Datopotamab deruxtecan (Datroway®; Daiichi Sankyo, previously known as DS-1062 and TROP2 ADC, see ADC Drug Map) an antibody-drug conjugate or ADC, being jointly developed and commercialized globally by Daiichi Sankyo and AstraZeneca, has been approved in Japan for the treatment of adult patients with hormone receptor (HR) positive, HER2 negative (IHC 0, IHC 1+ or IHC 2+/ISH-) unresectable or recurrent breast cancer after prior chemotherapy.
HR Positive, HER2 Negative
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide. [1] More than two million breast cancer cases were diagnosed in 2022 with more than 665,000 deaths globally. [1]
In Japan, breast cancer is the most common cancer in women.[2] Approximately 92,000 cases of breast cancer were diagnosed in Japan in 2022, with approximately 17,600 deaths.[2] It is estimated that 70% of diagnosed cases are considered what has been historically called HR positive, HER2 negative breast cancer (measured as HER2 score of IHC 0, IHC 1+ or IHC 2+/ISH-).[3]
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. [3]
Approximately 70% of diagnosed cases are considered what has been historically called HR positive, HER2 negative breast cancer (measured as HER2 score of IHC 0, IHC 1+ or IHC 2+/ISH-). [3]
Endocrine therapies are widely given consecutively in the early lines of treatment for HR positive metastatic breast cancer. [4] However, after initial treatment, further efficacy from endocrine therapy is often limited. [4] The current standard of care (SOC) following endocrine therapy is chemotherapy, which is associated with poor response rates
and outcomes. [4][5][6][7]
First approved in Japan
Datopotamab deruxtecan is the first ever trophoblast cell surface antigen 2 (TROP-2) directed medicine to be approved in Japan for HR positive, HER2 negative breast cancer. It is the second DXd ADC drug approved based on Daiichi Sankyo’s proprietary DXd ADC Technology.**
Datopotamab deruxtecan is comprised of a humanized anti-TROP-2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.
TROP-2
TROP-2 is a transmembrane glycoprotein encoded by the Tacstd2 gene. It is an intracellular calcium signal transducer that is differentially expressed in many cancers. It signals cells for self-renewal, proliferation, invasion, and survival. Although TROP-2 is also expressed in many normal tissues, TROP2 overexpression is generally associated with poor survival in human solid tumors. [8] [9]
The approval of datopotamab deruxtecan by the Japan Ministry of Health, Labour and Welfare (MHLW)* is based on results from the TROPION-Breast01 phase 3 trial (NCT05104866) which enrolled 732 patients in Africa, Asia, Europe, North America and South America.
Global study
The study is a global, randomized, multicenter, open-label phase 3 trial evaluating the efficacy and safety of intravenous datopotamab deruxtecan (6 mg/kg) once per 21-day cycle versus investigator’s choice of single-agent chemotherapy (eribulin, capecitabine, vinorelbine or gemcitabine) in adult patients with unresectable or metastatic HR positive, HER2 negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who progressed on and are not suitable for endocrine therapy per investigator assessment and have received at least one additional systemic therapy for unresectable or metastatic disease.
Following disease progression or discontinuation of datopotamab deruxtecan or chemotherapy, patients had the option to receive subsequent treatment at the discretion of their physician. Crossover between trial arms was not permitted.
Study results
In this TROPION-Breast01 trial, datopotamab deruxtecan significantly reduced the risk of disease progression or death by 37% compared to investigator’s choice of chemotherapy (hazard ratio [HR]=0.63, 95% confidence interval [CI]: 0.52-0.76; p<0.0001) in patients with HR positive, HER2 negative metastatic breast cancer as assessed by blinded independent central review (BICR).
In this study, median progression-free survival (PFS) was 6.9 months in patients treated with datopotamab deruxtecan compared to 4.9 months in those treated with chemotherapy.
Adverse events
In TROPION-Breast01, adverse reactions occurred in 93.6% (337/360 patients) of the 360 patients (including 31 Japanese patients) in the datopotamab deruxtecan (6 mg/kg) arm.
The most common adverse reactions included nausea (51.1%), stomatitis (50.0%), alopecia (36.4%), fatigue (23.6%), and dry eye (21.7%). In Japanese patients, interstitial lung disease (ILD) occurred in 6.5% of patients treated with datopotamab deruxtecan.
A new alternative
“This first global approval of datopotamab deruxtecan provides patients in Japan with metastatic HR positive, HER2 negative breast cancer a new alternative to conventional chemotherapy, which is often associated with poorvresponse rates,” noted Wataru Takasaki, PhD, Senior Advisor, Daiichi Sankyo.
“Datopotamab deruxtecan also is the second DXd antibody drug conjugate approved in Japan based on technology invented by Daiichi Sankyo,emphasizing our commitment to creating new, innovative standards of care for patients with cancer.”
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Note: * Additional regulatory submissions for datopotamab deruxtecan in breast cancer are under review in by the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA) and the National Medical Products Administration (NMPA), the State Council of the People’s Republic of China, and other regions.
** Tthe first approved ADC based on this technology is trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca)
Clinical trials
A Phase-3, Open-Label, Randomized Study of Dato-DXd Versus Investigator’s Choice of Chemotherapy (ICC) in Participants With Inoperable or Metastatic HR-Positive, HER2-Negative Breast Cancer Who Have Been Treated With One or Two Prior Lines of Systemic Chemotherapy (TROPION-Breast01) – ClinicalTrials.gov ID NCT05104866
Highlights of Prescribing Information
Trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca)[Prescribing Information]
References
[1] Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May-Jun;74(3):229-263. doi: 10.3322/caac.21834. Epub 2024 Apr 4. PMID: 38572751.
[2] World Health Organization. Global Cancer Observatory: Japan. Last accessed in December 2024.
[3] National Cancer Institute. SEER Cancer Stat Facts: Female Breast Cancer Subtypes. Last accessed in December 2024.
[4] Manohar PM, Davidson NE. Updates in endocrine therapy for metastatic breast cancer. Cancer Biol Med. 2021 Oct 5;19(2):202–12. doi: 10.20892/j.issn.2095-3941.2021.0255. Epub ahead of print. PMID: 34609096; PMCID: PMC8832960.
[5] Cortes J, O’Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Diéras V, Delozier T, Vladimirov V, Cardoso F, Koh H, Bougnoux P, Dutcus CE, Seegobin S, Mir D, Meneses N, Wanders J, Twelves C; EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus E7389) investigators. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011 Mar 12;377(9769):914-23. doi: 10.1016/S0140-6736(11)60070-6. Epub 2011 Mar 2. PMID: 21376385.
[6] Yuan P, Hu X, Sun T, Li W, Zhang Q, Cui S, Cheng Y, Ouyang Q, Wang X, Chen Z, Hiraiwa M, Saito K, Funasaka S, Xu B. Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial. Eur J Cancer. 2019 May;112:57-65. doi: 10.1016/j.ejca.2019.02.002. Epub 2019 Mar 29. PMID: 30928806.
[7] Jerusalem G, de Boer RH, Hurvitz S, Yardley DA, Kovalenko E, Ejlertsen B, Blau S, Özgüroglu M, Landherr L, Ewertz M, Taran T, Fan J, Noel-Baron F, Louveau AL, Burris H. Everolimus Plus Exemestane vs Everolimus or Capecitabine Monotherapy for Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer: The BOLERO-6 Randomized Clinical Trial. JAMA Oncol. 2018 Oct 1;4(10):1367-1374. doi: 10.1001/jamaoncol.2018.2262. PMID: 29862411; PMCID: PMC6233772.
[8] Shvartsur A, Bonavida B. Trop2 and its overexpression in cancers: regulation and clinical/therapeutic implications. Genes Cancer. 2015 Mar;6(3-4):84-105. doi: 10.18632/genesandcancer.40. PMID: 26000093; PMCID: PMC4426947.
[9] Zeng P, Chen MB, Zhou LN, Tang M, Liu CY, Lu PH. Impact of TROP2 expression on prognosis in solid tumors: A Systematic Review and Meta-analysis. Sci Rep. 2016 Sep 20;6:33658. doi: 10.1038/srep33658. PMID: 27645103; PMCID: PMC5028884.
This article was first published in ADC Review | Journal of Antibody-drug Conjugates on December 27, 2024.
Featured image: Breast Cancer, Breast Cancer Awareness Ribbon, Pink. Photo courtesy: © 2016 -2024 Fotolia/Adobe. Used with permission.
DOI
 an antibody-drug conjugate or ADC, being jointly developed and commercialized globally by Daiichi Sankyo and AstraZeneca, has been approved in Japan for the treatment of adult patients with hormone receptor (HR) positive, HER2 negative (IHC 0, IHC 1+ or IHC 2+/ISH-) unresectable or recurrent breast cancer after prior chemotherapy.){kind=link}