A systematic review and meta-analysis of randomized trials on the role of targeted therapy in the management of advanced gastric cancer: Evidence does not translate?

Abstract

It is still uncertain if targeted therapy-based regimens in advanced gastric cancer actually produce survival benefit. To shed light on this important question, we performed a systematic review and meta-analyses on each relevant targeted-pathway. By searching literature databases and proceedings of major cancer meetings in the time-frame 2005-2014, 22 randomized clinical trials exploring targeted therapy for a total of 7022 advanced gastric cancer patients were selected and included in the final analysis. Benefit was demonstrated for antiangiogenic agents in terms of overall survival (HR 0.759; 95%CI 0.655-0.880; p < 0.001). Conversely no benefit was found for EGFR pathway (HR 1.077; 95%CI 0.847-1.370; p = 0.543). Meta-analysis of HER-2 pathway confirmed improvement in terms of survival outcome, already known for this class of drugs (HR 0.823; 95%CI 0.722-0.939; p = 0.004). Pooled analysis demonstrated a significant survival benefit (OS: HR 0.823; PFS: HR 0.762) with acceptable tolerability profile for targeted-based therapies as compared to conventional treatments. This finding conflicts with the outcome of most individual studies, probably due to poor trial design or patients selection. In conclusion, our findings demonstrate a significant survival benefit for targeted therapy in its whole, which can be ascribed to anti-angiogenic and anti-HER2 agents.

Keywords: ADME, absorption, distribution, metabolism, and excretion; Ab, monoclonal antibody; BSC, best supportive care; CHT, chemotherapy; EGFR, epidermal growth factor receptor; GC, gastric cancer; HER2, human epidermal growth factor receptor 2; HER3, human epidermal growth factor receptor 3; MET, mesenchymal epithelial transition factor; NGS, next generation sequencing; NSCLC, non-small cell lung cancer; OR, odds-ratio; OS, overall survival; PARP, poly ADP ribose polymerase; PFS, progression free survival; PI3K, phosphatidylinositide 3-kinases; PRISMA, preferred reporting items for systematic reviews and meta-analyses; RAF, rapidly accelerated fibrosarcoma; RAS, rat sarcoma viral oncogene homolog; RCTs, randomized clinical trials; RR, response rate; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR: VEGF receptor; aGC, advanced gastric cancer; angiogenesis; gastric cancer; mTOR, mammalian target of rapamycin; mTORC, mTOR complex; meta-analysis; randomized clinical trials; systemic chemotherapy; targeted pathways; targeted therapy.

Figure 1.

PRISMA chart showing the trial exclusion and inclusion process in the meta-analysis. SEER, Surveillance, Epidemiology, and End Results.

Figure 2.

Comparison of OS according to involved pathway and treatment line ((A) all pathways), ((B) anti-angiogenic drugs), ((C) anti-EGFR drugs) and ((D) anti-HER2 drugs), between patients treated with a targeted therapy-containing regimen versus conventional schedule. Abbreviation: overall survival, OS; hazard ratio, HR; chemotherapy, CHT; best supportive care, BSC.

Figure 3.

Comparison of PFS according to involved pathway and treatment line ((A) all pathways), ((B) anti-angiogenic drugs), ((C) anti-EGFR drugs) and ((D) anti-HER2 drugs), between patients treated with a targeted therapy-containing regimen vs. conventional schedule. Abbreviation: overall survival, OS; hazard ratio, HR; chemotherapy, CHT; best supportive care, BSC.

Figure 4.

Funnel plot (Begg's test) assessing publication bias.