AstraZeneca and Daiichi Sankyo’s ADC Enhertu Receives Conditional Approval Recommendation in the EU for Heavily Pretreated HER2-Positive Metastatic Breast Cancer

On December 14, trastuzumab deruxtecan, developed by AstraZeneca and Daiichi Sankyo Company Limited, received a recommendation from the Committee for Medicinal Products for Human Use (CHMP) of the European Union for conditional marketing authorization, for use in patients with unresectable or metastatic HER2-positive breast cancer who have previously received two or more anti-HER2-based regimens.

According to statistics, 520,000 women in Europe are diagnosed with breast cancer each year, and 137,000 die from the disease, approximately 20% of whom have HER2-positive (HER2+) breast cancer. HER2, or human epidermal growth factor receptor 2, is a tyrosine kinase receptor protein that promotes cell growth. It is expressed on the surface of various tumor cells, including those in gastric cancer, breast cancer, and lung cancer. Its overexpression is associated with a specific genetic alteration known as HER2 amplification and is often linked to aggressive disease and poorer prognosis.

Trastuzumab deruxtecan is an antibody-drug conjugate (ADC) targeting HER2, composed of trastuzumab, a humanized monoclonal antibody targeting HER2, and a derivative of exatecan, a novel topoisomerase I inhibitor (DX-8951 derivative, DX), linked by a tetrapeptide linker. In December 2019, the drug was approved by the FDA for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received two or more anti-HER2 therapies, under the brand name Enhertu. In March this year, the drug also received conditional early approval in Japan for the treatment of patients with HER2-positive, unresectable or metastatic breast cancer that has recurred after prior chemotherapy (limited to patients who are refractory to or intolerant of standard therapy).

The conditional approval of Enhertu in the European Union is based on the positive results from the Phase II registration study, DESTINY-Breast01, whose initial findings were published in The New England Journal of Medicine and The Lancet Oncology. Furthermore, the latest results from this study were presented at the 2020 San Antonio Breast Cancer Symposium (SABCS). The data showed that as of June 8, 2020, the median follow-up duration for patients treated with trastuzumab deruxtecan (5.4 mg/kg) was 20.5 months, with an objective response rate (ORR) of 61.4% and a median duration of response (DoR) of 20.8 months. The median progression-free survival (PFS) was 19.4 months. In an exploratory milestone analysis of overall survival (OS), with a maturity assessment of 35%, it was estimated that 74% of patients were still alive at 18 months.

Compared with the results from the first phase of the study, Enhertu (trastuzumab deruxtecan) continues to demonstrate impressive efficacy and sustained responses in patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 therapies.

Moreover, trastuzumab deruxtecan is being evaluated in multiple Phase III studies in patients with metastatic breast cancer expressing HER2. Among these, DESTINY-Breast02 aims to assess its use as third-line treatment for patients with HER2-positive metastatic breast cancer, DESTINY-Breast03 aims to evaluate its use as second-line treatment for patients with HER2-positive metastatic breast cancer, and DESTINY-Breast04 aims to explore its efficacy in treating HER2-low metastatic breast cancer.

In addition to breast cancer, trastuzumab deruxtecan is also being developed for the treatment of HER2-positive gastric cancer and lung cancer. The indication for treating HER2-positive unresectable advanced or recurrent gastric cancer was approved in Japan this September. Furthermore, its supplemental Biologics License Application (sBLA) for the treatment of HER2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma has been accepted by the FDA and granted Priority Review designation. Additionally, the FDA has granted Breakthrough Therapy Designation to this drug for the treatment of metastatic non-small cell lung cancer (NSCLC) with HER2 mutations in patients who have experienced disease progression during or after platinum-based chemotherapy.

Trastuzumab deruxtecan (development code: DS-8201) is an antibody-drug conjugate (ADC) developed by Daiichi Sankyo Company Limited. In March 2019, AstraZeneca and Daiichi Sankyo reached a $6.9 billion collaboration agreement for this drug. Under the agreement, AstraZeneca and Daiichi Sankyo will jointly develop and commercially promote the drug globally, while Daiichi Sankyo will retain exclusive marketing rights in Japan and be solely responsible for its production and supply.

Given the significant market potential of antibody-drug conjugates (ADCs), AstraZeneca and Daiichi Sankyo Company Limited entered into a new global development and commercialization agreement in July for DS-1062, Daiichi Sankyo’s ADC targeting trophoblast cell-surface antigen 2 (TROP2). The deal is reportedly valued at up to $6 billion. DS-1062 is an ADC developed by Daiichi Sankyo using its proprietary DXd ADC technology, comprising a monoclonal antibody targeting the TROP2 protein linked to the DXd payload, and is being developed for the treatment of tumors such as non-small cell lung cancer (NSCLC). TROP2 is a transmembrane glycoprotein that is highly expressed in various solid tumors, including NSCLC.