TIDMAZN
RNS Number : 5247T
AstraZeneca PLC
25 July 2022
25 July 2022 07:00 BST
Enhertu granted Priority Review in the US for
patients with HER2-low metastatic breast cancer
Based on DESTINY-Breast04 results which showed AstraZeneca and
Daiichi Sankyo's Enhertu is the first HER2-directed therapy to
demonstrate a survival benefit in this population
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-low
(immunohistochemistry [IHC] 1+ or IHC 2+/in-situ hybridisation
[ISH]-negative) breast cancer who have received a prior therapy in
the metastatic setting. The application has been granted Priority
Review.
Enhertu is a specifically engineered HER2-directed antibody drug
conjugate (ADC) being jointly developed and commercialised 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. The Prescription Drug User Fee Act
date, the FDA action date for their regulatory decision, is during
the fourth 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 safe and 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 partners.
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: "The data from DESTINY-Breast04 represent the
first time a HER2-targeted therapy has shown a survival benefit in
patients with HER2-low metastatic breast cancer. For more than two
decades, only patients with HER2-positive breast cancer have been
able to benefit from HER2-targeted therapies. If approved, Enhertu
will redefine how we classify and treat metastatic breast cancer,
enabling patients whose tumours have lower levels of HER2
expression the opportunity to benefit from a HER2-directed
therapy."
Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: "The
results seen in the DESTINY-Breast04 trial represent a significant
advance and reinforce the potential for Enhertu to become a new
standard of care for patients with previously treated HER2-low
metastatic breast cancer. The prioritisation of this application by
the FDA and inclusion in both the Real-Time Oncology Review and
Project Orbis initiatives support the importance of these data, and
we look forward to working with the FDA to potentially bring
Enhertu to patients with HER2-low metastatic breast cancer as
quickly as possible."
The sBLA is based on data from the DESTINY-Breast04 Phase III
trial that were presented at the presidential plenary session of
the 2022 American Society of Clinical Oncology Annual Meeting and
simultaneously published in The New England Journal of Medicine .
(1)
In the trial, Enhertu demonstrated superior and clinically
meaningful efficacy in progression-free survival (PFS) and overall
survival (OS) i n previously treated patients with HER2-low
metastatic breast cancer with hormone receptor (HR)-positive or
HR-negative disease versus standard of care physician's choice of
chemotherapy.
The safety profile of Enhertu was consistent with previous
clinical trials with no new safety concerns identified.
Interstitial lung disease or pneumonitis rates were consistent with
that observed in late-line HER2-positive breast cancer trials of
Enhertu, as determined by an independent adjudication committee.
The majority (10%) were primarily low Grade (Grade 1 or 2) with
five Grade 3 (1.3%), no Grade 4 and three Grade 5 (0.8%) events
reported.
This Priority Review follows receipt of Breakthrough Therapy
Designation (BTD) in the US in April 2022 in metastatic HER2-low
breast cancer, the fifth BTD in the US for Enhertu.
Regulatory reviews for Enhertu in the HER2-low patient
population are also underway in the European Union (EU) and Japan,
and Enhertu is already approved in the US, the EU and many other
countries across the globe for patients with previously treated
HER2-positive (IHC 3+ or IHC 2+/ISH-positive) metastatic breast
cancer.
Notes
Breast cancer and HER2 expression
Breast cancer is the most common cancer and is one of the
leading causes of cancer-related deaths worldwide and in the
US.(2,3) More than two million cases of breast cancer were
diagnosed in 2020 resulting in nearly 685,000 deaths globally.(2)
In the US, more than 290,000 new cases are expected to be diagnosed
in 2022, resulting in more than 43,000 deaths.(4)
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, and is one of many biomarkers
expressed in breast cancer tumours.(5) HER2 expression is currently
defined as either positive or negative, and is determined by an IHC
test which estimates the amount of HER2 protein on a cancer cell,
and/or an ISH test, which counts the copies of the HER2 gene in
cancer cells.(5,6)
HER2-positive cancers are defined as IHC 3+, IHC 2+/ISH+, and
HER2-negative cancers are currently defined as IHC 0, IHC 1+ or IHC
2+/ISH-.(5) Approximately half of all patients with breast cancer
have tumours with low HER2 expression, with a HER2 IHC score of 1+,
or a HER2 IHC score of 2+ in combination with a negative ISH test,
an expression level not currently eligible for HER2-targeted
therapy.(7-10) Low HER2 expression occurs in both HR-positive and
HR-negative disease.(11)
DESTINY-Breast04
DESTINY-Breast04 is a global, randomised, open-label, Phase III
trial evaluating the efficacy and safety of Enhertu (5.4mg/kg)
versus physician's choice of chemotherapy (capecitabine, eribulin,
gemcitabine, paclitaxel or nab-paclitaxel) in patients with
HR-positive or HR-negative, HER2-low unresectable and/or metastatic
breast cancer previously treated with one or two prior lines of
chemotherapy. Patients were randomised 2:1 to receive either
Enhertu or chemotherapy.
The primary endpoint of DESTINY-Breast04 is PFS in patients with
HR-positive disease based on blinded independent central review
(BICR). Key secondary endpoints include PFS based on BICR in all
randomised patients (HR-positive and HR-negative disease), OS in
patients with HR-positive disease and OS in all randomised patients
(HR-positive and HR-negative disease). Other secondary endpoints
include PFS based on investigator assessment, objective response
rate based on BICR and on investigator assessment, duration of
response based on BICR and safety.
DESTINY-Breast04 enrolled 557 patients at multiple sites in
Asia, Europe and North America. For more information about the
trial, visit ClinicalTrials.gov .
Enhertu
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 a prior
anti-HER2-based regimen either in the metastatic setting, or in the
neoadjuvant or adjuvant setting and have developed disease
recurrence during or within six months of completing therapy, based
on results from the DESTINY-Breast03 trial.
Enhertu (5.4mg/kg) is approved in several 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.
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 (GEJ)
adenocarcinoma who have received a prior trastuzumab-based regimen
based on the results from the DESTINY-Gastric01 trial.
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.
Regulatory applications for Enhertu are currently under review
in China, Japan and several other countries for the treatment of
adult patients with HER2-positive unresectable or metastatic breast
cancer who have received a prior anti-HER2-based regimen based on
the results from the DESTINY-Breast03 trial.
Enhertu is under review in Europe and Japan for the treatment of
adult patients with unresectable or metastatic HER2-low (IHC 1+ or
IHC 2+/ISH-) breast cancer who have received a prior systemic
therapy in the metastatic setting or developed disease recurrence
during or within six months of completing adjuvant chemotherapy,
based on the results from the DESTINY-Breast04 trial. Patients with
HR-positive breast cancer must additionally have received or be
ineligible for endocrine therapy.
Enhertu is under review in the US for the treatment of adult
patients with unresectable or metastatic non-small cell lung cancer
whose tumours have a HER2 (ERBB2) mutation and who have received a
prior systemic therapy based on the results from the DESTINY-Lung01
trial, and in Europe for the treatment of adult patients with
locally advanced or metastatic HER2-positive gastric or GEJ
adenocarcinoma who have received a prior anti-HER2-based regimen
based on the DESTINY-Gastric01 and DESTINY-Gastric02 trials.
Daiichi Sankyo collaboration
Daiichi Sankyo Company, Limited (TSE: 4568) [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 the manufacturing and supply of Enhertu and datopotamab
deruxtecan.
AstraZeneca in breast cancer
Driven by a growing understanding of breast cancer biology,
AstraZeneca is challenging and redefining the current clinical
paradigm for how breast cancer is classified and treated to deliver
even more 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 the next-generation oral
selective oestrogen receptor degrader (SERD) and potential new
medicine camizestrant.
PARP inhibitor Lynparza (olaparib) is a targeted treatment
option that has been studied in HER2-negative 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 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,
datopotamab deruxtecan.
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, 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 .
Contacts
For details on how to contact the Investor Relations Team,
please click here . For Media contacts, click here .
References
1. Modi S, et al. Trastuzumab Deruxtecan in Previously Treated
HER2-Low Advanced Breast Cancer. N Engl J Med. 2022;387:9-20.
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. Centers for Disease Control and Prevention. Available at:
https://gis.cdc.gov/Cancer/USCS/#/AtAGlance/. Accessed July
2022.
4. American Cancer Society. Cancer Facts & Figures 2022. Available at: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2022.html. Accessed July 2022.
5. Iqbal N, et al. Human Epidermal Growth Factor Receptor 2
(HER2) in Cancers: Overexpression and Therapeutic Implications. Mol
Biol Int. 2014;852748.
6. Wolff A, et al. Human Epidermal Growth Factor Receptor 2
Testing in Breast Cancer: American Society of Clinical
Oncology/College of American Pathologists Clinical Practice
Guideline Focused Update. Arch Pathol Lab Med.
2018;142(11):1364-1382.
7. Schalper K, et al. A retrospective population-based
comparison of HER2 immunohistochemistry and fluorescence in situ
hybridization in breast carcinomas. Arch Pathol Lab Med.
2014;138:213-219.
8. 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.
9. Schettini F, et al. Clinical, pathological, and PAM50 gene
expression features of HER2-low breast cancer. npj Breast Cancer.
2021;7:1;https://doi.org/10.1038/s41523-020-00208-2.
10. Denkert C, et al. Clinical and molecular characteristics of
HER2-low-positive breast cancer: pooled analysis of individual
patient data from four prospective, neoadjuvant clinical trials.
2021. Lancet Oncol;22:1151-61.
11. Miglietta F, et al. Evolution of HER2-low expression from
primary to recurrent breast cancer. NPJ Breast Cancer.
2021;7:137;10.1038/s41523-021-00343-4.
Adrian Kemp
Company Secretary
AstraZeneca PLC
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