HER2-Expressing Gastric Cancer Cells Respond to Treatment With Trastuzumab Deruxtecan

For the treatment of patients with HER2-amplified gastric cancers in addition to those with HER2 moderate-, low-, and non-expressing disease, trastuzumab deruxtecan (Enhertu; DS-8201) has shown to be an effective therapeutic option, according to data presented during the virtual AACR Annual Meeting 2021.¹

Trastuzumab (Herceptin) and trastuzumab deruxtecan, at various concentrations, demonstrated cytostatic and cytotoxic effects in 49 gastric cancer cell lines examined on the study. Cell proliferation was inhibited by trastuzumab deruxtecan in 55.1% of cell lines (n = 27/49) vs 44.9% (n = 22/49) of cell lines with trastuzumab.

The inhibition rates for these agents were calculated at 10 µg/ml and 100 µg/ml for trastuzumab deruxtecan, and 200 µg/ml for trastuzumab in each HER2 expression group. The ADC was found to inhibit cell proliferation more, at a lower concentration than trastuzumab.

Additionally, the IC50 value of trastuzumab deruxtecan was calculated in 63.3% (n = 30/49) of cell lines, while the IC50 value of trastuzumab was calculated in 1 cell line (NCI-N87). Notably, the cell lines with HER2 overexpression and non-expression proved to be sensitive to the ADC (P <.0001).

“Trastuzumab deruxtecan sensitivity had a significant correlation with HER2 expression level in HER2 overexpression and showed a tendency to correlate in the HER2 moderate-/low-expression level, as well,” lead study author Seo Young Yu, of Yonsei University College of Medicine, said in an oral presentation on the data.

HER2-positive gastric cancer is more aggressive than other gastric cancers, and as such, is associated with a poor prognosis. The humanized anti-HER2 monoclonal antibody trastuzumab has shown clinical benefit in this patient population; however, those with HER2-expressing or -amplified disease accounts for only 10% to 20% of all patients with gastric or gastroesophageal cancers.

To overcome this limitation, antibody-drug conjugates like trastuzumab deruxtecan have been developed to enable the direct delivery of a cytotoxic payload to cancer cells. Due to the high membrane permeability of its payload, trastuzumab deruxtecan has a bystander killing effect that can induce the death of neighboring cells.

To date, predictive biomarkers for response to trastuzumab deruxtecan beyond HER2 amplification or overexpression have yet to be studied. As such, in this research, investigators set out to identify a new target for patients with HER-low gastric cancer.

In a panel of 49 gastric cancer cell lines, 26 of which originated from somatic intrachromosomal recombination, HER2 expression was evaluated; genetic alterations were examined via next-generation sequencing, RNA expression through RNA sequencing, and protein expression through immunoblot and flow cytometry analysis.

Using flow cytometry, the 49 gastric cancer cell-line panel was then divided into 3 groups based on HER2 status: HER2 overexpression, HER2 moderate/low expression, and HER2 non-expression. Investigators then compared the anticancer effects of trastuzumab deruxtecan vs trastuzumab through the use of a CCK-8 assay.

Additionally, the sensitivity of trastuzumab deruxtecan vs trastuzumab was evaluated and HER2-related factors like HER expression level, HER2 extracellular domain (ECD), NRG1 status, were evaluated, according to Yu.

The primary objectives of the study were to identify the correlation between HER2 expression level and the anticancer effect of trastuzumab deruxtecan, as well as to determine the HER2-associated molecule related to the sensitivity of the ADC.

HER2 status for the 49-cell panel was analyzed using 4 breast cancer cell lines for quantitative control: SK-BR-3 (HER2 3+), ZR-75-1 (HER2 2+), MCF-7 (HER2 1+), and HCC1937 (HER2 0). In the group of HER2 moderate-/low-expression, trastuzumab deruxtecan sensitivity showed a tendency to correlate with HER2 expression level.

HER2 ECD was expressed according to HER2 expression level, and most of the cell lines with high expression of HER2 ECD showed sensitivity to trastuzumab deruxtecan. NGR1 expression was relatively low among the 49 gastric cancer cell lines studied and was not found to be correlated with trastuzumab deruxtecan sensitivity, according to Yu.

Notably, trastuzumab deruxtecan sensitivity was observed, even in the HER2 non-expression group (n = 12/17; 70.6%). As a result of analyzing genetic alterations, RNA and protein expression in this group, RTK amplification was confirmed, and MET amplification was the most abundant in this group, Yu said. Additionally, 5 of 6 (83.3%) MET-amplified cell lines demonstrated sensitivity to trastuzumab deruxtecan.

_Reference

_{Yu S, Park J, Kwon W, et al. Trastuzumab deruxtecan (T-DXd) sensitivity in various levels of HER2 expressing gastric cancer cells. Presented at: AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Abstract 945.}