FDA Approves Trastuzumab Deruxtecan for HER2-Low/Ultralow Breast Cancer

The FDA has approved trastuzumab deruxtecan (Enhertu) for the treatment of adults with unresectable or metastatic HR-positive, HER2-low or HER2-ultralow breast cancer, that has progressed on 1 or more endocrine therapies in a metastatic setting.1

The recent findings from DESTINY-Breast06 further support trastuzumab deruxtecan’s use as a transformative therapy in HER2-expressing breast cancer. | Image Credit: Pawel - stock.adobe.com

The approval is based on findings from the phase 3 DESTINY-Breast06 (NCT04494425) trial.

“Endocrine therapy is typically used in the initial treatment of HR-positive metastatic breast cancer and following progression, subsequent chemotherapy is associated with poor outcomes,” said Aditya Bardia, MD, MPH, program director of breast oncology, director of translational research, UCLA Health Jonsson Comprehensive Cancer Center, and investigator of the DESTINY-Breast06 trial, in a statement. “With a median progression-free survival exceeding 1 year and a response rate of more than 60%, trastuzumab deruxtecan offers a potential new standard of care for patients with HR-positive, HER2-low or HER2-ultralow metastatic breast cancer following endocrine therapy.”

Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate (ADC) developed using Daiichi Sankyo's proprietary DXd ADC Technology. It represents the lead ADC in Daiichi Sankyo's oncology portfolio and is a cornerstone of AstraZeneca’s ADC scientific platform. Approved across multiple indications, trastuzumab deruxtecan is indicated for various HER2-positive and HER2-low cancers, including breast, gastric, non-small cell lung cancer, and other solid tumors.

In the DESTINY-Breast06 trial, trastuzumab deruxtecan demonstrated a 36% reduction in the risk of disease progression or death compared with chemotherapy (HR, 0.64; 95% CI, 0.54-0.76; P < .0001) in patients with chemotherapy-naïve HER2-low or HER2-ultralow metastatic breast cancer. Patients treated with trastuzumab deruxtecan achieved a median progression-free survival of 13.2 months vs 8.1 months for those receiving chemotherapy.

The confirmed objective response rate was significantly higher with trastuzumab deruxtecan at 62.6% compared with 34.4% with chemotherapy. Exploratory analyses indicated consistent efficacy in patients with HER2-low and HER2-ultralow expression.

Central laboratory testing revealed that approximately 85% to 90% of HR-positive, HER2-negative metastatic breast cancer cases had actionable HER2 expression, with many previously classified as IHC 0 redefined as HER2-low or HER2-ultralow.

The safety profile of trastuzumab deruxtecan in this trial was consistent with previous studies, with no new safety concerns identified.

At a recent Institute for Value-Based Medicine® event, Dawn Klemow, MD, assistant clinical professor, The University of Texas Southwestern Medical Center, discussed how ADCs such as trastuzumab deruxtecan have become a critical tool in breast cancer treatment.2

“The DESTINY-04 [DESTINY-Breast04; NCT03734029] trial first came out looking at the benefit of antibody drug conjugates in HER2-low disease, showing basically a doubling of progression-free survival over doctors’ chemotherapy choice, and then more recently, DESTINY-06 [DESTINY-Breast06;] showing that there's an equal benefit in HER2-ultralow,” said Klemow to The American Journal of Managed Care® (AJMC®).

The recent findings from DESTINY-Breast06 further support trastuzumab deruxtecan’s use as a transformative therapy in HER2-expressing breast cancer.

“Building on the practice-changing previous approvals for Enhertu, this new approval brings this important medicine to an earlier treatment setting and a broader patient population with HER2-expressing metastatic breast cancer,” said Dave Fredrickson, executive vice president, oncology hematology business unit, AstraZeneca, in a statement.1 “The approval also highlights the importance of testing metastatic breast cancer tumors for detectable staining with a standard IHC test to identify those who may be eligible for treatment with Enhertu following endocrine therapy.”