Is tucatinib/tucatinib effective for low HER2 expression?

Tucatinib is a highly selective HER2 tyrosine kinase inhibitor that was originally developed to target tumor populations with clear overexpression or amplification of HER2. As the concept of "HER2 low expression" has gradually attracted attention in recent years, some patients have also begun to care about whether tucatinib is also effective in tumors with low HER2 expression. From the current international mainstream point of view, the therapeutic value of tucatinib in people with low HER2 expression is still limited, and it is not yet considered a standard choice.

Low HER2 expression usually refers to a tumor status in which immunohistochemical testing shows HER2 1+ or 2+ but in situ hybridization is negative. The biological behavior of this type of tumors is significantly different from that of HER2-positive tumors, and the driving effect of the HER2 signaling pathway is relatively weak. As a small molecule tyrosine kinase inhibitor, tucatinib's core mechanism of action is to highly inhibit the kinase activity of the HER2 receptor, thereby blocking downstream proliferation and survival signals. When the expression level of HER2 on the surface of tumor cells is not enough to become the main driving factor, the target of the drug itself will be difficult to fully exert its effect.

Overseas data generally believe that low HER2 expression is more suitable for intervention through new treatment strategies such as antibody drug conjugates (ADCs). These drugs do not rely solely on the strength of the HER2 signaling pathway, but use HER2 as a "delivery portal" to achieve precise release of cytotoxic drugs. In contrast, tucatinib is more dependent on HER2 signaling, and its efficacy is highly correlated with the clear HER2-positive status.

From a clinical practice perspective, there is currently insufficient evidence to support the use of tucatinib in the routine treatment of patients with low HER2 expression. International guidelines and expert consensus still position it for HER2-positive breast cancer and colorectal cancer, especially in specific groups with brain metastases or after multiple lines of treatment. In patients with low HER2 expression, blind use of tucatinib may lead to insufficient efficacy and increased risk of unnecessary medication.

Reference materials:https://www.tukysa.com/