REG - AstraZeneca PLC - Enhertu granted Priority Review for HER2-low mBC

AstraZenecaAnnouncement

25/07/2022 07:00

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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
(https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2022/enhertu-efficacy-results-in-her2-low-breast-cancer.html)
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
(https://www.nejm.org/doi/10.1056/NEJMoa2203690?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed)
.(1)

 

In the trial, Enhertu demonstrated superior and clinically meaningful efficacy
in progression-free survival (PFS) and overall survival (OS) in 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
(https://www.astrazeneca.com/media-centre/press-releases/2022/enhertu-granted-btd-her2-low-breast-cancer.html)
(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
(https://clinicaltrials.gov/ct2/show/NCT03734029) .

 

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 (http://www.astrazeneca.com/)  and follow the
Company on Twitter @AstraZeneca (https://twitter.com/AstraZeneca) .

 

Contacts
For details on how to contact the Investor Relations Team, please click here
(https://www.astrazeneca.com/investor-relations.html#Contacts) . For Media
contacts, click here (https://www.astrazeneca.com/media-centre/contacts.html)
.

 

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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