Novel Antibody-Drug Conjugate Doubles Progression-Free Survival in Metastatic Breast Cancer With Low HER2 Expression Levels

For immediate release
June 5, 2022


Rachel Facci

ASCO Perspective
“This trial’s findings show that trastuzumab deruxtecan doubles progression-free survival compared to chemotherapy alone in patients with HR+, HER2-low breast cancer. By effectively creating a new category of breast cancer, HER2-low, this trial will redefine how we classify breast cancer and will significantly expand the population of patients who can benefit from HER2-targeted therapy,” said Jane Lowe Meisel, MD, ASCO Expert in breast cancers.

CHICAGO — The use of trastuzumab deruxtecan (Enhertu®), a new HER2-targeting antibody-drug conjugate, doubled progression-free survival compared to standard-of-care treatment with conventional chemotherapy. It also significantly improved overall survival for patients with metastatic breast cancers expressing low levels of the HER2 receptor, regardless of hormone receptor status. These practice-changing findings identify a new subset of breast cancer - called HER2-low - and redefine how a large proportion of metastatic patients will be treated. This new research will be presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

Study at a Glance


Effectiveness of trastuzumab deruxtecan vs. standard chemotherapy.


557 patients in Asia, Europe, and North America with HR-negative or HR-positive, HER2-low, unresectable, and/or metastatic breast cancer.


At a median follow-up time of 18.4 months, patients who were HR+ and received trastuzumab deruxtecan had:

  • A 49% reduction in risk of the cancer progressing and a 36% reduction in risk of death compared to those who received standard chemotherapy.
  • A progression-free survival (PFS), the time during which the tumor was stable or shrank, of 10.1 months vs. 5.4 months for those who received standard chemotherapy.
  • An overall survival (OS) of 23.9 vs. 17.5 months for those who received standard chemotherapy.

The rates of adverse events associated with trastuzumab deruxtecan or chemotherapy treatment were similar; however, lung toxicity did occur and is an important safety concern that will need to be closely monitored.


The results of DESTINY-Breast04 are practice changing. The efficacy of trastuzumab deruxtecan supports the use of HER2-low as a new, therapeutically targetable category for metastatic breast cancer. 

Key Findings
In the DESTINY-Breast04 study, patients received either standard chemotherapy of the physicians’ choice (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel), or trastuzumab deruxtecan, a new antibody-drug conjugate that links trastuzumab, a HER2 monoclonal antibody, to deruxtecan, a topoisomerase I inhibitor that interrupts DNA replication in cancer cells. Trastuzumab (Herceptin®) has been proven to be effective in cancers with high HER2 expression (called HER2-positive breast cancer) but not in cancers with low HER2 expression levels, hence trastuzumab has only been available for a subset of breast cancer patients.

The primary endpoint, PFS, in patients with cancers that were HER2-low and hormone receptor positive (HR+), was nearly double for trastuzumab deruxtecan vs. standard chemotherapy (10.1 vs. 5.4 months). The secondary endpoint of OS was also significantly better in the HER2-low, HR+ subgroup of patients who received trastuzumab deruxtecan compared to standard therapy (23.9 vs. 17.5 months).

Treatment-related adverse events were fewer in the trastuzumab deruxtecan group than in patients who received standard chemotherapy (52.6% vs 67.4%). This is consistent with previous clinical trials of these drugs. No new safety concerns were identified.

“Our study shows that trastuzumab deruxtecan may be a new and highly effective targeted therapy option available for this newly defined patient population,” said lead author Shanu Modi, MD, who is a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. “It is important for patients to know what level of HER2 their cancer expresses, not just whether it’s positive or negative, especially as HER2-low status can be determined using commonly available tests.”

HER2 expression is determined by a test that measures the amount of HER2 protein on a cancer cell and/or a test that counts the copies of the HER2 gene in cancer cells.

An estimated 290,560 new cases of breast cancer will be diagnosed in the United States in 2022i. Of those people who receive a diagnosis of the most aggressive form of the disease, metastatic breast cancer, approximately 15-20% of such cancers will be considered HER2 positive and would be eligible to be treated with HER2-targeted therapies. The remaining 80% or so of metastatic breast cancers are currently categorized as HER2-negative, and of these cancers, approximately 55-60% express low levels of HER2.

About the Study
DESTINY-Breast04, a double-blind phase III trial, enrolled 557 patients in Asia, Europe, and North America with HER2-low metastatic breast cancer who had been treated with one to two prior lines of chemotherapy for metastatic disease. Participants were randomly assigned, on a two-to-one basis, to either trastuzumab deruxtecan or the physician’s choice of several standard chemotherapy drugs.

The primary endpoint was PFS in patients with HR+ disease. Key secondary endpoints included PFS for all patients (both HR+ and HR- disease) as well as OS in all patients and those with HR+ disease. Other endpoints were objective response rate, duration of response, safety, and an exploratory analysis of patients with HR-negative disease.

Trastuzumab deruxtecan is already approved in more than 40 countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received prior anti-HER2-based treatment. On April 27, 2022, the United States Food and Drug Administration granted Breakthrough Therapy Designation for trastuzumab deruxtecan in HER2-low metastatic breast cancerii.

The study was funded by Daiichi Sankyo, Inc., and AstraZeneca.

Next Steps
Use of trastuzumab deruxtecan is currently being studied in patients with HER2-low metastatic breast cancer in several ongoing studies, several of which are exploring the minimum HER2-expression threshold required for trastuzumab deruxtecan activity.

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[i] NCI SEER cancer statistics:

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