REG - AstraZeneca PLC - Enhertu granted BTD for HER2-low breast cancer

AstraZenecaAnnouncement

27/04/2022 07:16

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RNS Number : 4534J  AstraZeneca PLC  27 April 2022

27 April 2022 07:00 BST

 

Enhertu granted Breakthrough Therapy Designation in the US for patients with
HER2-low metastatic breast cancer

 

Based on DESTINY-Breast04 results where AstraZeneca and Daiichi Sankyo's
Enhertu demonstrated a significant improvement in both progression-free
survival and overall survival

 

Enhertu has now been granted five Breakthrough Therapy Designations, including
three in breast cancer and one in both lung and gastric cancers

 

AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) has been
granted Breakthrough Therapy Designation (BTD) in the US for the treatment of
adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC
2+/ISH-negative) 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. Patients with hormone receptor
(HR) positive breast cancer should additionally have received or be ineligible
for endocrine therapy.

 

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's (FDA) BTD is designed to accelerate the
development and regulatory review of potential new medicines that are intended
to treat a serious condition and address a significant unmet medical need. The
new medicine needs to have shown encouraging preliminary clinical results that
demonstrate substantial improvement on a clinically significant endpoint over
available medicines.

 

Up to half of all patients with breast cancer have tumours with a HER2
immunohistochemistry (IHC) score of 1+, or 2+ in combination with a negative
in-situ hybridisation (ISH) test, a level of HER2 expression not currently
eligible for HER2-targeted therapy.(1-4) Low HER2 expression occurs in both
HR-positive and HR-negative disease.(5)

( )

HER2 testing is routinely used to determine appropriate treatment options for
patients with metastatic breast cancer. Targeting the lower range of
expression in the HER2 spectrum may offer another approach to delay disease
progression and extend survival in patients with metastatic breast cancer.(6)
Currently chemotherapy remains the only treatment option for patients with
HR-positive tumours following progression on endocrine (hormone) therapy.(7)
Few targeted options are available for those who are HR-negative.(8)

 

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca said:
"Today's news is a significant validation of the potential we see for the
historic DESTINY-Breast04 trial to enable a paradigm shift in how breast
cancer is classified by targeting the full spectrum of HER2 expression.
Enhertu continues to show transformative potential, and this milestone
represents an important advance for patients with HER2-low metastatic breast
cancer who are in urgent need of new treatment options and better outcomes."

 

Ken Takeshita, Global Head, R&D, Daiichi Sankyo said: "Historically, only
patients with HER2-positive metastatic breast cancer were shown to benefit
from HER2-directed therapy. DESTINY-Breast04, in which Enhertu showed a
clinically meaningful survival benefit in patients with HER2-low metastatic
breast cancer, is the first trial to demonstrate that selecting patients for
treatment based on low expression of HER2 has the potential to change the
diagnostic and treatment paradigms for these patients. This Breakthrough
Therapy Designation acknowledges the potential of Enhertu to fulfil an unmet
medical need and we look forward to working closely with the FDA to bring the
first HER2-directed therapy to patients with metastatic breast cancer whose
tumours have lower levels of HER2 expression."

 

The FDA granted the BTD based on data from the pivotal DESTINY-Breast04 Phase
III trial which reported positive high-level results
(https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2022/enhertu-improves-pfs-and-os-in-her2-low-bc.html)
 in February 2022. In the trial, Enhertu 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 in all randomised patients with
HR-positive and HR-negative disease versus physician's choice of chemotherapy,
which is the current standard of care. The safety profile of Enhertu was
consistent with previous clinical trials with no new safety concerns
identified. The data will be presented at an upcoming medical meeting.

 

This is the third BTD for Enhertu in breast cancer. Enhertu previously
received BTD's for the treatment of second-line HER2-positive metastatic
breast cancer in 2021 and later-line HER2-positive metastatic breast cancer in
2017. Two additional BTD's for Enhertu were granted in 2020 for HER2-mutant
metastatic non-small cell lung cancer (NSCLC) and HER2-positive metastatic
gastric 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.(9,10) More than two million
cases of breast cancer were diagnosed in 2020 resulting in nearly 685,000
deaths globally.(9) In the US, more than 290,000 new cases are expected to be
diagnosed in 2022, resulting in more than 43,000 deaths.(11)

 

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.(12) HER2 expression is currently defined as either positive or
negative, and is determined by an IHC test which measures 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.(12,13) 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-.(12)

 

DESTINY-Breast04

DESTINY-Breast04 is a global, randomised, open-label, registrational 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 (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 (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 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 is also currently under review in the US for the treatment of adult
patients with unresectable or metastatic non-small cell lung cancer (NSCLC)
whose tumours have a HER2 (ERBB2) mutation and who have received a prior
systemic therapy, 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
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 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

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.

 

References

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

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

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

8. 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.
Accessed April 2022.

9. 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.

10. CDC. United States Cancer Statistics: Data Visualizations. Available at:
https://gis.cdc.gov/Cancer/USCS/#/AtAGlance/. Last accessed: April 2022.

11. 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.
Last accessed: April 2022.

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

13. 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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