Fam-Trastuzumab Deruxtecan-nxki Doubles Progression-Free Survival in HER2-Low Metastatic Breast Cancer

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Shanu Modi, MD

Shanu Modi, MD

The use of fam-trastuzumab deruxtecan-nxki doubled progression-free survival compared with the standard-of-care treatment plus 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 patients with metastatic breast cancer will be treated. The results of the DESTINY-Breast04 trial were presented by Shanu Modi, MD, and colleagues during the Plenary Session of the 2022 ASCO Annual Meeting (Abstract LBA3).

An estimated 290,560 new cases of breast cancer will be diagnosed in the United States in 2022. Approximately 15% to 20% of metastatic breast 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; of these cancers, approximately 55% to 60% express low levels of HER2.

The antibody-drug conjugate trastuzumab deruxtecan links the HER2 monoclonal antibody trastuzumab to deruxtecan, a topoisomerase I inhibitor that interrupts DNA replication in cancer cells. Trastuzumab has been proven to be effective in cancers with high HER2 expression but not in cancers with low HER2 expression, and thus it has been available only for a subset of patients with breast cancer.

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

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 progression-free survival in patients with hormone receptor–positive disease. Key secondary endpoints included progression-free survival for all patients (both hormone receptor–positive and –negative disease) as well as overall survival in all patients and those with hormone receptor–positive disease. Other endpoints were objective response rate, duration of response, safety, and an exploratory analysis of patients with hormone receptor–negative disease.

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

Treatment-related adverse events were fewer with trastuzumab deruxtecan than with 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 Dr. Modi, who is a medical oncologist at Memorial Sloan Kettering Cancer Center, 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.”

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

ASCO Perspective

“This trial’s findings show that trastuzumab deruxtecan doubles progression-free survival compared to chemotherapy alone in patients with hormone receptor–positive, HER2-low breast cancer,” commented Jane Lowe Meisel, MD, an ASCO expert in 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.”

Disclosure: The study was funded by Daiichi Sankyo and AstraZeneca. For full disclosures of the study authors, visit


The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.