Daiichi Sankyo and AstraZeneca Announce Positive Phase III DESTINY-Breast06 Results for Trastuzumab Deruxtecan in HR-Positive, HER2-Low and HER2-Ultra-Low Metastatic Breast Cancer

On April 29, positive results from the Phase III clinical trial DESTINY-Breast06 showed that, compared with standard chemotherapy, intravenous Trastuzumab Deruxtecan (brand name: Enhertu®, hereinafter referred to as "Trastuzumab Deruxtecan") demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) in patients with HR-positive, HER2-low (IHC 1+ or IHC 2+/ISH-) metastatic breast cancer who had previously received at least one line or more of endocrine therapy.

A statistically significant and clinically meaningful improvement in PFS was observed in the overall study population (patients with HER2-low and HER2-ultralow [defined as IHC 0, membranous staining; IHC >0 <1+] metastatic breast cancer). Prespecified subgroup analyses showed consistent, clinically meaningful improvements in both HER2-low and HER2-ultralow patients.

Overall survival (OS) data were not yet mature at the time of analysis. However, early trends in OS improvement were observed with trastuzumab deruxtecan compared to standard chemotherapy in both HER2-low and the overall study population. The study will continue as planned to further evaluate OS and other secondary endpoints.

Trastuzumab Deruxtecan is a HER2-targeted DXd antibody-drug conjugate (ADC) designed with Daiichi Sankyo's proprietary technology. It is being jointly developed and commercialized globally by Daiichi Sankyo and AstraZeneca.

It is estimated that approximately 60% to 65% of HR-positive, HER2-negative breast cancers are HER2-low, and about 25% may be HER2-ultralow. Endocrine therapy is often widely used in the early treatment of HR-positive metastatic breast cancer. However, after two lines of treatment, the efficacy of endocrine therapy is usually relatively limited. The current standard therapy after endocrine treatment is chemotherapy, but its response rate and prognosis are poor.


DESTINY-Breast06 Study Results Indicate That Trastuzumab Deruxtecan Has the Potential to Become a New Standard Treatment for Patients with HER2-Low and HER2-Ultra-Low Metastatic Breast Cancer Who Have Previously Received at Least One Line of Endocrine Therapy. These data highlight the potential of trastuzumab deruxtecan in treating various types of HR-positive breast cancer, reshaping the treatment landscape for metastatic breast cancer.

About DESTINY-Breast06

DESTINY-Breast06 is a global, randomized, open-label, Phase III clinical trial designed to evaluate the efficacy and safety of trastuzumab deruxtecan (5.4 mg/kg) versus investigator’s choice of chemotherapy (capecitabine, paclitaxel, or nab-paclitaxel) in patients with HR-positive, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (defined as IHC 0, membrane staining [IHC>0<1+]) advanced or metastatic breast cancer. Patients in the study had not received chemotherapy for advanced or metastatic disease and had experienced disease progression within six months after first-line endocrine therapy combined with a CDK4/6 inhibitor or had previously received at least two lines of endocrine therapy for metastatic disease.

The primary endpoint is progression-free survival (PFS) in the HR-positive, HER2-low patient population as determined by blinded independent central review (BICR). Key secondary endpoints include overall survival (OS) in HER2-low patients, PFS assessed by BICR, and OS in the overall study population (HER2-low and HER2-ultralow). Other secondary endpoints include objective response rate, duration of response, time to first subsequent therapy or death, time to second subsequent therapy or death, and safety. Separate analyses of the HER2-ultralow subgroup were not statistically significant.

DESTINY-Breast06 enrolled 866 patients (HER2-low: n=713; HER2-ultralow: n=153) at multiple research centers in Asia, Europe, North America, and South America. For more information about this study, please visit ClinicalTrials.gov.

About Breast Cancer and HER2 Expression

Globally, breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths. In 2022, there were over 2 million confirmed cases of breast cancer worldwide, with more than 665,000 deaths. While the survival rate for patients diagnosed with early-stage breast cancer is high, only about 30% of patients diagnosed with metastatic disease or progressed to metastatic disease survive five years after diagnosis.

HR-Positive, HER2-Negative is the most common breast cancer subtype, accounting for approximately 70% of all breast cancers. HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of various tumor cells, including breast cancer. Patients with high levels of HER2 expression (IHC 3+ or IHC2+/ISH+) are classified as HER2-positive and are suitable for HER2-targeted therapy, representing approximately 15% to 20% of all breast cancer patients. For a long time, tumors not classified as HER2-positive were categorized as HER2-negative; however, many of these tumors still exhibit some level of HER2 expression. It is estimated that about 60% to 65% of HR-positive, HER2-negative breast cancers are HER2-low, and an additional 25% may be HER2-ultralow.

Prior to the approval of trastuzumab deruxtecan for the treatment of HER2-low metastatic breast cancer after chemotherapy based on the DESTINY-Breast04 study, no targeted therapies had been approved specifically for treating patients with HER2-low expression. Currently, there are also no targeted therapies approved specifically for treating patients with HER2-ultra-low expression.

About Trastuzumab Deruxtecan

Trastuzumab deruxtecan (known as fam-trastuzumab deruxtecan-nxki in the United States) is an antibody-drug conjugate (ADC) targeting HER2. Trastuzumab deruxtecan is designed using Daiichi Sankyo's proprietary DXd-ADC technology, representing the leading ADC product in Daiichi Sankyo's oncology portfolio and the most advanced project in AstraZeneca's ADC scientific platform. Trastuzumab deruxtecan consists of a HER2 monoclonal antibody connected to several topoisomerase I inhibitor payloads (exatecan derivatives, DXd) via a cleavable tetrapeptide linker.

Based on the results obtained from the DESTINY-Breast03 study, trastuzumab deruxtecan (5.4 mg/kg) has been approved in more than 60 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or IHC 2+/in situ hybridization [ISH]+) breast cancer who have received a prior anti-HER2-based therapy in the metastatic setting or developed disease recurrence during or within 6 months after completing neoadjuvant or adjuvant therapy.

Based on the results obtained from the DESTINY-Breast04 study, trastuzumab deruxtecan (5.4 mg/kg) has been approved in more than 55 countries and regions worldwide for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/[ISH]-) breast cancer who have received prior systemic therapy in the metastatic setting, or whose disease recurred within 6 months of completing adjuvant chemotherapy or during adjuvant chemotherapy.

Based on the results obtained from the DESTINY-Lung02 study, trastuzumab deruxtecan (5.4 mg/kg) has been approved in more than 35 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have HER2 (ERBB2) activating mutations as detected by locally or regionally approved testing methods and who have previously received one systemic therapy. Confirmation of clinical benefit in confirmatory studies will support full approval of this indication in the United States.

Based on the results obtained from the DESTINY-Gastric01 and/or DESTINY-Gastric02 studies, trastuzumab deruxtecan (6.4 mg/kg) has been approved in more than 45 countries/regions worldwide for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have previously received a trastuzumab-based treatment regimen.

Based on the efficacy results from the DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02 studies [to be confirmed], trastuzumab deruxtecan (5.4 mg/kg) has been approved in the United States for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have previously received systemic therapy and have no satisfactory alternative treatment options. The full approval of this indication will be supported upon the validation and confirmation of clinical benefit in confirmatory trials.

About the Trastuzumab Deruxtecan Clinical Development Program

A comprehensive clinical development program aimed at evaluating the efficacy and safety of trastuzumab deruxtecan monotherapy in treating various HER2-targeted cancers is currently underway globally. Research involving combination with other anti-cancer treatments, such as immunotherapy, is also being conducted.

Regarding the collaboration between Daiichi Sankyo and AstraZeneca

Daiichi Sankyo and AstraZeneca reached global collaborations in March 2019 and July 2020 respectively to jointly develop and commercialize trastuzumab deruxtecan and datopotamab deruxtecan. Daiichi Sankyo holds exclusive rights to each ADC product in the Japanese market. Daiichi Sankyo is responsible for the production and supply of trastuzumab deruxtecan and datopotamab deruxtecan.

Editor: Muyan

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