Based on ground-breaking DESTINY-Breast03
results showing AstraZeneca and Daiichi Sankyo’s Enhertu reduced
the risk of disease progression or death by 72% versus trastuzumab
Application being evaluated under FDA
Real-Time Oncology Review and Project Orbis
AstraZeneca and Daiichi Sankyo have received notification of
acceptance of the supplemental Biologics License Application (sBLA)
of Enhertu (trastuzumab deruxtecan) for the treatment of adult
patients in the US with unresectable or metastatic HER2-positive
breast cancer who have received a prior anti-HER2-based regimen.
The application has also been granted Priority Review.
Enhertu is a HER2-directed antibody drug conjugate (ADC) being
jointly developed by AstraZeneca and Daiichi Sankyo.
The Food and Drug Administration (FDA) grants Priority Review to
applications for medicines that, if approved, would offer
significant improvements over available options by demonstrating
safety or efficacy improvements, preventing serious conditions, or
enhancing patient compliance.1 The Prescription Drug User Fee Act
(PDUFA) date, the FDA action date for their regulatory decision is
during the second quarter of 2022.
The sBLA is being reviewed under the Real-Time Oncology Review
(RTOR) programme and Project Orbis, two initiatives of the FDA
which are designed to bring effective cancer treatments to patients
as early as possible. RTOR allows the FDA to review components of
an application before submission of the complete application.
Project Orbis provides a framework for concurrent submission and
review of oncology medicines among participating international
Breast cancer is the most common cancer worldwide, with more
than two million cases diagnosed in 2020, resulting in nearly
685,000 deaths globally.2 Approximately one in five cases of breast
cancer are considered HER2-positive.3 Despite initial treatment
with trastuzumab and a taxane, patients with HER2-positive
metastatic breast cancer will often experience disease
progression.4 More treatment options are needed to further delay
progression and extend survival.4-6
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca said: “This review across geographies and the Priority
Review in the US as part of Project Orbis is so important because
it speaks to the transformative potential of Enhertu based on the
unprecedented progression-free survival benefit in this setting.
The news reinforces the importance of bringing this potential new
option to patients as quickly as possible.”
Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: “This
regulatory review of Enhertu in the US marks the first time this
medicine is participating in both the Real-Time Oncology Review and
Project Orbis programmes. The FDA’s prioritisation of our
application underscores the potential of this medicine and the
continued need to expedite the availability of new treatment
options, while making it possible to potentially receive approvals
in several countries concurrently.”
The sBLA is based on data from the DESTINY-Breast03 trial
presented during the European Society for Medical Oncology (ESMO)
In the trial, Enhertu demonstrated a 72% reduction in the risk
of disease progression or death compared to T-DM1 (hazard ratio
[HR] 0.28; 95% confidence interval [CI]: 0.22-0.37; p=7.8x10-22) in
patients with HER2-positive unresectable and/or metastatic breast
cancer previously treated with trastuzumab and a taxane.
DESTINY-Breast03 also recorded that nearly all patients treated
with Enhertu during the trial were alive at one year (94.1%)
compared to 85.9% of patients treated with T-DM1. Confirmed
objective response rate (ORR) more than doubled in the Enhertu arm
versus the T-DM1 arm (79.7% vs. 34.2%). The safety profile of
Enhertu was consistent with previous clinical trials, with no new
safety concerns identified and no Grade 4 or 5 treatment-related
interstitial lung disease events.
In September 2021, Enhertu received its fourth Breakthrough
Therapy Designation (BTD) in the US for the treatment of adult
patients with unresectable or metastatic HER2-positive breast
cancer who have received one or more prior anti-HER2-based
Enhertu is approved for the treatment of adult patients with
unresectable or metastatic HER2-positive breast cancer who have
received two or more prior anti-HER2-based regimens in more than 30
countries based on the results from the DESTINY-Breast01 trial.
Enhertu is being further assessed in a comprehensive clinical
development programme evaluating efficacy and safety across
multiple HER2-targetable cancers, including breast, gastric, lung
and colorectal cancers.
HER2-positive breast cancer
Breast cancer is the most common cancer and is one of the
leading causes of cancer-related deaths in women worldwide.2 More
than two million patients with breast cancer were diagnosed in
2020, resulting in nearly 685,000 deaths globally.2 Approximately
one in five cases of breast cancer are considered
HER2 is a tyrosine kinase receptor growth-promoting protein
expressed on the surface of many types of tumours, including
breast, gastric, lung and colorectal cancers.7 HER2 protein
overexpression may occur as a result of HER2 gene amplification and
is often associated with aggressive disease and poor prognosis in
Despite initial treatment with trastuzumab and a taxane, people
with HER2-positive metastatic breast cancer will often experience
disease progression.4 More treatment options are needed to further
delay progression and extend survival.4-6
DESTINY-Breast03 is a global head-to-head, randomised,
open-label, registrational Phase III trial evaluating the safety
and efficacy of Enhertu (5.4mg/kg) versus T-DM1 in patients with
HER2-positive unresectable and/or metastatic breast cancer
previously treated with trastuzumab and a taxane.
The primary efficacy endpoint of DESTINY-Breast03 is
progression-free survival (PFS) based on blinded independent
central review. Secondary efficacy endpoints include overall
survival, objective response rate, duration of response, PFS based
on investigator assessment and safety.
DESTINY-Breast03 enrolled approximately 500 patients at multiple
sites in Asia, Europe, North America, Oceania and South America.
For more information about the trial, visit ClinicalTrials.gov.
Enhertu is a HER2-directed ADC. Designed using Daiichi Sankyo’s
proprietary DXd ADC technology, Enhertu is the lead ADC in the
oncology portfolio of Daiichi Sankyo and the most advanced
programme in AstraZeneca’s ADC scientific platform. Enhertu
consists of a HER2 monoclonal antibody attached to a topoisomerase
I inhibitor payload, an exatecan derivative, via a stable
tetrapeptide-based cleavable linker.
Enhertu (5.4mg/kg) is approved in more than 30 countries for the
treatment of adult patients with unresectable or metastatic
HER2-positive breast cancer who have received two or more prior
anti-HER2-based regimens based on the results from the
DESTINY-Breast01 trial. A Type II Variation is currently under
review by the European Medicines Agency (EMA) for the treatment of
adult patients with unresectable or metastatic HER2 positive breast
cancer who have received one or more prior anti-HER2-based regimens
based on the results from the DESTINY-Breast03 trial.
Enhertu (6.4mg/kg) is approved in several countries for the
treatment of adult patients with locally advanced or metastatic
HER2-positive gastric or gastroesophageal junction adenocarcinoma
who have received a prior trastuzumab-based regimen based on the
results from the DESTINY-Gastric01 trial. A Type II Variation is
currently under review by the EMA for the treatment of adult
patients with locally advanced or metastatic HER2-positive gastric
or gastroesophageal junction adenocarcinoma who have received a
prior anti-HER2-based regimen.
Enhertu development programme
A comprehensive development programme is underway globally,
evaluating the efficacy and safety of Enhertu monotherapy across
multiple HER2-targetable cancers, including breast, gastric, lung
and colorectal cancers. Trials in combination with other anticancer
treatments, such as immunotherapy, are also underway.
Enhertu was highlighted in the Clinical Cancer Advances 2021
report as one of two significant advancements in the “ASCO Clinical
Advance of the Year: Molecular Profiling Driving Progress in GI
Cancers,” based on data from both the DESTINY-CRC01 and
DESTINY-Gastric01 trials, as well as one of the targeted therapy
advances of the year in non-small cell lung cancer (NSCLC), based
on the interim results of the HER2-mutated cohort of the
Daiichi Sankyo collaboration
Daiichi Sankyo Company, Limited (referred to as Daiichi Sankyo)
and AstraZeneca entered into a global collaboration to jointly
develop and commercialise Enhertu (a HER2-directed ADC) in March
2019, and datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in
July 2020, except in Japan where Daiichi Sankyo maintains exclusive
rights. Daiichi Sankyo is responsible for 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. AstraZeneca aims to continue to
transform outcomes for HR-positive breast cancer with foundational
medicines Faslodex (fulvestrant) and Zoladex (goserelin) and
investigational agents next-generation oral SERD and
PARP inhibitor Lynparza (olaparib) is a targeted treatment
option for 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 metastatic breast cancer
patients with an inherited BRCA mutation and are exploring new
opportunities to treat these patients earlier in their disease.
Building on the first approval of Enhertu, a HER2-directed ADC,
in previously treated HER2-positive metastatic breast cancer,
AstraZeneca and Daiichi Sankyo are exploring its potential in
earlier lines of treatment and in new breast cancer settings.
To bring much needed treatment options to patients with
triple-negative breast cancer, an aggressive form of breast cancer,
AstraZeneca is testing immunotherapy Imfinzi (durvalumab) in
combination with other oncology medicines, including Lynparza and
Enhertu, evaluating the potential of AKT kinase inhibitor,
capivasertib, in combination with chemotherapy, and collaborating
with Daiichi Sankyo to explore the potential of TROP2-directed ADC,
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 (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, 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.com and follow the
Company on Twitter @AstraZeneca.
For details on how to contact the Investor Relations Team,
please click here. For Media contacts, click here.
1. FDA. Priority Review. Available at:
Accessed January 2022. 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. Ahn S, et al. HER2 status in breast cancer:
changes in guidelines and complicating factors for interpretation.
J Pathol Transl Med. 2020; 54(1): 34-44. 4. Barok M, et al.
Trastuzumab emtansine: mechanism of action and drug resistance.
Breast Cancer Res. 2014; 16(2):209. 5. Mounsey, L et al. Changing
Natural History of HER2-Positive Breast Cancer Metastatic to the
Brain in the Era of New Targeted Therapies. Clin Breast Cancer.
2018; 18(1):29-37. 6. Martinez-S Sáez O, et al. Current and Future
Management of HER2-Positive Metastatic Breast Cancer. JCO Oncol
Pract. 2021. 10.1200/OP.21.00172. 7. Iqbal N, et al. Human
Epidermal Growth Factor Receptor 2 (HER2) in Cancers:
Overexpression and Therapeutic Implications. Mol Biol Int.
2014;852748. 8. Pillai R, et al. HER2 mutations in lung
adenocarcinomas: A report from the Lung Cancer Mutation Consortium.
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