The integration of immune checkpoint inhibitors with VEGF targeted agents in advanced gastric and gastroesophageal adenocarcinoma: a review on the rationale and results of early phase trials

Abstract

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.

Keywords: Angiogenesis; Combination therapy; Cytotoxic lymphocyte antigen-4; Esophageal cancer; Gastric cancer; Gastroesophageal cancer; Immune checkpoint inhibitor; Programmed death ligand-1; Programmed death-1; Vascular endothelial growth factor.

Fig. 1

Rationale for combining VEGFR2 and PD-1/PD-L1 blockade. Tumor hypoxia leads to VEGFA/ANG induced disruptive tumor vascularization in a HIF-1a dependent manner. In turn, an immunosuppressive TME becomes established characterized by Treg, MDSCs, and M2 TAMs which inhibit CD4+ and CD8+ effector T cell mediated tumor immune response. In addition, the PD-1/PD-L1 axis is central in maintaining the immune suppressive TME by inhibiting CD4+ and CD8+ effector T cells. VEGFR2 blockade leads to tumor vessel normalization which potentiates PD1/PDL1 blockade by reversing established immune suppressive mechanisms. VEGFR2, vascular endothelial growth factor receptor 2; PD-1/L-1, programmed-death-1/ligand-1; ANG, angiopoietin; HIF-1a, hypoxia inducible factor-1a; Treg, regulatory T cell; MDSC, myeloid derived suppressor cell; TAM, tumor associated macrophages; DC, dendritic cells