REG - AstraZeneca PLC - Enhertu recommended for EU approval in HER2-low BC

AstraZenecaAnnouncement

19/12/2022 07:30

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RNS Number : 0763K  AstraZeneca PLC  19 December 2022

19 December 2022 07:20 GMT

 

Enhertu recommended for approval in the EU by CHMP for patients

with HER2-low metastatic breast cancer

 

AstraZeneca and Daiichi Sankyo's Enhertu is the first HER2-directed therapy to
demonstrate a significant survival benefit vs. chemotherapy in this patient
population

 

AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) has been
recommended for approval in the European Union (EU) as monotherapy for the
treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+
or IHC 2+/ISH-) breast cancer who have received prior chemotherapy in the
metastatic setting or developed disease recurrence during or within six months
of completing adjuvant chemotherapy.

 

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

 

The Committee for Medicinal Products for Human Use (CHMP) of the European
Medicines Agency based its positive opinion on results from the
DESTINY-Breast04
(https://www.astrazeneca.com/media-centre/press-releases/2022/enhertu-efficacy-results-in-her2-low-breast-cancer.html)
Phase III trial, which were presented at the American Society of Clinical
Oncology 2022 Annual Meeting and simultaneously published in The New England
Journal of Medicine (https://www.nejm.org/doi/pdf/10.1056/NEJMoa2203690) .(1)

 

In the trial, Enhertu reduced the risk of disease progression or death by 50%
versus physician's choice of chemotherapy (based on a hazard ratio  HR  of
0.50; 95% confidence interval  CI : 0.40-0.63; p<0.001) in patients with
HER2-low metastatic breast cancer with HR-positive or HR-negative disease. A
median progression-free survival (PFS) of 9.9 months was seen with Enhertu
versus 5.1 months in those treated with chemotherapy, as assessed by blinded
independent central review (BICR). A 36% reduction in the risk of death (HR
0.64; 95% CI: 0.49-0.84; p=0.001) was seen with Enhertu compared to
chemotherapy with a median overall survival (OS) of 23.4 months versus 16.8
months.

 

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca,
said: "Enhertu is the first-ever HER2-directed medicine to show a survival
benefit in patients with HER2-low metastatic breast cancer, confirming the
importance of targeting lower levels of HER2 expression in patients previously
classified as HER2-negative. The CHMP's recommendation is encouraging and
supports our ambition to evolve the way breast cancer is classified and
treated to ultimately improve patient outcomes."

 

Ken Takeshita, Global Head, R&D Daiichi Sankyo, said: "This positive CHMP
opinion recognises the unmet need in the European Union for patients with
HER2-low metastatic breast cancer. Currently, once patients with HR-positive
disease progress on hormone therapy there are limited effective treatments,
and few targeted options are available for patients with HR-negative disease.
We look forward to the European Commission decision and aim to bring Enhertu
to eligible patients as soon as possible."

 

The safety profile observed in patients treated with Enhertu in the
DESTINY-Breast04 trial was consistent with that seen in other trials of
Enhertu in breast cancer with no new safety signals identified.

 

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.(2) More than two million patients with breast
cancer were diagnosed in 2020 with nearly 685,000 deaths globally.(2) In
Europe, approximately 531,000 breast cancer patients are diagnosed annually
with nearly 141,000 deaths.(3)

 

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.(4)

 

HER2 expression is currently determined by an immunohistochemistry (IHC) test
which estimates the amount of HER2 protein on a cancer cell, and/or an in situ
hybridisation (ISH) test, which counts the copies of the HER2 gene in cancer
cells.(4,5) HER2 tests provide IHC and ISH scores across the full HER2
spectrum and are routinely used to determine appropriate treatment options for
patients with metastatic breast cancer.

 

HER2-positive cancers are currently defined as HER2 expression measured as IHC
3+ or IHC 2+/ISH+, and HER2-negative cancers are defined as HER2 expression
measured as IHC 0, IHC 1+ or IHC 2+/ISH-.(4) However, approximately half of
all breast cancers are HER2-low, defined as a HER2 score of IHC1+ or IHC
2+/ISH-.(6-8) HER2-low occurs in both HR-positive and HR-negative disease.(9)

 

Currently, patients with HR-positive metastatic breast cancer and HER2-low
disease have limited effective treatment options following progression on
endocrine (hormone) therapy.(10) Additionally, few targeted options are
available for those with 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 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 40 countries for the treatment of
adult patients with unresectable or metastatic HER2-positive breast cancer who
have received a (or one or more) 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 the results from the DESTINY-Breast03 trial. Enhertu also 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 (5.4mg/kg) is approved in Brazil and the US 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 of the DESTINY-Breast04
trial.

 

Enhertu (5.4mg/kg) is approved under accelerated approval in the US for the
treatment of adult patients with unresectable or metastatic non-small cell
lung cancer whose tumours have activating HER2 (ERBB2) mutations, as detected
by an FDA-approved test, and who have received a prior systemic therapy based
on the results from the DESTINY-Lung02 trial. Continued approval for this
indication may be contingent upon verification and description of clinical
benefit in a confirmatory 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
and/or the DESTINY-Gastric02 trial.

 

Enhertu development programme

A comprehensive global development programme is underway 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 in breast, non-small cell lung and gastric
cancer are currently under review in several countries.

 

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
(https://www.astrazeneca.com/media-centre/press-releases/2019/astrazeneca-and-daiichi-sankyo-enter-collaboration-for-novel-her-2-targeting-antibody-drug-conjugate.html)
, and datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in July 2020
(https://www.astrazeneca.com/media-centre/press-releases/2020/astrazeneca-and-daiichi-sankyo-enter-collaboration-to-develop-and-commercialise-new-antibody-drug-conjugate.html)
, 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
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 (fulvestrant) and Zoladex (goserelin) and aims
to reshape the HR-positive space with ngSERD and potential new medicine
camizestrant as well as a potential first-in-class AKT kinase inhibitor,
capivasertib. 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 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 triple-negative breast
cancer, an aggressive form of breast cancer, AstraZeneca is evaluating the
potential of datopotamab deruxtecan alone and in combination with
immunotherapy Imfinzi (durvalumab), capivasertib 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, 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.   WHO. International Agency of Cancer Research. Cancer Today. Breast
Cancer. 2020. Available at:
https://gco.iarc.fr/today/data/factsheets/cancers/20-Breast-fact-sheet.pdf
(https://gco.iarc.fr/today/data/factsheets/cancers/20-Breast-fact-sheet.pdf) .
Accessed December 2022.

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

5.   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.

6.   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.

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.   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.

9.   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.

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

11.  American Cancer Society. Breast Cancer Hormone Receptor Status.
Available at:
https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-hormone-receptor-status.html
(https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-hormone-receptor-status.html)
. Accessed December 2022.

 

Adrian Kemp

Company Secretary

AstraZeneca PLC

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