Emerging Therapies in the Management of Advanced-Stage Gastric Cancer

Abstract

Globally, gastric malignancy contributes to significant cancer-related morbidity and mortality. Despite a recent approval of two targeted agents, trastuzumab and ramucirumab, the treatment options for advanced-stage gastric cancer are limited. Consequently, the overall clinical outcomes for patients with advanced-stage gastric cancer remain poor. Numerous agents that are active against novel targets have been evaluated in the course of randomized trials; however, most have produced disappointing results because of the molecular heterogeneity of gastric cancer. The Cancer Genome Atlas (TCGA) project proposed a new classification system for gastric cancer that includes four different tumor subtypes based on molecular characteristics. This change led to the identification of several distinct and potentially targetable pathways. However, most agents targeting these pathways do not elicit any meaningful clinical benefit when employed for the treatment of advanced-stage gastric cancer. Most advanced-stage gastric cancer trials currently focus on agents that modulate tumor microenvironments and cancer cell stemness. In this review, we summarize data regarding novel compounds that have shown efficacy in early phase studies and show promise as effective therapeutic agents, with special emphasis on those for which phase III trials are either planned or underway.

Keywords: The Cancer Genome Atlas; andecaliximab; claudiximab; gastric cancer; gastroesophageal cancer; immune checkpoint inhibitor; immunotherapy; napabucasin.

Figure 1

Summary of treatment of advanced stage GC/GEC as recommended by major guidelines (see text).

Figure 2

Mechanism of action of cytotoxic lymphocyte associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) and its ligands (PD-L1) (Brahmer et al., ; Topalian et al., ; Tsai and Hsu, 2017). CTLA-4 plays role in de novo immune stimulation during antigen priming by antigen presenting cells (APCs), macrophages and dendritic cells (DCs). Following antigen exposure, CTLA-4 is expressed on T cells and competes with CD 28 for binding at B7 (B7-1/CD 80 and B7-2/CD 86) on APCs. This generates inhibitory signals for T-cells which shuts off antigen priming by APCs in the tumor draining lymph nodes. CTLA-4 inhibitors namely ipilimumab and tremelimumab restores antigen priming by blocking CTLA-4 on T cells. On the other hand PD-1/PD-L1 axis plays important role in the adaptive resistance by tumors cells against host immune system. PD-1 is expressed on immune cells like T-cells, B-cells and monocytes. The expression of PD-L1 is upregulated on tumor cells and APCs in response to interferon gamma secreted from activated T-cells via activation of JAK2/STAT3 pathway. PDL-2 is also a ligand for PD-1 and is exclusively expressed on DCs. Engagement of PD-L1/L2 by PD-1 inhibits proliferation, migration and effector functions of T-cells. This effect is blunted by PD-1 inhibitors (pembrolizumab and nivolumab) and PD-L1 inhibitors (atezolizumab, durvalumab and avelumab).

Figure 3

Microscopic structure of tight junctions showing claudin 18.2 with binding site for monoclonal antibody claudiximab.

Figure 4

Mechanism and site of action of andecaliximab.

Figure 5

STAT 3 signaling pathway and site of action of napabucasin. Attachment of cytokines to its receptors activates Janus kinases which in turn phosphorylates STAT 3. The phosphorylation of STAT 3 leads to dimerization and activation of STAT 3. STAT 3 enters the nuclei to bind at STAT 3 binding sites on DNA which triggers transcription of several proteins which regulate cell proliferation, survival, angiogenesis, invasion and migration. Through Beta-catenin pathway STAT 3 induces genes responsible to trigger the formation and maintenance of stem cells.