Enhertu Reduces Risk of Disease Progression or Death by 50% in HER2-Low Metastatic Breast Cancer, Pivotal Phase 3 Data Show

Today, AstraZeneca and Daiichi Sankyo presented the pivotal Phase 3 clinical trial results of Enhertu, a significant antibody-drug conjugate (ADC), in treating patients with unresectable or metastatic breast cancer exhibiting low HER2 expression at the ASCO Annual Meeting plenary session. The results demonstrated that, compared to chemotherapy, Enhertu reduced the risk of disease progression or death by 50% in the HER2-low patient population! The press release noted that this outcome indicates Enhertu has the potential to transform the treatment paradigm for approximately half of breast cancer patients.

In the global cancer statistics of 2020, breast cancer surpassed lung cancer to become the most common cancer type worldwide. Breast cancer is typically divided into three types based on the receptor profiles expressed by tumor cells: HR-positive/HER2-negative, HER2-positive, and triple-negative breast cancer. Treatment methods vary depending on the classification. For breast cancer patients with HER2-positive tumors, targeted therapy aimed at HER2 can be utilized. Previously, patients with HER2-negative tumors were not suitable for HER2-targeted therapy.

In this clinical trial, the patient group treated with Enhertu is referred to as HER2-low patients. These patients are traditionally classified as HER2-negative, but their tumors actually express a small amount of HER2, scoring 1+ in immunohistochemistry (IHC) staining tests, or 2+ in IHC but negative in in situ hybridization (ISH) tests. This group of patients is large, accounting for up to 50% of breast cancer patients. However, according to current classifications, they are not suitable for HER2-targeted therapy. Previous HER2-targeted monoclonal antibody therapies have also not shown significant efficacy in this population.

Enhertu is an innovative antibody-drug conjugate jointly developed by AstraZeneca and Daiichi Sankyo. Compared with antibody therapies targeting HER2, Enhertu does not need to exert its efficacy by inhibiting HER2 activity; the HER2 expressed on tumor cells merely serves as a signal to guide the ADC to deliver cytotoxic drugs into the cells, which may allow it to be effective in tumors with lower levels of HER2 expression.

This innovative ADC utilizes Daiichi Sankyo's DXd ADC technology platform, incorporating various technological innovations in the cytotoxic drug and linker of the ADC. For instance, the DNA topoisomerase I inhibitor (DXd) conjugated with the antibody has a unique mechanism of action, demonstrating 10 times higher activity compared to the common chemotherapy drug irinotecan. Moreover, this cytotoxic payload exhibits strong cell membrane permeability, enabling it to kill neighboring cancer cells after eradicating the cancer cells that have ingested the ADC, thereby producing a "bystander effect."

The phase 3 clinical trial named DESTINY-Breast04 showed that in the HR-positive, HER2-low patient population, Enhertu reduced the risk of disease progression or death by 49% (HR=0.51, p<0.001) compared with chemotherapy chosen by physicians. The median progression-free survival (PFS) was 10.1 months in the Enhertu group and 5.4 months in the chemotherapy group.

Notably, in the overall patient population with low HER2 expression regardless of HR positivity or negativity, Enhertu reduced the risk of disease progression or death by 50% compared to chemotherapy (HR=0.50, p<0.001). This patient group includes some who were previously defined as having triple-negative breast cancer.

▲Enhertu in HR-positive and overall patient population PFS data (Image Source: Reference [3])

Enhertu also demonstrated outstanding efficacy in extending patients' lives. Compared with chemotherapy, in the HR-positive patient population, it reduced the risk of death by 36% (HR=0.64, p=0.003). The median overall survival (OS) was 23.9 months in the Enhertu group and 17.5 months in the chemotherapy group.

In the overall HER2-low patient population, Enhertu also reduced the risk of death by 36% (HR=0.64, p=0.001), with a median OS of 23.4 months in the Enhertu group and 16.8 months in the chemotherapy group. Detailed data have been published in the prestigious medical journal *The New England Journal of Medicine*.

▲Enhertu in HR-positive and overall patient populations OS data (Image source: Reference [3])

Exploratory analyses in different patient subgroups showed that Enhertu demonstrated consistent efficacy regardless of prior treatment with a CDK4/6 inhibitor or the number of previous chemotherapy regimens. In the IHC 1+ patient population (meaning over 10% of cells showed faint or partial staining in immunohistochemistry), the efficacy of Enhertu was similar to that in the IHC 2+/ISH- patient population. Among Asian patients, Enhertu showed a trend toward better efficacy.

▲Subgroup efficacy data analysis of Enhertu (Image source: Reference [3], click to view larger image)

Based on this positive result, the FDA has granted Enhertu a Breakthrough Therapy Designation for the treatment of this patient population.

One of the principal investigators of this clinical trial, Dr. Shanu Modi from Memorial Sloan Kettering Cancer Center, stated: "The results of DESTINY-Breast04 are the first to show that HER2-targeted therapy can provide a survival benefit in patients with low HER2 expression, meaning we must reconsider how we categorize patients with metastatic breast cancer. The efficacy demonstrated by Enhertu highlights its potential to establish a new standard of care for approximately half of the patients with metastatic breast cancer! These patients, although currently classified as HER2-negative, actually have tumors that express low levels of HER2."

Appendix: Overview of DESTINY-Breast04 Trial Results (Image Source: Reference [1], Click to Enlarge)

References:

[1] Enhertu reduced the risk of disease progression or death by 50% vs. chemotherapy in patients with HER2-low metastatic breast cancer with HR-positive and HR-negative disease. Retrieved June 5, 2022, from https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2022/enhertu-efficacy-results-in-her2-low-breast-cancer.html

[2] Novel Antibody-Drug Conjugate Doubles Progression-Free Survival in Metastatic Breast Cancer With Low HER2 Expression Levels. Retrieved June 5, 2022, from https://www.asco.org/about-asco/press-center/news-releases/novel-antibody-drug-conjugate-doubles-progression-free

[3] Jacot et al., (2022). Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. The New England Journal Of Medicine, DOI: 10.1056/NEJMoa2203690

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