The phase 2 DAISY trial confirms that T-DXd efficacy depends on HER2 expression in breast cancer cases. However, it shows that T-DXd also has moderate activity in HER2-non-expressing patients, suggesting an alternative mechanism of action.
Breast cancer is among the five most common causes of cancer mortality. Despite improvements in its treatment, 5-year survival rates of metastatic breast cancer (mBC) still remain low, at 30%. There are three predominant sub-types of breast cancer, including hormone receptor-positive, hormone receptor-positive, human epidermal growth factor receptor(HER)2-overexpressing, and triple-negative breast cancer. The HER2-overexpressing sub-type is treated with anti-HER2 in combination with taxanes as the standard first-line treatment.
Trastuzumab deruxtecan (T-DXd), a third-generation antibody–drug conjugate (ADC), offers promise due to its high drug-to-antibody ratio and potent cytotoxic payload. The phase 2 DAISY trial aimed to evaluate the effectiveness of T-DXd in patients with mBC across different HER2 expression levels in order to more fully understand its mechanism of action and resistance mechanisms. The findings of the study were published in the journal Nature Medicine.
T-DXd Response Associated Not Just to HER2 Expression
The trial enrolled 186 patients with mBC, stratifying them into cohorts based on HER2 status. Cohort 1 consisted of patients with HER2-overexpressing mBC, while cohort 2 comprised patients with HER2-low, and cohort 3 comprised patients with HER2-non-expressing mBC. The primary endpoint was the confirmed objective response rate (ORR), which was significantly higher in cohort 1 (70.6%) compared to cohorts 2 (37.5%) and 3 (29.7%). Additionally, patients in cohort 1 exhibited a longer median progression-free survival (PFS) of 11.1 months, compared to that of cohort 2 (6.7 months) and cohort 3 (4.2 months). Notably, patients in cohort 1 demonstrated a clinical benefit rate of 85.3%.
The study further explored HER2 expression patterns and their correlation with treatment responses. Spatial distribution analysis revealed a significant association between cluster 6, characterized by low HER2 staining and moderate cell density, and non-response in HER2-overexpressing tumors. However, no such association was found in HER2-low tumors. Moreover, no significant predictive value of HER2 expression levels was observed in HER2-non-expressing tumors.
The mechanisms of action of T-DXd were explored, focusing on its distribution and impact on the tumor microenvironment. T-DXd uptake was correlated with HER2 expression. Furthermore, while T-DXd did not significantly alter the immune microenvironment overall, it decreased programmed death-ligand 1 (PD-L1) expression in HER2-overexpressing tumors, possibly due to its cytotoxic effects.
Investigation into resistance mechanisms revealed potential genomic alterations associated with primary and secondary resistance. Whole-exome sequencing identified ERBB2 amplifications and hemizygous deletions as potential indicators of resistance. Additionally, SLX4 mutations were detected in resistant tumors, implicating its role in mediating T-DXd resistance. Cell viability assays further supported SLX4’s involvement in resistance, suggesting its potential as a therapeutic target.
The Bottom Line
The study found that T-DXd response was related to HER2 expression. It was also found that higher T-DXd efficacy in HER2-overexpressing mBC. It also found that HER2 expression was lower in resistant cases. This confirms evidence from a previous study that the HER2 quantitative continuous score (QCS) could be used to predict outcomes with T-DXd use. However, the study also found modest activity of T-DXd in patients who did not express HER2, suggesting that drug efficacy is also related to other mechanisms independent of HER2. These findings provide a rationale for ongoing trials in mBC patients with ultra-low HER2.
Source:
Mosele, F., Deluche, É., Lusque, A., Bescond, L. L., Filleron, T., Pradat, Y., Ducoulombier, A., Pistilli, B., Bachelot, T., Viret, F., Lévy, C., Signolle, N., Alfaro, A., Tran, D. T. N., Garberis, I., Talbot, H., Christodoulidis, S., Vakalopoulou, M., Droin, N., . . . Varga, A. (2023). Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial. Nature Medicine, 29(8), 2110–2120. https://doi.org/10.1038/s41591-023-02478-2
