Enhertu Receives FDA Approval for HER2-Low and Ultralow Breast Cancer

On 27 January 2025, the US Food and Drug Administration (FDA) approved treatment for patients with HER2-low or HER2-ultralow unresectable or metastatic breast cancer who had previously received at least one endocrine therapy in the metastatic setting, using trastuzumab deruxtecan (T-DXd; Enhertu).

This important decision was based on the results of the phase 3 DESTINY-Breast06 trial. The trial compared T-DXd with investigator's choice of chemotherapy in patients with hormone receptor (HR)-positive, HER2-low or HER2-ultralow advanced or metastatic breast cancer.

The FDA also approved Ventana's PATHWAY anti-HER-2 (4B5) Rabbit Monoclonal Primary Antibody assay as a companion diagnostic device to identify patients with HER2-ultralow breast cancer (IHC 0 with membrane staining) for treatment with Enhertu. This test had previously been approved to identify patients with HER2-low breast cancer (IHC 1+ or IHC 2+/FISH-) for treatment with Enhertu.

HER2-Low and HER2-Ultralow: What Do They Mean?

HER2 status is an important biomarker used to measure the amount of human epidermal growth factor receptor 2 (HER2) protein in breast cancer cells. HER2-low and HER2-ultralow are new categories arising from research to better understand subgroups of HER2-negative breast cancer and expand treatment options. Their current definitions are as follows:

Low HER2 Expression (HER2-Low)

• Definition: HER2-low status means that immunohistochemistry (IHC) detects HER2 protein at a score of 1+ or 2+, but in situ hybridization (ISH) is negative for HER2 gene amplification.
• Clinical Features: This group generally includes HR-positive patients and describes a situation in which HER2 expression is detectable but does not reach the positive category.

Ultralow HER2 Expression (HER2-Ultralow)

• Definition: HER2-ultralow status means that HER2 protein is detected in fewer than 10% of tumor cells with weak or incomplete membrane staining. An IHC score between 0 and 1+ can be used as a way of thinking about it.
• Clinical Features: HER2-ultralow tumors generally have clinicopathological features different from HER2-low or HER2-negative (HER2-null) tumors. Examples include:
  • A higher Ki-67 proliferation index (rapid cell proliferation).
  • Different surgical and treatment outcomes depending on hormone receptor status.

HER2-Null

• Definition: HER2-null means that HER2 expression is not detected at all; in other words, the cells show no HER2 staining.
• Clinical Features: HER2-null tumors are less frequently hormone receptor-positive than HER2-ultralow and HER2-low tumors.

FDA Approval Based on the DESTINY-Breast06 Trial

Breast cancer is the most common cancer among women worldwide, highlighting the need to continually improve treatment options. Until now, trastuzumab deruxtecan has been used as a treatment with proven effectiveness only in HER2-positive or HER2-low tumors. It is now being investigated in HR-positive tumors and in patients with HER2-low or HER2-ultralow expression, although studies demonstrating its effectiveness in these settings are limited. The need for effective and tolerable treatments in later lines of therapy, particularly in these patient groups, makes this trial especially important.

Study Design and Methods

In the phase III DESTINY-Breast06 trial, 866 patients with HR-positive, HER2-low or HER2-ultralow metastatic breast cancer whose disease had progressed after at least one endocrine therapy were randomly assigned to two groups:

1. Trastuzumab Deruxtecan Group (T-DXd): This group received the antibody-drug conjugate T-DXd.
2. Chemotherapy Group: This group received standard chemotherapy selected by the physician.

The patients had not previously received chemotherapy and were enrolled because of resistance to endocrine therapy. The trial evaluated the effectiveness of T-DXd in terms of progression-free survival (PFS) and other treatment outcomes.

Results: A Substantial Improvement in Progression-Free Survival

Of the patients, 713 had HER2-low and 153 had HER2-ultralow breast cancer.

The results showed that T-DXd substantially prolonged progression-free survival (PFS):

• T-DXd Group: Median progression-free survival was 13.2 months.
• Chemotherapy Group: Median progression-free survival was only 8.1 months.

This finding indicates that T-DXd reduced cancer progression by 38% compared with chemotherapy (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75; P<0.001).

T-DXd was also found to be effective across all patient subgroups, particularly in patients with rapid progression after endocrine therapy (<6 months). This demonstrates the drug's promise for a broad group of patients.

Adverse Events

Grade 3 or higher adverse events occurred in 52.8% of patients in the trastuzumab deruxtecan group and 44.4% in the chemotherapy group. Interstitial lung disease (ILD) or pneumonitis occurred in 49 patients (11.3%) in the trastuzumab deruxtecan group; 3 of these events were grade 5. In contrast, only 1 patient (0.2%) in the chemotherapy group had grade 2 pneumonitis.