First Phase III results in breast cancer for
AstraZeneca and Daiichi Sankyo’s datopotamab deruxtecan
Plans for global regulatory submissions
underway
Positive high-level results from the TROPION-Breast01 Phase III
trial showed datopotamab deruxtecan (Dato-DXd) 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.
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.
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: “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.”
Ken Takeshita, MD, Global Head, Oncology R&D, Daiichi
Sankyo, said: “The positive topline 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.”
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.1,2 Standard initial treatment for these patients
is endocrine therapy but most patients with advanced disease will
develop resistance, underscoring the need for additional
options.3,4 TROP2 is a protein broadly expressed in HR-positive,
HER2-low or negative breast cancer.5,6
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 durvalumab versus investigator’s choice of therapy in
patients with Stage I-III TNBC with residual disease after
neoadjuvant therapy.
HR-positive breast cancer 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.1
Breast cancer is considered HR-positive, HER2-low or negative
when tumors test positive for estrogen and/or progesterone hormone
receptors and negative or low for HER2 (measured as HER2 score of
IHC 0, IHC 1+ or IHC 2+/ISH-).2,7 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.2
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.5,6
TROPION-Breast01 TROPION-Breast01 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.
TROPION-Breast01 enrolled more than 700 patients at sites in
Asia, Europe, North America, South America and Africa. For more
information visit ClinicalTrials.gov.
Datopotamab deruxtecan (Dato-DXd) Datopotamab deruxtecan
(Dato-DXd) is an investigational TROP2-directed ADC. Designed using
Daiichi Sankyo’s proprietary DXd ADC technology, datopotamab
deruxtecan is one of five lead ADCs in the oncology pipeline of
Daiichi Sankyo, and one of the most advanced programs in
AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is
comprised of 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.
A comprehensive development program is underway globally with
more than 12 trials evaluating 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. Beyond the
TROPION program, datopotamab deruxtecan is also being evaluated in
novel combinations in several ongoing trials. AstraZeneca is also
researching a potential diagnostic test to help identify patients
most likely to benefit from treatment with datopotamab
deruxtecan.
Daiichi Sankyo collaboration AstraZeneca and Daiichi
Sankyo entered into a global collaboration to jointly develop and
commercialize fam-trastuzumab deruxtecan-nxki in March 2019 and
datopotamab deruxtecan in July 2020, except in Japan where Daiichi
Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is
responsible for the manufacturing and supply of fam-trastuzumab
deruxtecan-nxki and datopotamab deruxtecan.
AstraZeneca in breast cancer Driven by a growing
understanding of breast cancer biology, AstraZeneca is starting to
challenge, and redefine, the current clinical paradigm for how
breast cancer is classified and treated to deliver even more
effective treatments to patients in need – with the bold ambition
to one day eliminate breast cancer as a cause of death.
AstraZeneca has a comprehensive portfolio of approved and
promising compounds in development that leverage different
mechanisms of action to address the biologically diverse breast
cancer tumor environment.
With fam-trastuzumab deruxtecan-nxki, a HER2-directed ADC,
AstraZeneca and Daiichi Sankyo are aiming to improve outcomes in
previously treated HER2-positive and HER2-low metastatic breast
cancer and are exploring its potential in earlier lines of
treatment and in new breast cancer settings.
In HR-positive breast cancer, AstraZeneca continues to improve
outcomes with foundational medicines fulvestrant and goserelin and
aims to reshape the HR-positive space with next-generation SERD and
potential new medicine camizestrant as well as a potential
first-in-class AKT kinase inhibitor, capivasertib. AstraZeneca is
also collaborating with Daiichi Sankyo to explore the potential of
TROP2-directed ADC, datopotamab deruxtecan, in this setting.
PARP inhibitor olaparib is a targeted treatment option that has
been studied in early and metastatic breast cancer patients with an
inherited BRCA mutation. AstraZeneca with Merck & Co., Inc.,
known as MSD outside the US and Canada, continues to research
olaparib in these settings and to explore its potential in earlier
disease.
To bring much-needed treatment options to patients with
triple-negative breast cancer, an aggressive form of breast cancer,
AstraZeneca is evaluating the potential of datopotamab deruxtecan
alone and in combination with immunotherapy durvalumab,
capivasertib in combination with chemotherapy, and durvalumab in
combination with other oncology medicines, including olaparib and
fam-trastuzumab deruxtecan-nxki.
AstraZeneca in oncology AstraZeneca is leading a
revolution in oncology with the ambition to provide cures for
cancer in every form, following the science to understand cancer
and all its complexities to discover, develop and deliver
life-changing medicines to patients.
The Company's focus is on some of the most challenging cancers.
It is through persistent innovation that AstraZeneca has built one
of the most diverse portfolios and pipelines in the industry, with
the potential to catalyze changes in the practice of medicine and
transform the patient experience.
AstraZeneca has the vision to redefine cancer care and, one day,
eliminate cancer as a cause of death.
AstraZeneca AstraZeneca is a global, science-led
biopharmaceutical company that focuses on the discovery,
development, and commercialization of prescription medicines in
Oncology, Rare Diseases, and BioPharmaceuticals, including
Cardiovascular, Renal & Metabolism, and Respiratory &
Immunology. Based in Cambridge, UK, AstraZeneca operates in over
100 countries and its innovative medicines are used by millions of
patients worldwide. Please visit astrazeneca-us.com and follow the
Company on social media @AstraZeneca.
References
- 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.
- National Cancer Institute. Surveillance, Epidemiology and End
Results Program. Available at:
https://seer.cancer.gov/statfacts/html/breast-subtypes.html.
Accessed September 2023.
- 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.
- 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.
- 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.
- 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.
- 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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Brendan McEvoy +1 302 885 2677 Jillian Gonzales +1 302 885 2677
US Media Mailbox: usmediateam@astrazeneca.com
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