Molecularly Targeted Therapies for Gastric Cancer. State of the Art

Abstract

Many phase III trials failed to demonstrate a survival benefit from the addition of molecular therapy to conventional chemotherapy for advanced and metastatic gastric cancer, and only three agents were approved by the FDA. We examined the efficacy and safety of novel drugs recently investigated. PubMed, Embase and Cochrane Library were searched for phase III randomized controlled trials published from January 2016 to December 2020. Patients in the experimental arm received molecular therapy with or without conventional chemotherapy, while those in the control arm had conventional chemotherapy alone. The primary outcomes were overall and progression-free survival. The secondary outcomes were the rate of tumor response, severe adverse effects, and quality of life. Eight studies with a total of 4223 enrolled patients were included. The overall and progression-free survival of molecular and conventional therapy were comparable. Most of these trials did not find a significant difference in tumor response rate and in the number of severe adverse effects and related deaths between the experimental and control arms. The survival benefits of molecular therapies available to date for advanced and metastatic gastric cancer are rather unclear, mostly due to inaccurate patient selection, particularly concerning oncogene amplification and copy number.

Keywords: EGFR inhibitors; MET inhibitors; angiogenesis inhibitors; chemotherapy; gastric cancer; molecular target therapy.

Figure 1

Targeted therapy and oncogenic pathways in gastric cancer. Activation of ERK-AMP KINASE: ligand binding to a growth factor receptor activates the small GTP-binding RAS protein, which interacts with RAF protein kinase. RAF phosphorylates and activates MEK (MAP kinase or ERK kinase), which then activates ERK (extracellular signal-regulated kinase) by phosphorylation of tyrosine and threonine residues. Activated ERK translocates into the nucleus where it phosphorylates the Elk-1 transcription. PI3K/AKT/MTOR Pathway: PI3K/AKT/MTOR signaling constitutes an important pathway that consists of two steps: phosphatidylinositol 3-kinase (PI3K) and its downstream molecule serine/threonine protein kinase B (PKB; also known as AKT). The PI3/AKT/mTOR pathway is stimulated by RTK and cytokine receptor activation. Tyrosine residues are then phosphorylated and provide anchor sites for PI3K translocation to the membrane, thus participating in the transduction of various extracellular matrix molecules and cytokines, including mTOR, a serine/threonine protein kinase and a member of the PI3K-associated kinase protein family.

Figure 2

Prisma flow diagram.

Figure 3

Risk of bias. To assess the risk of bias of each included study, the revised version of the Cochrane tool (RoB 2) was employed. The RoB 2 tool is structured into domains through which bias might be introduced into the result. These domains were identified based on both empirical evidence and theoretical considerations.

Figure 4

Forest plot of comparison: molecular-targeted therapy alone/plus chemotherapy versus chemotherapy alone/placebo. Main analyses; outcome: overall survival.

Figure 5

Forest plot of comparison: molecular-targeted therapy alone/plus chemotherapy versus chemotherapy alone/placebo. Main analyses; outcome: progression free survival.

Figure 6

Forest plots of comparison: molecular-targeted therapy alone/plus chemotherapy versus chemotherapy alone/placebo. Secondary analyses; outcome: serious adverse effects and related-deaths.

Figure 7

(a) Forest plot of comparison: molecular-targeted therapy alone/plus chemotherapy versus chemotherapy alone/placebo. Main analyses; outcome: overall survival (data from Cochrane and present review pooled). (b) Forest plot of comparison: molecular-targeted therapy alone/plus chemotherapy versus chemotherapy alone/placebo. Main analyses; outcome: progression free survival (data from Cochrane and present review pooled).

Figure 7

(a) Forest plot of comparison: molecular-targeted therapy alone/plus chemotherapy versus chemotherapy alone/placebo. Main analyses; outcome: overall survival (data from Cochrane and present review pooled). (b) Forest plot of comparison: molecular-targeted therapy alone/plus chemotherapy versus chemotherapy alone/placebo. Main analyses; outcome: progression free survival (data from Cochrane and present review pooled).