combination with antiangiogenic agents and immune checkpoint inhibitors like PD-1/PD-L1 inhibitors in several phase I/II trials. This review highlights the trials investigating these novel combinations as well as their preclinical rationale.
几种靶向治疗方法已在晚期胃癌(GC)和胃食管交界处腺癌(GEJC)患者中显示出疗效,包括抗血管生成剂和免疫检查点抑制剂。抗血管内皮生长因子受体 2 抗体雷莫芦单抗在 GC 中显示出疗效,但疗效有限,部分原因是 MET 介导的耐药性。其他 VEGF 靶向药物,如具有广泛多激酶抑制谱的 VEGF 酪氨酸激酶抑制剂(TKIs),如regorafenib 和 cabozantinib,在早期临床试验中也显示出适度的单药活性。对于免疫检查点抑制剂,pembrolizumab(抗 PD-1)单药治疗作为 PD-L1 表达的 GC 和 GEJC 人群的三线治疗方法具有生存优势,并已获准在该治疗中使用。来自临床前数据的广泛肿瘤微环境免疫调节作用支持了抗血管生成剂和免疫检查点双重阻断的临床研究原理。此外,FDA 已批准抗 VEGF/VEGFR 与抗 PD-1/PD-L1 药物联合用于治疗肝细胞癌和肾细胞癌。在几项 I/II 期试验中,当用抗血管生成剂和免疫检查点抑制剂(如 PD-1/PD-L1 抑制剂)双重阻断联合治疗难治性 GC/GEJC 患者时,已显示出有希望的临床活性。这篇综述强调了这些新型联合治疗的临床试验及其临床前原理。
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