Daiichi Sankyo and AstraZeneca's TROP2 ADC Datopotamab Deruxtecan Receives CDE Acceptance for NDA in HR+/HER2- Metastatic Breast Cancer

• This submission is based on the global Phase III clinical trial TROPION-Breast01. The study results showed that in patients with HR-positive, HER2-negative breast cancer who were previously treated with endocrine therapy and at least one systemic therapy, and who had inoperable or metastatic disease, Datopotamab deruxtecan demonstrated a median PFS of 6.9 months, significantly reducing the risk of disease progression or death by 37%.
  
  

• Dato-DXd is a TROP2-targeted antibody-drug conjugate (ADC) designed with proprietary technology, and it is also the second innovative ADC drug submitted for marketing approval in China by Daiichi Sankyo following Enhertu.
  
  

Recently, the Center for Drug Evaluation (CDE) of the China National Medical Products Administration officially accepted the new drug marketing authorization application submitted by Daiichi Sankyo for datopotamab deruxtecan (Dato-DXd), an antibody-drug conjugate (ADC) targeting TROP2, which was jointly developed and promoted with AstraZeneca. The drug is intended for the treatment of adult patients with unresectable or metastatic breast cancer that is hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+, or IHC 2+/ISH-) who have previously received systemic therapy at the unresectable or metastatic disease stage.

The new drug marketing authorization application for Datopotamab Deruxtecan submitted this time is based on data from the pivotal Phase III clinical study TROPION-Breast 01. The results of the study, presented at the 2023 European Society for Medical Oncology (ESMO) Congress, showed that for the primary endpoint of progression-free survival (PFS), as assessed by blinded independent central review (BICR), Datopotamab Deruxtecan significantly reduced the risk of disease progression or death by 37% (hazard ratio [HR] = 0.63; 95% confidence interval [CI]: 0.52-0.76; p<0.0001) compared to investigator’s choice chemotherapy (ICC) in patients with HR-positive, HER2-negative (IHC0, IHC1+ or IHC2+/ISH-) metastatic breast cancer who had been previously treated with endocrine therapy. The median PFS in the Datopotamab Deruxtecan treatment group was 6.9 months, compared to 4.9 months in the ICC group. Consistent PFS benefits were observed across different subgroups. Additionally, the objective response rate (ORR) was 36.4% in the Datopotamab Deruxtecan treatment group, compared to 22.9% in the chemotherapy group.

In the interim analysis of the other primary endpoint, overall survival (OS), as of the data cutoff date, datopotamab deruxtecan also demonstrated a trend of improvement over the chemotherapy group (HR = 0.84; 95% CI: 0.62-1.14). The study is currently ongoing, and OS will be further evaluated.

In terms of safety, the overall safety profile of Deda Botu Monoclonal Antibody was favorable, with no new safety concerns identified. The incidence of treatment-related adverse events of Grade 3 or higher in the Deda Botu Monoclonal Antibody group was 21%, which was only half that of the chemotherapy group (45% in the chemotherapy group).

About the TROPION-Breast01 Study

TROPION-Breast01 is a global, randomized, multi-center, open-label Phase III study designed to evaluate the efficacy and safety of Dato-DXd versus investigator’s choice of chemotherapy (eribulin, capecitabine, vinorelbine, or gemcitabine) in patients with inoperable or metastatic HR-positive, HER2-low, or HER2-negative (IHC 0, IHC 1+, or IHC 2+/ISH-) breast cancer whose disease has progressed after prior endocrine therapy as assessed by the investigator or who are not suitable for endocrine therapy and have received at least one prior systemic therapy.

The dual primary endpoints of TROPION-Breast01 are PFS (assessed by BICR) and OS. Key secondary endpoints include ORR, duration of response, investigator-assessed PFS, disease control rate, and time to first subsequent treatment.

TROPION-Breast01 enrolled more than 700 patients at research centers in Asia, Europe, North America, South America, and Africa. For more information, please visit ClinicalTrials.gov.

Regarding HR-Positive, HER2-Negative Breast Cancer

Breast cancer is the most common cancer among women in China and one of the leading causes of cancer-related deaths. In 2022, nearly 360,000 breast cancer cases were diagnosed in China, with nearly 75,000 deaths.

If the tumor tests positive for estrogen and/or progesterone receptors, and the HER2 test result is low or negative (HER2 score of IHC 0, IHC 1+, or IHC 2+/ISH-), it is considered HR-positive, HER2-negative breast cancer2,3. HR-positive, HER2-negative breast cancer is the most common subtype, accounting for more than 65% of confirmed cases2. Among patients diagnosed with HR-positive, HER2-negative breast cancer, approximately 30% are expected to survive five years after diagnosis2.

The standard initial treatment for this breast cancer subtype is endocrine therapy, but most patients with advanced disease will develop resistance, necessitating other treatment options.

TROP2 is a protein widely expressed in a variety of solid tumors, including HR-positive, HER2-negative breast cancer6. The expression of TROP2 is associated with increased tumor progression and shorter survival in breast cancer patients6,7.

About Datopotamab Deruxtecan (Dato-DXd)

Datozumab is an investigational TROP2-targeted ADC. Datozumab is designed using Daiichi Sankyo's proprietary DXd-ADC technology, and it is one of six ADCs in Daiichi Sankyo’s oncology pipeline as well as one of the most advanced programs in AstraZeneca’s ADC scientific platform. Datozumab consists of a humanized anti-TROP2 IgG1 monoclonal antibody (developed in collaboration with Sapporo Medical University) linked via a cleavable tetrapeptide linker to multiple topoisomerase I inhibitor payloads (a derivative of exatecan, DXd).

The comprehensive development project TROPION is being conducted globally, with 10 studies in China concurrently evaluating the efficacy and safety of datopotamab deruxtecan in treating various tumors, including non-small cell lung cancer, triple-negative breast cancer (TNBC), and HR-positive, HER2-low or negative breast cancer. In addition to the TROPION project, datopotamab deruxtecan is also being assessed as part of novel combination therapies in several ongoing studies.

About Daiichi Sankyo's DXd ADC Portfolio

Daiichi Sankyo's DXd ADC portfolio currently includes six ADC drugs in clinical development, covering various types of cancer. Trastuzumab deruxtecan (HER2-targeted ADC) and datopotamab deruxtecan (TROP2-targeted ADC) are being co-developed by Daiichi Sankyo and AstraZeneca and commercialized globally. Patritumab deruxtecan (HER3-DXd, HER3-targeted ADC), ifinatamab deruxtecan (I-DXd, B7-H3 ADC), and raludotatug deruxtecan (R-DXd, CDH6-targeted ADC) are being co-developed by Daiichi Sankyo and Merck & Co. and commercialized globally. Daiichi Sankyo is independently developing DS-3939 (TA-MUC1-targeted ADC). Each ADC is designed using Daiichi Sankyo’s proprietary DXd ADC technology to target cancer cells expressing specific cell surface antigens and deliver cytotoxic payloads into the cancer cells. Each ADC consists of a monoclonal antibody connected via a cleavable tetrapeptide linker to multiple topoisomerase I inhibitor payloads (a derivative of exatecan, DXd).

Dedabotumab, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, and DS-3939 are all investigational drugs that have not been approved in any country/region for any indication. Their safety and efficacy have not been fully established.

Editor: Mu Mian

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