Daiichi Sankyo Submits NDA for Trastuzumab Deruxtecan (DS-8201) to Address Unmet Need in HER2-Positive Metastatic Breast Cancer

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Daiichi Sankyo Announces Submission of New Drug Application (NDA) to Japan’s Ministry of Health, Labour and Welfare (MHLW) for Trastuzumab Deruxtecan (DS-8201) in HER2-Positive Metastatic Breast CancerDaiichi Sankyo recently announced that it has submitted a New Drug Application (NDA) to Japan’s Ministry of Health, Labour and Welfare (MHLW), seeking approval for trastuzumab deruxtecan (DS-8201) for the treatment of patients with HER2-positive metastatic breast cancer. This agent is a next-generation antibody-drug conjugate (ADC) targeting HER2, with the potential to address unmet medical needs in HER2-positive breast cancer and to redefine the standard of clinical care for this disease.

DS-8201 is a next-generation antibody-drug conjugate (ADC) that links trastuzumab, a humanized monoclonal antibody targeting HER2, to a novel topoisomerase I inhibitor, an exatecan derivative (DX-8951 derivative, DXd), via a tetrapeptide linker. This mechanism enables targeted delivery of the cytotoxic agent into cancer cells, thereby reducing systemic exposure to the cytotoxic drug compared with conventional chemotherapy.

In March this year, AstraZeneca and Daiichi Sankyo reached an immuno-oncology collaboration deal worth up to $6.9 billion to jointly develop DS-8201 for the treatment of patients with various cancers characterized by different levels of HER2 expression or HER2 mutations, including gastric cancer, colorectal cancer, lung cancer, and HER2-low breast cancer. Under the agreement, the two parties will jointly develop and commercialize DS-8201 globally, with Daiichi Sankyo retaining exclusive rights in the Japanese market and taking full responsibility for manufacturing and supply.

Based on robust clinical efficacy data, the U.S. FDA previously granted Breakthrough Therapy Designation and Fast Track Designation to DS-8201 for patients with HER2-positive, locally advanced or metastatic breast cancer who have experienced disease progression following treatment with Roche’s three major HER2-targeted therapies: Herceptin (trastuzumab, a HER2-targeted monoclonal antibody), Perjeta (pertuzumab, a HER2-targeted monoclonal antibody), and Kadcyla (trastuzumab emtansine, T-DM1, a HER2-targeted ADC). Additionally, the MHLW has granted Sakigake designation to DS-8201 for the treatment of HER2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma.

This New Drug Application (NDA) is primarily based on the positive results from the pivotal Phase II clinical study, DESTINY-Breast01. This open-label, global, multicenter study evaluated the dosage, efficacy, and safety of DS-8201 in patients with HER2-positive metastatic breast cancer. Additionally, this NDA includes data from a Phase I clinical study (NCT02564900), which was conducted in patients with advanced HER2-positive breast cancer who had previously been treated with Kadcyla, a HER2-targeted antibody-drug conjugate (ADC). The results showed that among all evaluable patients, treatment with DS-8201 yielded an objective response rate (ORR) of 59.5%, a disease control rate (DCR) of 93.7%, a median time to response (TTR) of 1.6 months, a median duration of response (DOR) of 20.7 months, a median progression-free survival (PFS) of 22.1 months, and a median overall survival (OS) that was not yet reached.

Post hoc subgroup analyses of the Phase I study also revealed that: (1) among patients who had previously received the HER2-targeted monoclonal antibody Perjeta, treatment with TS-8201 resulted in an objective response rate (ORR) of 62.5%, a disease control rate (DCR) of 93.8%, and a median progression-free survival (PFS) of 16.4 months; (2) among patients with hormone receptor (HR)-positive tumors, the ORR was 59.5% and the DCR was 92.4%; among patients with HR-negative tumors, the ORR was 61.3% and the DCR was 96.8%. The detailed results of this Phase I study have been published in the medical journal The Lancet Oncology.

(Image source: Reference 3)

In the Phase II DESTINY-Breast01 study, the objective response rate (ORR) assessed by the Independent Review Committee (IRC) confirmed the clinical activity observed in the Phase I study; detailed results will be presented at an upcoming medical conference. In the DESTINY-Breast01 study, the safety and tolerability profile of DS-8201 was consistent with the Phase I data published in The Lancet Oncology. The most common adverse events (≥30%, all grades) included nausea, decreased appetite, vomiting, alopecia, fatigue, anemia, diarrhea, and constipation. Cases of drug-related interstitial lung disease (ILD)/pneumonitis, including Grade 5 events, have also been reported in the clinical development program.

Notably, phase I clinical study data released at the end of last year showed that in patients with HER2-low metastatic breast cancer (IHC 2+/ISH- or IHC 1+) who had previously received multiple anticancer therapies (median: 7.5 regimens), treatment with DS-8201 achieved an objective response rate (ORR) of 44.2%, a disease control rate (DCR) of 79.1%, a duration of response (DOR) of 9.4 months, and a median progression-free survival (PFS) of 7.6 months. Subgroup analysis revealed that among patients with HER2-low, hormone receptor (HR)-positive disease, the ORR was 47.4%, the DCR was 81.6%, the DOR was 11.0 months, and the median PFS was 7.9 months.

(Image source: Reference 3)

Globally, breast cancer is the most common cancer type and the leading cause of cancer-related deaths among women. Approximately 20% of breast cancers are HER2-positive. Although several HER2-targeted therapies have been approved in recent years with significant treatment advancements, there remains a substantial unmet clinical need in the population of patients with advanced HER2-positive metastatic breast cancer, as these patients ultimately experience disease progression after receiving currently available therapies and cannot be cured.

HER2 is a growth-promoting protein that functions as a tyrosine kinase receptor, present on the surface of certain cancer cells, and is associated with aggressive disease and poor prognosis in breast cancer patients. Tumor cells are typically tested for HER2 using one of two methods: immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH). IHC results are reported as IHC 0, IHC 1+, IHC 2+, or IHC 3+. An IHC 3+ result and/or FISH amplification is considered HER2-positive. Currently, there are no HER2-targeted therapies available for tumors that are HER2 FISH-negative with IHC 2+ or IHC 1+ status.

Structure of DS-8201 and Comparison with Roche’s HER2-Targeted ADC Drug Kadcyla (T-DM1) (Image Source: Reference 3)

References:

1、Daiichi Sankyo Advances [Fam-] Trastuzumab Deruxtecan (DS-8201) in Japan with Regulatory Submission in HER2 Positive Metastatic Breast Cancer

2、Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study

3、Collaboration on trastuzumab deruxtecan Investor conference call presentation