• 07 Oct 2024
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• News Article

ENHERTU® sNDA Submitted in Japan for Patients with HER2 Low or HER2 Breast Cancer

ENHERTU® Supplemental New Drug Application Submitted in Japan for Patients with HER2 Low or HER2 Ultralow Metastatic Breast Cance

Overview

Daiichi Sankyo today announced that it has submitted a supplemental New Drug Application (sNDA) to Japan’s Ministry of Health, Labour and Welfare (MHLW) for ENHERTU® (trastuzumab deruxtecan) for the treatment of adult patients with HER2 low (IHC 1+ or IHC 2+/ISH-) or ultralow (IHC 0 with membrane staining) unresectable or recurrent breast cancer.

About Breast Cancer

• Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide, with more than 665,000 deaths globally.
• In Japan, breast cancer is the most common cancer in women, with approximately 92,000 cases of breast cancer diagnosed in 2022.
• Hormone receptor (HR) positive, HER2 negative is the most common breast cancer subtype, accounting for approximately 70% of all breast cancers.
• It is estimated that approximately 60% to 65% of HR positive, HER2 negative breast cancers are HER2 low and potentially an additional 25% may be HER2 ultralow.

Behind sNDA

The sNDA is based on data from the DESTINY-Breast06 phase 3 trial presented as a late-breaking oral presentation at the 2024 American Society of Clinical Oncology (#ASCO24) Annual Meeting and recently published in The New England Journal of Medicine.

From Daiichi Sankyo

• “This submission builds on the current HER2 low indication and if approved will provide the opportunity for the earlier use of ENHERTU for patients with HER2 low expression as well as expanding into the HER2 ultralow patient population,” said Toshinori Agatsuma, PhD, Executive Officer, Head of R&D Division in Japan, Daiichi Sankyo. 
• “The DESTINY-Breast06 results represent the first time a HER2 directed therapy has shown a clinically meaningful benefit in these patient populations and we look forward to working with regulatory authorities in Japan to bring ENHERTU to these patients.”

Additional regulatory submissions for ENHERTU based on data from DESTINY-Breast06 are under review in the EU and U.S.

About DESTINY-Breast06

• DESTINY-Breast06 is a global, randomized, open-label, phase 3 trial evaluating the efficacy and safety of ENHERTU (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 (IHC 0 with membrane staining) advanced or metastatic breast cancer. 
• Patients in the trial had no prior chemotherapy for advanced or metastatic disease and received at least two lines of prior endocrine therapy in the metastatic setting. 
• Patients also were eligible if they had received one prior line of endocrine therapy combined with a CDK4/6 inhibitor in the metastatic setting and experienced disease progression within six months of starting first-line treatment or received endocrine therapy as an adjuvant treatment and experienced disease recurrence within 24 months.

The Endpoints

• The primary endpoint is progression-free survival (PFS) in the HR positive, HER2 low patient population as measured by blinded independent central review (BICR). 
• Key secondary endpoints include PFS by BICR in the overall trial population (HER2 low and HER2 ultralow), overall survival (OS) in patients in the HER2 low patient population and OS in the overall trial population. 
• Other secondary endpoints include objective response rate, duration of response, time to first subsequent treatment or death, time to second subsequent treatment or death and safety. 
• Analysis of the HER2 ultralow subgroup was not powered to demonstrate statistical significance.

DESTINY-Breast06: Volunteer Enrollment

• DESTINY-Breast06 enrolled 866 patients (n=713 for HER2 low and n=153 for HER2 ultralow) at multiple sites in Asia, Europe, North America, Oceania and South America. 
• For more information about the trial, visit ClinicalTrials.gov.

About Breast Cancer and HER2 Expression

• Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide. 
• More than two million breast cancer cases were diagnosed in 2022 with more than 665,000 deaths globally.
• In Japan, breast cancer is the most common cancer in women, with approximately 92,000 cases of breast cancer diagnosed in 2022.
• While survival rates are high for those diagnosed with early breast cancer, only about 30% of patients diagnosed with or who progress to metastatic disease are expected to live five years following diagnosis.

About the Receptor: HER2

• HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including breast cancer.
• Patients with high levels of HER2 expression (IHC 3+ or IHC2+/ISH+) are classified as HER2 positive and treated with HER2 targeted therapies, representing approximately 15 to 20% of all breast cancers.
• Historically, tumors that were not classified as HER2 positive were classified as HER2 negative, despite the fact that many of these tumors still carry some level of HER2 expression.
• It is estimated that approximately 60% to 65% of HR positive, HER2 negative breast cancers are HER2 low and potentially an additional 25% may be HER2 ultralow.4,5

Endocrine Therapies

• Endocrine therapies are widely given consecutively in the early lines of treatment for HR positive metastatic breast cancer. 
• However, following two lines of endocrine therapy, further efficacy with additional endocrine treatment is often limited. 
• The current standard of care following endocrine therapy is chemotherapy, which is associated with poor response rates and outcomes.

Prior to the approval of ENHERTU following chemotherapy in HER2 low metastatic breast cancer based on the DESTINY-Breast04 trial, there were no targeted therapies approved specifically for patients with HER2 low expression.13 There are no targeted therapies specifically approved for patients with HER2 ultralow expression.14

About ENHERTU

• ENHERTU (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) is a HER2 directed antibody drug conjugate (ADC). 
• Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, ENHERTU is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform. 
• ENHERTU consists of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

ENHERTU Apprvoals

• ENHERTU (5.4 mg/kg) is approved in more than 65 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (immunohistochemistry (IHC) 3+ or in-situ hybridization (ISH)+) breast cancer who have received a prior anti-HER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial.
• ENHERTU (5.4 mg/kg) is approved in more than 65 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial.
• ENHERTU (5.4 mg/kg) is approved in more than 45 countries worldwide for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial. Continued approval in the U.S. for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
• ENHERTU (6.4 mg/kg) is approved in more than 45 countries 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 received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01, DESTINY-Gastric02 and/or DESTINY-Gastric06 trials. Full approval in China for this indication will depend on whether a randomized controlled confirmatory clinical trial can demonstrate clinical benefit in this population.
• ENHERTU (5.4 mg/kg) is approved in the U.S. for the treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options based on efficacy results from the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02 trials. Continued approval for this indication in the U.S. may be contingent upon verification and description of clinical benefit in a confirmatory trial.