2 April 2024
Datopotamab deruxtecan
Biologics License Application accepted in the US for patients with
previously treated metastatic HR-positive, HER2-negative breast
cancer
Application based on results from the
TROPION-Breast01 Phase III trial
Additional BLA under review in the US
for AstraZeneca and Daiichi Sankyo's datopotamab deruxtecan for
patients with advanced nonsquamous non-small cell lung
cancer
AstraZeneca and Daiichi Sankyo's Biologics
License Application (BLA) for datopotamab deruxtecan (Dato-DXd) has
been accepted in the US for the treatment of adult patients with
unresectable or metastatic hormone receptor (HR)-positive,
HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have
received prior systemic therapy for unresectable or metastatic
disease. The Prescription Drug User Fee Act date, the
US Food and Drug Administration (FDA) action date for its
regulatory decision, is during the first quarter of
2025.
The BLA is based on results from
the pivotal TROPION-Breast01 Phase III
trial in which datopotamab deruxtecan demonstrated a statistically
significant and clinically meaningful improvement for the dual
primary endpoint of progression-free survival (PFS) compared to
investigator's choice of chemotherapy in patients with unresectable
or metastatic HR-positive, HER2-negative breast cancer previously
treated with endocrine-based therapy and at least one systemic
therapy. For the dual primary endpoint of overall survival (OS),
interim results numerically favoured datopotamab deruxtecan over
chemotherapy but were not mature at the time of data cut-off. The
trial is ongoing and OS will be assessed at future
analyses.
Datopotamab deruxtecan is a specifically
engineered TROP2-directed DXd antibody drug conjugate (ADC)
discovered by Daiichi Sankyo and being jointly developed by
AstraZeneca and Daiichi Sankyo.
Susan Galbraith, Executive Vice President,
Oncology R&D, AstraZeneca, said: "Despite marked progress in
the treatment of HR-positive, HER2-negative breast cancer, most
patients with advanced disease develop endocrine resistance and
face the prospect of one or several lines of chemotherapy. If
approved, datopotamab deruxtecan has the potential to provide these
patients an efficacious and better tolerated alternative to
conventional chemotherapy."
Ken Takeshita, MD, Global Head,
R&D, Daiichi Sankyo, said: "The FDA's acceptance of the BLA
brings us closer to providing patients with previously treated
HR-positive, HER2-negative breast cancer an alternative option to
conventional chemotherapy earlier in the metastatic setting.
Following our recently accepted application for advanced
nonsquamous non-small cell lung cancer in the US, along with
additional regulatory reviews underway in China, the EU, Japan and
other regions, we are working swiftly to bring datopotamab
deruxtecan as a potential new treatment option to patients around
the world."
Results from
TROPION-Breast01 were presented
during a Presidential Symposium at the 2023 European Society for
Medical Oncology Congress and in an oral presentation at the 2023
San Antonio Breast Cancer Symposium.
The safety profile of datopotamab
deruxtecan was consistent with that observed in other ongoing
trials with no new safety concerns identified.
An additional BLA for datopotamab
deruxtecan based on results from the pivotal TROPION-Lung01 Phase
III trial is under review in the US for the treatment of adult
patients with locally advanced or
metastatic nonsquamous non-small cell lung cancer (NSCLC) who have
received prior systemic therapy. Additional
regulatory submissions for datopotamab deruxtecan in lung and
breast cancer are underway globally.
Notes
HR-positive
breast cancer
More than 275,000 breast cancer cases were
diagnosed in the US in 2022.1 HR-positive,
HER2-negative breast cancer is the most common subtype, accounting
for more than 65% of diagnosed cases.2 Breast cancer is
considered HR-positive, HER2-negative when tumours test positive
for oestrogen and/or progesterone hormone receptors and negative
for HER2 (measured as HER2 score of IHC 0, IHC 1+ or IHC
2+/ISH-).2,3 Standard initial treatment for this subtype
of breast cancer 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-negative breast cancer and is associated with
increased tumour progression and poor survival.6,7
TROPION-Breast01
TROPION-Breast01 is a global, randomised,
multicentre, open-label Phase III trial evaluating the efficacy and
safety of datopotamab deruxtecan versus investigator's choice of
single-agent chemotherapy (eribulin, capecitabine, vinorelbine or
gemcitabine) in patients with unresectable or metastatic
HR-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast
cancer who have 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.
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, time to first subsequent therapy and safety. TROPION-Breast01
enrolled more than 700 patients in Africa, Asia, Europe, North
America and South America. 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
six DXd ADCs in the oncology pipeline of Daiichi Sankyo, and one of
the most advanced programmes in AstraZeneca's ADC scientific
platform. Datopotamab deruxtecan is comprised of a humanised
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 global clinical development
programme is underway with more than 20 trials evaluating the
efficacy and safety of datopotamab deruxtecan across multiple
cancers, including NSCLC, triple-negative breast cancer (TNBC) and
HR-positive, HER2-negative breast cancer.
Daiichi Sankyo collaboration
AstraZeneca and Daiichi Sankyo entered into a
global collaboration to jointly develop and commercialise
Enhertu 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 Enhertu 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 tumour environment.
With Enhertu (trastuzumab deruxtecan), 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 Faslodex and Zoladex (goserelin) and aims to
reshape the HR-positive space with first-in-class AKT inhibitor,
Truqap, and next-generation SERD and potential new medicine
camizestrant. AstraZeneca is also collaborating with Daiichi Sankyo
to explore the potential of TROP2-directed ADC, datopotamab
deruxtecan, in this setting.
PARP inhibitor Lynparza (olaparib) is a targeted
treatment option that has been studied in early and metastatic
breast cancer patients with an inherited BRCA mutation. AstraZeneca
with MSD (Merck & Co., Inc. in the US and Canada) continue to
research Lynparza in these settings and to
explore its potential in earlier disease.
To bring much-needed treatment
options to patients with TNBC, an aggressive form of breast cancer, AstraZeneca is evaluating
the potential of datopotamab deruxtecan alone and in combination
with immunotherapy Imfinzi (durvalumab), Truqap in combination with
chemotherapy, and Imfinzi in combination with other
oncology medicines, including Lynparza and Enhertu.
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 catalyse 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
(LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical
company that focuses on the discovery, development, and
commercialisation of prescription medicines in Oncology, Rare
Diseases, and BioPharmaceuticals, including Cardiovascular, Renal
& Metabolism, Respiratory & Immunology and Vaccines &
Immune Therapies. Based in Cambridge, UK, AstraZeneca operates in
over 100 countries and its innovative medicines are used by
millions of patients worldwide. Please visit astrazeneca.com and
follow the Company on social media @AstraZeneca.
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References
1. World Health
Organization. Global Cancer Observatory: United States of America.
Available at:
https://gco.iarc.who.int/media/globocan/factsheets/populations/840-united-states-of-america-fact-sheet.pdf.
Accessed April 2024.
2. National Cancer
Institute. SEER cancer stat facts: female breast cancer subtypes.
Available at: https://seer.cancer.gov/statfacts/html/breast-subtypes.html.
Accessed April 2024.
3. Iqbal N, et al. Human
Epidermal Growth Factor Receptor 2 (HER2) in Cancers:
Overexpression and Therapeutic Implications. Mol Biol Int. 2014;852748.
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 MR, 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.
Sacituzumab govitecan: Antibody-drug conjugate in triple negative
breast cancer and other solid tumours. Breast Cancer Res Treat. 2022
Aug;194(3): 569-575.
Adrian Kemp
Company
Secretary
AstraZeneca
PLC