A first patient was dosed in DESTINY-Breast09 (NCT04784715), a global head-to-head Phase 3 clinical trial evaluating the safety and efficacy of trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca; previously known as DS-8201).
The DESTINY-Breast09 study is designed to evaluate trastuzumab deruxtecan with or without pertuzumab compared to standard of care (THP: taxane, trastuzumab, and pertuzumab) as a potential first-line treatment in patients with HER2 positive metastatic breast cancer.
Trastuzumab deruxtecan is an antibody-drug conjugate or ADC composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor.
The drug was approved in late December 2019 by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting. This indication was approved under the FDA’s Accelerated Approval based on tumor response rate and duration of response. However, continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
First in the metastatic setting
This is the first trial to evaluate trastuzumab deruxtecan in the first-line metastatic setting in patients with HER2-positive breast cancer. Many patients with HER2 positive metastatic breast cancer have an aggressive form of the disease due to progression from an earlier stage cancer, with a significant proportion having their disease relapse after receiving THP or other standard anti-HER2 therapies in an adjuvant setting.
Research has also shown that patients often progress in less than two years following initial treatment for HER2-positive metastatic breast cancer.1 While there have been substantial advances in the treatment of these patients, there remains an ongoing need to improve outcomes, and as a result, more effective HER2-directed treatments and novel combination regimens are needed.
HER2+ Breast cancer
Breast cancer remains the most common cancer and is one of the leading causes of cancer-related deaths in women worldwide.  More than two million cases of breast cancer are diagnosed each year, resulting in nearly 685,000 deaths globally.
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast, gastric, lung, and colorectal cancers.
Overexpression of HER2 may be associated with a specific HER2-gene alteration known as HER2-amplification and is often associated with aggressive disease and poor prognosis in breast cancer. Approximately one in five cases of breast cancer are considered HER2-positive.
In the first-line HER2 positive metastatic breast cancer setting, approximately 50% of cases are considered de novo, meaning the disease is metastatic from initial diagnosis, while the remaining cases occur due to disease progression from early-stage disease.
While research has shown that patients with recurrent disease have worse clinical outcomes than patients with de novo metastatic disease, patients diagnosed with de novo metastatic disease also often progress in less than two years. The current standard of care for patients with first-line metastatic breast cancer is the THP regimen, which was approved nearly a decade ago.
More effective HER2-directed treatments and novel combination regimens are needed for patients with first-line HER2-positive metastatic breast cancer.
Advances in first-line treatment
“There have been no significant advances in first-line metastatic breast cancer treatment in nearly a decade, and most patients still progress on the current standard of care THP regimen, highlighting the need for more effective HER2 directed treatments and novel combination regimens,” noted Gilles Gallant, BPharm, Ph.D., FOPQ, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo.
“Based on the encouraging results we are seeing in patients who have received prior treatment for HER2-positive metastatic breast cancer, we have initiated DESTINY-Breast09 to evaluate whether earlier use of trastuzumab deruxtecan alone or as part of a novel combination regimen may help improve outcomes for patients in the first-line metastatic setting as compared to the current standard of care,” Gallant concluded.
An Observational Study in Patients With HER2 Positive Metastatic Breast Cancer (SystHERs Registry) – NCT01615068
Trastuzumab Deruxtecan (T-DXd) With or Without Pertuzumab Versus Taxane, Trastuzumab and Pertuzumab in HER2-positive Metastatic Breast Cancer (DESTINY-Breast09) – NCT04784715
Highlights of prescribing information
Trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca)[Prescribing information]
Trastuzumab (Herceptin®; Genentech/Roche) [Prescribing Information]
Pertuzumab (Perjeta®; Genentech/Roche)[Prescribing Information]
Docetaxel (Taxotere®; Sanofi) [Prescribing Information]
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Featured Image: PBreast Cancer, Breast Cancer Awareness Ribbon, Pink.. Courtesy: © 2016 – 2021 Fotolia/Adobe. Used with permission.
The first edition of this article was published online in ADC Review | Journal of Antibody-drug Conjugates