Study: A win for some patients with HER2-negative metastatic breast cancer

Contents

STUDY AT A GLANCE

What is this study about?

This study reports on the DESTINY 04 clinical trial that looked at the drug trastuzumab deruxtecan (Enhertu or T-DXd) for people with metastatic breast cancer. Enhertu is a type of targeted therapy that was developed to treat HER2-positive breast cancer. Participants whose cancer was previously labeled as HER2-negative and who received Enhertu had better outcomes than people with HER2-negative breast cancer who received standard chemotherapy. These results challenge prior thinking that cancers are either HER2-positive or HER2-negative and reclassify the tumor marker HER2 into a third possible result called HER2-low that can guide treatment for metastatic breast cancer. These results offer a new treatment option for many people with hard-to-treat metastatic breast cancers.

Update: On 08/05/2022 the FDA approved Enhertu to treat people with metastatic, HER2-low breast cancer who have received prior chemotherapy in the metastatic setting or who developed disease recurrence during or within six months of completing chemotherapy.

What is HER2 and how is it tested?

HER2 is a protein found on all breast cells. It controls how the cells grow and divide. When breast cells have too much HER2, cells can multiply too quickly. Growth may then become uncontrolled and lead to cancer.

Pathologists use a biomarker test to measure the amount of HER2 protein on the surface of tumor cells. HER2 scores range from 0 to 3+ (3 or higher). In the past, a tumor with a score of 0 to 1+ was called HER2-negative; a score of 2+ was considered borderline, while a score of 3+ was considered HER2-positive. Updated scores and associated HER2 results are shown in the table below.

Results of a test for HER2 status:

HER2 scores have long been used to guide treatment decisions. Treatment for people with HER2-positive breast cancer almost always includes drugs that target HER2 (often called “anti-HER2 therapy”). Several drugs specifically target HER2-positive breast cancer cells, including Herceptin (trastuzumab), Perjeta (pertuzumab), Tukysa (tucatinib) and Phesgo (pertuzumab, trastuzumab and hyaluronidase).

What is trastuzumab deruxtecan?

Trastuzumab deruxtecan (Enhertu or T-DXd) is related to the drug trastuzumab (Herceptin), which has been used to treat HER2-positive breast cancer since the late 1990s. Enhertu is an antibody-drug conjugate, a type of combination targeted therapy drug—trastuzumab combined with chemotherapy—for more powerful cancer-fighting action. Enhertu finds and directly delivers chemotherapy to cells with HER2. Enhertu was first approved to treat HER2-positive metastatic breast cancer in 2019. Currently, it is one of three antibody-drug conjugates used to treat breast cancer.

Why is this study important?

The results of this study offer an immediate new treatment option for some people with HER2-negative metastatic breast cancers. Doctors look for the presence of the HER2 protein in breast cancer cells to guide treatment. In the past, people with breast cancer were considered HER2-positive if they had a “HER2 score” of 3 or more. Cancers scored below 3 were called HER2-negative. This study demonstrates for the first time that an anti-HER2 drug can be effective against breast cancers with HER2 scores of 1 or 2.

These results will change standard practice regarding HER2 testing for metastatic breast cancer. They are relevant to both hormone receptor-positive (HR+) and hormone receptor-negative (HR-) metastatic breast cancers.

Study findings

The DESTINY-Breast04 phase 3 clinical trial tested the anti-HER2 drug trastuzumab deruxtecan (Enhertu or T-DXd) in people with previously treated metastatic HER2-low breast cancer. Doctors enrolled 557 people with metastatic breast cancer. Of these, 493 had hormone receptor-positive breast cancer and 63 had hormone receptor-negative breast cancer.

The participants had HER2-low cancers. HER2-low was defined as a score of 1+ or 2+ on a biomarker test for HER2 levels. Everyone in the study had been previously treated with chemotherapy. The HR+ group had also tried at least one endocrine (hormone) therapy. Nearly 90 percent of participants had tried at least two lines of prior therapy. Most had tried three or more treatments.

Participants were placed into two groups. One group received the antibody conjugate anti-HER2 drug Enhertu. The other group received the chemotherapy chosen by their doctor—either capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel.

The study looked at the time during which cancer did not grow or spread (known as progression-free survival) and how long participants lived (known as overall survival). Enhertu was more effective than chemotherapy, improving both progression-free and overall survival. Across groups, people who took Enhertu did better, as shown by these data:

The median time of treatment was 8.2 months for people in the Enhertu group and 3.5 months in the chemotherapy group. Nearly all participants in the trial experienced at least one side effect related to the therapies.

The most common side effects associated with Enhertu were nausea, fatigue and hair loss. They occurred more often in the Enhertu group than in the chemotherapy group. People taking Enhertu also experienced low blood cell counts, a common side effect of many cancer treatments.

Lung problems are a serious possible side effect of Enhertu; 12.1 percent of those in the Enhertu arm of the study developed lung disease. The median time to onset was around four months after starting treatment but ranged from 26 days to 710 days.

Strengths and limitations

Strengths

• The trial included people with hormone receptor-positive and hormone receptor-negative breast cancer.
• All HER2 testing was done by the same lab to eliminate variations in testing.
• The number of people with hormone receptor-negative breast cancer in the trial was small but still considered sufficient to yield results.
• The study followed participants for progression-free survival and overall survival. The research team also gathered information on the side effects experienced by both groups.

Limitations

• The trial mostly included non-Hispanic white and Asian people with few Black or Latino participants. it is unclear whether Black or Latino people with breast cancer would similarly benefit.
• The number of people with hormone receptor-negative breast cancer was small (see “Strengths”).

Conclusion

This study changes treatment guidelines for people with metastatic breast cancer. The results offer a new treatment option for many people who were previously told they have HER2-negative metastatic breast cancer and were not candidates for anti-HER2 targeted therapies.

What does this mean for me?

Enhertu is the first drug that effectively targets breast cancers with low HER2 scores. If you have previously been told you had HER2-negative or triple-negative metastatic breast cancer, this study may be immediately useful for you. It offers a new treatment option for some cancers that were previously identified as HER2-negative. The results apply to people with hormone receptor-positive or receptor-negative breast cancer, including those with triple-negative breast cancer.

As a next step, ask your doctor about the HER2 testing you had at diagnosis and whether Enhertu might be an option for you. Cancers with HER2 scores of 1+ or 2+ may respond to this drug. Depending on the kind of testing you previously had, you may need another HER2 test to confirm your score.

Reference

Modi S, Jacot W, Yamashita J, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. The New England Journal of Medicine 2022; 387: 9-20. Published online July 7, 2022.

Disclosure: FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

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posted 7/18/22