Breast cancer is the most common cancer in the world and a leading cause of cancer-related death.[1] More than two million breast cancer cases were diagnosed in 2020 with nearly 685,000 deaths globally.[2]

Metastatic HR+/HER2- breast cancer, or cancer that has spread to a distant part of the body. also referred to as stage IV (4) cancer, represents remaining unmet medical need in the treatment of patients who have progressed on endocrine therapy or are not eligible for endocrine therapy. For these patients there are limited treatment options beyond chemotherapy. [1]

HR-positive breast cancer
Breast cancer is considered HR-positive, HER2-low or negative when tumors test positive for oestrogen and/or progesterone hormone receptors and negative or low for HER2 (measured as HER2 score of IHC 0, IHC 1+ or IHC 2+/ISH-) [3][8] HR-positive, HER2-low or negative breast cancer is the most common subtype, accounting for more than 65% of diagnosed cases.2 Approximately 30% of patients diagnosed with HR-positive, HER2-low or negative metastatic breast cancer are expected to live five years after their diagnosis.[3]

One promising treatment option in this setting is datopotamab deruxtecan (or Dato-DXd), an investigational antibody-drug conjugates (ADC), designed using Daiichi Sankyo’s proprietary DXd ADC technology. The drug comprises a humanized anti-TROP2 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.

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TROP2 is a protein broadly expressed in several solid tumors, including HR positive, HER2-low or negative breast cancer. [5] TROP2 expression is associated with increased tumor progression and poor survival in patients with breast cancer.[6][7]

Clinical development
Results for the TROPION-Breast01 Phase III trial with datopotamab deruxtecan demonstrated a statistically significant and clinically meaningful improvement for the primary endpoint of progression-free survival (PFS) compared to investigator’s choice of chemotherapy in patients with inoperable or metastatic hormone receptor (HR)-positive, HER2-low or negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer previously treated with endocrine-based therapy and at least one systemic therapy.

In addition to clinical trials in breast cancer, more than 12 trials are designed to evaluate the efficacy and safety of datopotamab deruxtecan across multiple tumors, including non-small cell lung cancer, triple-negative breast cancer and hormone receptor-positive, HER2-low or negative breast cancer.

TROPION-Breast01 study, which enrolled more than 700 patients at sites in Asia, Europe, North America, South America and Africa, is global, randomized, multicenter, open-label Phase III trial evaluating the safety and efficacy of datopotamab deruxtecan versus investigator’s choice of single-agent chemotherapy (eribulin, capecitabine, vinorelbine or gemcitabine) in patients with inoperable or metastatic HR- positive, HER2-low or negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have previously progressed on or are not suitable for endocrine therapy per investigator assessment.

The dual primary endpoints of TROPION-Breast01 are PFS as assessed by blinded independent central review (BICR) and OS. Key secondary endpoints include objective response rate, duration of response, investigator-assessed PFS, disease control rate and time to first subsequent therapy.

In addition, a trend in improvement for the dual primary endpoint of overall survival (OS) was observed for datopotamab deruxtecan versus chemotherapy. Data for OS were not mature at this interim analysis and the trial will continue as planned to assess OS.

The safety profile of datopotamab deruxtecan was consistent with previous clinical trials in breast cancer with no new safety signals identified. All grade interstitial lung disease rates were low.

Datopotamab deruxtecan is a specifically engineered TROP2-directed DXd antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo.

“Today’s TROPION-Breast01 news is a significant development for patients with HR-positive, HER2-low or negative metastatic breast cancer whose tumors have become insensitive to endocrine therapy and who currently face poor outcomes. We are encouraged by these positive results,” said  Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca.

“The positive top-line results from TROPION-Breast01 demonstrate the potential for datopotamab deruxtecan to become an important treatment option for patients with HR-positive, HER2-low or HER2-negative breast cancer in the second-line metastatic setting. We look forward to realizing the full potential of this TROP2-directed antibody drug conjugate across breast cancer subtypes through our ongoing Phase III program, including two trials in patients with triple-negative breast cancer,” noted Ken Takeshita, MD, Global Head, Oncology R&D, Daiichi Sankyo.

More than two million people worldwide are diagnosed with breast cancer each year.[1] HR-positive, HER2-low or negative breast cancer is the most common subtype, accounting for more than 65% of diagnosed cases.[2][3] Standard initial treatment for these patients is endocrine therapy but most patients with advanced disease will develop resistance, underscoring the need for additional options.[4] [5] TROP2 is a protein broadly expressed in HR-positive, HER2-low or negative breast cancer.[6][7]

The data will be presented at a forthcoming medical meeting and shared with health authorities.

* AstraZeneca and Daiichi Sankyo have two additional Phase III trials evaluating datopotamab deruxtecan in breast cancer. TROPION-Breast02 is comparing datopotamab deruxtecan to chemotherapy in patients with previously untreated locally recurrent inoperable or metastatic triple negative breast cancer (TNBC) who are not candidates for anti-PDL1 therapy. TROPION-Breast03 is evaluating datopotamab deruxtecan with and without Imfinzi (durvalumab) versus investigator’s choice of therapy in patients with Stage I-III TNBC with residual disease after neoadjuvant therapy.

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) – NCT05104866

[1] Bardia A, Jhaveri K, Kalinsky K, Pernas S, Tsurutani J, Xu B, Hamilton E, Im SA, Nowecki Z, Sohn J, Laurentiis M, Jañez NM, Adamo B, Lee KS, Jung KH, Rubovszky G, Tseng LM, Lu YS, Yuan Y, Maxwell MJ, Haddad V, Khan SS, Rugo HS, Pistilli B. TROPION-Breast01: Datopotamab deruxtecan vs chemotherapy in pre-treated inoperable or metastatic HR+/HER2- breast cancer. Future Oncol. 2023 Jun 30. doi: 10.2217/fon-2023-0188. Epub ahead of print. PMID: 37387213.
[2] Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 10.3322/caac.21660.
[3] National Cancer Institute. Surveillance, Epidemiology and End Results Program. Available at: Accessed September 2023.
[4] Lin M, et al. Comparative Overall Survival of CDK4/6 Inhibitors Plus Endocrine Therapy vs. Endocrine Therapy Alone for Hormone receptor-positive, HER2-negative metastatic breast cancer. J Cancer. 2020; 10.7150/jca.48944.
[5] Lloyd M R, et al. Mechanisms of Resistance to CDK4/6 Blockade in Advanced Hormone Receptor–positive, HER2-negative Breast Cancer and Emerging Therapeutic Opportunities. Clin Cancer Res. 2022; 28(5):821-30.
[6] Goldenberg D, et al. The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target. Oncotarget. 2018;9(48): 28989-29006.
[7] Vidula N, et al. Trophoblast Cell Surface Antigen 2 gene (TACSTD2) expression in primary breast cancer. Breast Cancer Res Treat. 2022 Aug;194(3):569-575.
[8] Iqbal N, et al. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int. 2014;852748.

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