REG - AstraZeneca PLC - Enhertu improves PFS and OS in HER2-low BC

AstraZenecaAnnouncement

21/02/2022 07:00

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RNS Number : 2557C  AstraZeneca PLC  21 February 2022

This announcement contains inside information

 

21 February 2022 07:00 GMT

 

Enhertu significantly improved both progression-free and overall survival in
DESTINY-Breast04 trial in patients with HER2-low metastatic breast cancer

 

First HER2-low metastatic breast cancer Phase III results for AstraZeneca and
Daiichi Sankyo's Enhertu offer potential to redefine how the disease is
classified and treated

 

Positive high-level results from the pivotal DESTINY-Breast04 Phase III trial
showed Enhertu (trastuzumab deruxtecan) demonstrated a statistically
significant and clinically meaningful improvement in both progression-free
survival (PFS) and overall survival (OS) in patients with HER2-low
unresectable and/or metastatic breast cancer regardless of hormone receptor
(HR) status versus physician's choice of chemotherapy.

 

Enhertu is a HER2-directed antibody drug conjugate (ADC) being jointly
developed by AstraZeneca and Daiichi Sankyo.

 

All patients in the trial received a HER2 test, and the results were centrally
confirmed. HER2-low status was defined as an immunohistochemistry (IHC) score
of 1+ or IHC 2+ with a negative in-situ hybridisation (ISH) score.

 

Up to 55% of all patients with breast cancer have tumours with a HER2 IHC
score of 1+, or 2+ in combination with a negative ISH test, a level of HER2
expression not currently eligible for HER2-targeted therapy.(1,2) HER2-low
expression occurs in both HR-positive and HR-negative disease.(3)

 

HER2 testing is well established to determine an appropriate treatment
strategy in metastatic breast cancer. Targeting the lower range of HER2
expression may offer another approach to delay disease progression and extend
survival in patients with metastatic breast cancer.(4) Currently, chemotherapy
remains the only treatment option both for patients with HR-positive tumours
following progression on endocrine (hormone) therapy, and for those who are
HR-negative.(5)

 

DESTINY-Breast04 met its primary endpoint, where Enhertu demonstrated superior
PFS in previously treated patients with HR-positive HER2-low metastatic breast
cancer compared to the standard-of-care chemotherapy. The trial met the key
secondary endpoint of PFS in patients with HER2-low metastatic breast cancer
regardless of HR status (HR-positive or HR-negative). The trial also met the
key secondary endpoints of OS in patients with HR-positive disease and in
patients regardless of HR status at interim analysis.

 

The safety profile of Enhertu was consistent with previous clinical trials,
with no new safety concerns identified. Overall interstitial lung disease
(ILD) rates were consistent with that observed in late-line HER2-positive
breast cancer trials of Enhertu, with a lower rate of Grade 5 ILD observed as
determined by an independent adjudication committee.

 

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca said:
"Today's historic news from DESTINY-Breast04 could reshape how breast cancer
is classified and treated. A HER2-directed therapy has never-before shown a
benefit in patients with HER2-low metastatic breast cancer. These results for
Enhertu are a huge step forward and could potentially expand our ability to
target the full spectrum of HER2 expression, validating the need to change the
way we categorise and treat breast cancer."

 

Ken Takeshita, Global Head, R&D, Daiichi Sankyo said: "Enhertu continues
to redefine the treatment of HER2-targetable cancers. DESTINY-Breast04 is the
first ever Phase III trial of a HER2-directed therapy in patients with
HER2-low metastatic breast cancer to show statistically significant and
clinically meaningful benefit in progression-free and overall survival
compared to standard treatment. We look forward to sharing the detailed
findings of DESTINY-Breast04 with the medical community and initiating
discussions with regulatory agencies globally with the goal of bringing
Enhertu to patients with metastatic breast cancer previously considered to be
HER2-negative."

 

The data will be presented at a forthcoming medical meeting and shared with
global health authorities.

 

Enhertu (5.4mg/kg) is approved in more than 40 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 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.

 

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.(6) More than two million cases of breast
cancer were diagnosed in 2020 resulting in nearly 685,000 deaths globally.(6)

 

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.(7) HER2 expression is currently defined as either positive or
negative, and is determined by an IHC test which measures the amount of HER2
protein in a cancer cell, and/or an ISH test which counts the copies of the
HER2 gene in cancer cells.(7,8) HER2-positive cancers are defined as IHC 3+ or
IHC 2+/ISH+, and HER2-negative cancers are currently defined as IHC 0, IHC 1+
or IHC 2+/ISH-.(7)

 

DESTINY-Breast04 

DESTINY-Breast04 is a global, randomised, open-label, registrational Phase III
trial evaluating the efficacy and safety of Enhertu (5.4 mg/kg) versus
physician's choice of chemotherapy (capecitabine, eribulin, gemcitabine,
paclitaxel or nab-paclitaxel) in patients with HR-positive (n=480) or
HR-negative (n=60) 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 (regardless of
HR status), OS in patients with HR-positive disease and OS in all randomised
patients (regardless of HR status). Other secondary endpoints include PFS
based on BICR and investigator assessment, duration of response based on BICR
and safety.

 

DESTINY-Breast04 enrolled approximately 540 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 40 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 Europe,
Japan, the US and several other countries for the treatment of adult patients
with unresectable or metastatic HER2-positive breast cancer who have received
a prior anti-HER2-based regimen based on the results from the DESTINY-Breast03
trial.

 

Enhertu also is currently under review 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 (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 the next-generation oral selective oestrogen receptor degrader
(SERD) and potential new medicine camizestrant.

 

PARP inhibitor Lynparza (olaparib) is a targeted treatment option for
metastatic breast cancer patients with an inherited BRCA mutation. Lynparza
has also demonstrated a statistically significant and clinically meaningful
improvement in invasive disease-free survival versus placebo in the adjuvant
treatment of patients with germline BRCA-mutated HER2-negative early breast
cancer. 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, 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. Tarantino P, et al. HER2-Low Breast Cancer: Pathological and Clinical
Landscape. J Clin Oncol. 2020;38(17):1951-1962.

2. 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.

3. 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.

4. Eiger D, et al. The Exciting New Field of HER2-Low Breast Cancer Treatment.
Cancers. 2021; 10.3390/cancers13051015.

5. Matutino A, et al. Hormone receptor-positive, HER2-negative metastatic
breast cancer: redrawing the lines. Current Oncology. 2018; 25(S1):S131-S141.

6. 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.

7. Iqbal N, et al. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers:
Overexpression and Therapeutic Implications. Mol Biol Int. 2014;852748.

8. 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.

 

Adrian Kemp

Company Secretary

AstraZeneca PLC

 

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