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Review
. 2023 Jan;23(1):224-249.
doi: 10.5230/jgc.2023.23.e6.

Breakthroughs in the Systemic Treatment of HER2-Positive Advanced/Metastatic Gastric Cancer: From Singlet Chemotherapy to Triple Combination

Sun Young Rha  1   2   3 , Hyun Cheol Chung  1   4
Affiliations
Review

Breakthroughs in the Systemic Treatment of HER2-Positive Advanced/Metastatic Gastric Cancer: From Singlet Chemotherapy to Triple Combination

Sun Young Rha et al. J Gastric Cancer. 2023 Jan.

Abstract

Gastric cancer is heterogeneous in morphology, biology, genomics, and treatment response. Alterations in human epidermal growth factor receptor 2 (HER2) overexpression, microsatellite instability (MSI) status, programmed death-ligand 1 (PD-L1) levels, and fibroblast growth factor receptor 2 (FGFR2) can be used as biomarkers. Since the combination of fluoropyrimidine/platinum plus trastuzumab that was investigated in the ToGA trial was approved as a standard of care in HER2-positive patients in 2010, no other agents showed efficacy in the first- (HELOISE, LOGiC, JACOB trials) and second- (TyTAN, GATSBY, T-ACT trials) line treatments. Despite the success in treating breast cancer, various anti-HER2 agents, including a monoclonal antibody (pertuzumab), an antibody-drug conjugate (ADC; trastuzumab emtansine [T-DM1]), and a small molecule (lapatinib) failed to translate into clinical benefits until the KEYNOTE-811 (first-line) and DESTINY-Gastri01 (≥second-line) trials were conducted. The incorporation of HER2-directed treatment with immune checkpoint inhibitors in the form of a monoclonal antibody or ADC is now approved as a standard treatment. Despite the promising results of new agents (engineered monoclonal antibodies, bi-specific antibodies, fusion proteins, and small molecules) in the early phase of development, the management of HER2-positive gastric cancer requires further optimization to achieve precision medicine with a chemotherapeutic backbone. Treatment resistance is a complex process that can be overcome using a combination of chemotherapy, targeted agents, and immune checkpoint inhibitors, including novel agents. HER2 status must be reassessed in patients undergoing anti-HER2 treatment with disease progression after the first-line treatment. As a general guideline, patients who need systemic treatment should receive chemotherapy plus targeted agents, anti-angiogenic agents, immune checkpoint inhibitors, or their combinations.

Keywords: Gastric cancer; HER2; Immune checkpoint inhibitor; Targeted.

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Conflict of interest statement

No potential conflict of interest relevant to this article was reported.

Figures

Fig. 1
Fig. 1. Novel agents for HER2-directed treatment.
HER2 = human epidermal growth factor receptor 2.
Fig. 2
Fig. 2. History of drug approvals for the treatment of HER2-positive gastric cancer.
HER2 = human epidermal growth factor receptor 2; EC = European Commission; FDA = Food and Drug Administration; EMA = European Medicines Agency. *Regardless of HER2 state for the third line.
Fig. 3
Fig. 3. Recommendations for each line of treatment in HER2-positive gastric cancer.
HER2 = human epidermal growth factor receptor 2; FOLFIRI = 5-fluorouracil, folinic acid, and irinotecan; MSI = microsatellite instability.
See this image and copyright information in PMC

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