REG - AstraZeneca PLC - Enhertu approved in US for 2L HER2+ breast cancer

AstraZenecaAnnouncement

05/05/2022 07:15

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RNS Number : 4270K  AstraZeneca PLC  05 May 2022

05 May 2022 07:10 BST

 

Enhertu approved in the US for patients with HER2-positive metastatic

breast cancer treated with a prior anti-HER2-based regimen

 

Approval broadens indication for AstraZeneca and Daiichi

Sankyo's Enhertu to earlier use in metastatic breast cancer

 

Based on ground-breaking DESTINY-Breast03 results showing Enhertu reduced the
risk of disease progression or death by 72% versus trastuzumab emtansine
(T-DM1)

 

AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) has been
approved in the US 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.

 

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

 

The approval by the Food and Drug Administration (FDA) was based on positive
results from the DESTINY-Breast03 Phase III trial that showed Enhertu reduced
the risk of disease progression or death by 72% versus trastuzumab emtansine
(T-DM1) (hazard ratio  HR  0.28; 95% confidence interval  CI : 0.22-0.37;
p<0.0001) in patients with HER2-positive unresectable and/or metastatic
breast cancer previously treated with trastuzumab and a taxane.

 

The approval was granted under the FDA's Real-Time Oncology Review (RTOR)
programme and converts the accelerated approval
(https://www.astrazeneca.com/media-centre/press-releases/2019/enhertu-trastuzumab-deruxtecan-approved-in-the-us-for-her2-positive-unresectable-or-metastatic-breast-cancer-following-2-or-more-prior-anti-her2-based-regimens.html)
of Enhertu in later line HER2-positive metastatic breast cancer to standard
approval, broadening Enhertu's breast cancer indication in the US to earlier
lines of use in patients with HER2-positive metastatic breast cancer.

 

Erika Hamilton, MD, Director of the Breast Cancer and Gynecological Cancer
Research Program for Sarah Cannon Research Institute, Nashville, Tennessee,
US, said: "Enhertu has demonstrated significant progression-free survival in
the earlier metastatic setting, potentially establishing it as a new standard
of care in previously treated patients with HER2-positive metastatic breast
cancer. Today's approval is an important milestone for the clinical community
as we will now be able to offer Enhertu to these patients earlier in their
treatment."

 

Catherine Ormerod, Executive Vice President, Strategy and Mission, Living
Beyond Breast Cancer, said: "This is an important day for the breast cancer
community. With this approval, Enhertu now provides a new treatment option for
patients with HER2-positive metastatic breast cancer which can be used earlier
in treatment to potentially delay progression of disease."

 

Dave Fredrickson, Executive Vice President, Oncology Business Unit,
AstraZeneca, said: "Enhertu is already established in the later-line treatment
of patients with HER2-positive metastatic breast cancer, and we are thrilled
that with this approval, patients in the US will now be able to access the
transformative potential of Enhertu earlier in their treatment. We look
forward to bringing this important, potentially paradigm-shifting medicine to
even more patients across the globe in an earlier setting as quickly as
possible."

 

Ken Keller, Global Head, Oncology Business and President and CEO, Daiichi
Sankyo, Inc, said: "Today's FDA approval, which converts the accelerated
approval of Enhertu to regular approval, highlights the importance of the
FDA's accelerated pathway that allows for earlier approval of medicines to
treat serious medical conditions such as breast cancer. Data from
DESTINY-Breast03 not only confirmed the results of DESTINY-Breast01, but also
demonstrated the superiority of Enhertu in prolonging progression-free
survival compared to T-DM1 in an earlier setting of HER2-positive metastatic
breast cancer."

 

The DESTINY-Breast03 Phase III trial results were recently published online in
The New England Journal of Medicine
(https://www.nejm.org/doi/full/10.1056/NEJMoa2115022?query=featured_home) .(1)
In the trial, the safety profile of Enhertu was consistent with previous
clinical trials, with no new safety concerns identified and no Grade 4 or 5
treatment-related interstitial lung disease events.

 

Based on the DESTINY-Breast03 data, fam-trastuzumab deruxtecan-nxki (Enhertu)
recently was added to the NCCN Clinical Practical Guidelines in Oncology (NCCN
Guidelines(®)) as the Category 1 preferred regimen as second-line therapy for
recurrent unresectable (local or regional) or Stage IV HER2-positive
disease.(2)

 

The US regulatory submission was reviewed under Project Orbis, which provides
a framework for concurrent submission and review of oncology medicines among
participating international partners. Five national health authorities
collaborated with the FDA on this review, including the Australian Therapeutic
Goods Administration, the Brazilian Health Regulatory Agency (ANVISA), Health
Canada, Israel's Ministry of Health Pharmaceutical Administration and
Switzerland's Swissmedic.

 

This approval follows the recent Priority Review
(https://www.astrazeneca.com/media-centre/press-releases/2022/enhertu-granted-priority-review-for-breast-cancer.html)
and Breakthrough Therapy Designation
(https://www.astrazeneca.com/media-centre/press-releases/2021/enhertu-granted-btd-for-breast-cancer.html)
of Enhertu in the US in this earlier setting.

 

Regulatory applications for Enhertu are currently under review in Europe,
Japan 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.

 

Notes

 

Financial considerations

Following this approval for Enhertu in the US, an amount of $100m is due from
AstraZeneca to Daiichi Sankyo as a 2nd-line milestone payment in HER2-positive
metastatic breast cancer. In AstraZeneca, the milestones paid will be
capitalised as an addition to the upfront payment made in 2019 and subsequent
capitalised milestones and amortised through the profit and loss.

 

Sales of Enhertu in the US are recognised by Daiichi Sankyo. AstraZeneca
reports its share of gross profit margin from Enhertu sales in the US as
collaboration revenue in the Company's financial statements. For further
details on the financial arrangements, please consult the collaboration
agreement from March 2019.

 

HER2-positive breast cancer

Breast cancer is the most common cancer and is one of the leading causes of
cancer-related deaths worldwide and in the US.(3,4) More than two million
patients with breast cancer were diagnosed in 2020, with nearly 685,000 deaths
globally.(3) More than 290,000 new cases are expected in the US in 2022, with
more than 43,000 deaths.(5) Approximately one in five cases of breast cancer
are considered HER2-positive.(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.(7) HER2 protein overexpression may occur as a result of
HER2 gene amplification and is often associated with aggressive disease and
poor prognosis in breast cancer.(8)

 

Despite initial treatment with trastuzumab and a taxane, patients with
HER2-positive metastatic breast cancer will often experience disease
progression.(9) More treatment options are needed to further delay progression
and extend survival.(9-11)

 

DESTINY-Breast03

DESTINY-Breast03 is a global, head-to-head, randomised, open-label,
registrational Phase III trial evaluating the efficacy and safety of
Enhertu (5.4mg/kg) versus T-DM1 in patients with HER2-positive unresectable
and/or metastatic breast cancer previously treated with trastuzumab and a
taxane.

 

The primary efficacy endpoint of DESTINY-Breast03 is progression-free survival
(PFS) based on blinded independent central review. Secondary efficacy
endpoints include overall survival, objective response rate (ORR), duration of
response, PFS based on investigator assessment and safety.

 

DESTINY-Breast03 enrolled approximately 500 patients at multiple sites in
Asia, Europe, North America, Oceania and South America. For more information
about the trial, visit ClinicalTrials.gov
(https://clinicaltrials.gov/ct2/show/NCT03529110) .

 

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 the US 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 also approved in approximately 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 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 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 was granted Breakthrough Therapy Designation 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, based on the results of
the DESTINY-Breast04 trial. Patients with hormone receptor (HR) positive
breast cancer should additionally have received or be ineligible for endocrine
therapy.

 

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, based on 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
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

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. Cortes J, et al. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for
Breast Cancer. N Engl J Med 2022; 386:1143-1154.

2. Referenced with permission from the NCCN Clinical Practice Guidelines in
Oncology (NCCN Guidelines(®)) for Breast Cancer V2.2022. © National
Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed May,
2022. To view the most recent and complete version of the guideline, go online
to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their
content, use or application and disclaims any responsibility for their
application or use in any way.

3. 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.

4. Centers for Disease Control and Prevention. Available at:
https://gis.cdc.gov/Cancer/USCS/#/AtAGlance/
(https://gis.cdc.gov/Cancer/USCS/#/AtAGlance/) . Accessed May 2022.

5. American Cancer Society. Cancer Facts & Figures 2022. Available at:
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2022/2022-cancer-facts-and-figures.pdf.
Accessed May 2022.

6. 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.

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

8. Pillai R, et al. HER2 mutations in lung adenocarcinomas: A report from the
Lung Cancer Mutation Consortium. Cancer. 2017;1;123(21):4099-4105.

9. Barok M, et al. Trastuzumab emtansine: mechanisms of action and drug
resistance. Breast Cancer Res. 2014; 16(2):209.

10. Mounsey L, et al. Changing Natural History of HER2-Positive Breast Cancer
Metastatic to the Brain in the Era of New Targeted Therapies. Clin Breast
Cancer. 2018;18(1):29-37.

11. Martínez-Sáez O, et al. Current and Future Management of HER2-Positive
Metastatic Breast Cancer. JCO Oncol Pract. 2021. 10.1200/OP.21.00172.

 

Adrian Kemp

Company Secretary

AstraZeneca PLC

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