Daiichi Sankyo and AstraZeneca's ENHERTU® (trastuzumab deruxtecan) has been approved in the European Union (EU) as monotherapy indicated for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy. ENHERTU is a specifically engineered HER2 directed antibody drug conjugate (ADC) being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca. The approval by the European Commission follows the positive opinionof the Committee for Medicinal Products for Human Use and is based on results from the DESTINY-Breast04 phase 3 trial presented at the American Society of Clinical Oncology 2022 Annual Meeting and published in The New England Journal of Medicine.

In DESTINY-Breast04, ENHERTU significantly reduced the risk of disease progression or death by 50% versus physician's choice of chemotherapy (hazard ratio [HR]=0.50; 95% confidence interval [CI]: 0.40-0.63; p<0.0001) in patients with HER2 low metastatic breast cancer with hormone receptor (HR) positive or HR negative disease. A median progression-free survival (PFS) of 9.9 months (95% CI: 9.0-11.3) was seen with ENHERTU versus 5.1 months (95% CI: 4.2-6.8) in those treated with chemotherapy as assessed by blinded independent central review (BICR). A 36% reduction in the risk of death (HR=0.64; 95% CI: 0.49-0.84; p=0.001) also was seen with ENHERTU compared to chemotherapy with a median overall survival (OS) of 23.4 months (95% CI: 20.0-24.8) in patients treated with ENHERTU versus 16.8 months (95% CI: 14.5-20.0) in those treated with chemotherapy.

In DESTINY-Breast04, the safety profile of ENHERTU was consistent with previous clinical trials with no new safety concerns identified. Grade 3 or grade 4 treatment-related adverse events from a pooled safety analysis of patients treated with ENHERTU (5.4 mg/kg) across multiple tumor types in clinical studies included neutropenia (16.3%), anemia (9.2%), fatigue (7.5%), leukopenia (6.3%), thrombocytopenia (5.9%), nausea (5.6%), lymphopenia (4.8%), transaminases increased (3.9%), hypokalemia (3.5%), vomiting (2.2%), pneumonia (1.9%), diarrhea (1.8%), decreased appetite (1.7%), febrile neutropenia (1.2%), dyspnea (1.2%), blood bilirubin increased (1.1%), ejection fraction decreased (1.1%), and musculoskeletal pain (1.1%). Grade 5 adverse reactions occurred in 1.5% of patients, including interstitial lung disease (1.2%).

Financial Considerations: Following approval in the EU, an amount of $150 million is due from AstraZeneca to Daiichi Sankyo as a milestone payment in HER2 low metastatic breast cancer. Sales of ENHERTU in most EU territories are recognized by Daiichi Sankyo. For further details on the financial arrangements, please consult the collaboration agreement from March 2019.

About DESTINY-Breast04: DESTINY-Breast04 is a global, randomized, open-label, pivotal phase 3 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) versus physician's choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel) in patients with HR positive or HR negative, HER2 low unresectable and/or metastatic breast cancer previously treated with one or two prior lines of chemotherapy. Patients were randomized 2:1 to receive either ENHERTU or chemotherapy. The primary endpoint of DESTINY-Breast04 is PFS in patients with HR positive disease based on BICR.

Key secondary endpoints include PFS based on BICR in all randomized patients (HR positive and HR negative disease), OS in patients with HR positive disease and OS in all randomized patients (HR positive and HR negative disease). Other secondary endpoints include PFS based on investigator assessment, objective response rate based on BICR and on investigator assessment, duration of response based on BICR and safety. DESTINY-Breast04 enrolled 557 patients at multiple sites in Asia, Europe and North America.

About Breast Cancer and HER2 Expression: Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.1 More than two million cases of breast cancer were diagnosed in 2020 with nearly 685,000 deaths globally.1 In Europe, approximately 531,000 cases of breast cancer are diagnosed annually with nearly 141,000 deaths. 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, and is one of many biomarkers expressed in breast cancer tumors. HER2 expression is currently determined by an immunohistochemistry (IHC) test which estimates the amount of HER2 protein on a cancer cell, and/or an in-situ hybridization (ISH) test, which counts the copies of the HER2 gene in cancer cells.3,4 HER2 tests provide IHC and ISH scores across the full HER2 spectrum and are routinely used to determine appropriate treatment options for patients with metastatic breast cancer.

HER2 positive cancers are currently defined as HER2 expression measured as IHC 3+ or IHC 2+/ISH+, and HER2 negative cancers are defined as HER2 expression measured as IHC 0, IHC 1+ or IHC 2+/ISH-.3 However, approximately half of all breast cancers are HER2 low, defined as a HER2 score of IHC 1+ or IHC 2+/ISH-.5,6,7 HER2 low occurs in both HR positive and HR negative disease. Currently, patients with HR positive metastatic breast cancer and HER2 low disease have limited effective treatment options following progression on endocrine (hormone) therapy. Additionally, few targeted options are available for those with HR negative disease.