TIDMAZN
RNS Number : 9426S
AstraZeneca PLC
19 July 2022
19 July 2022 07:00 BST
Enhertu approved in the EU for patients with HER2-positive
metastatic breast cancer treated with one or more prior
anti-HER2-based regimens
Approval broadens indication for AstraZeneca and Daiichi
Sankyo's Enhertu across Europe to earlier use in HER2-positive
metastatic breast cancer
Based on ground-breaking DESTINY-Breast03 results in which
Enhertu demonstrated a 72% reduction in the risk of disease
progression or death vs. trastuzumab emtansine (T-DM1)
AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab
deruxtecan) has been approved in the European Union (EU) as a
monotherapy for the treatment of adult patients with unresectable
or metastatic HER2-positive breast cancer who have received one or
more prior anti-HER2-based regimens.
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 European Commission (EC) follows the
positive opinion of the Committee for Medicinal Products for Human
Use and is based on results from the DESTINY-Breast03 Phase III
trial, which were published in The New England Journal of Medicine
.(1) In the trial, 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<0.000001)
in patients with HER2-positive unresectable and/or metastatic
breast cancer previously treated with trastuzumab and a taxane.
In Europe, more than 530,000 patients are diagnosed with breast
cancer each year.(2) Approximately one in five patients with breast
cancer are considered HER2-positive.(3) Despite initial treatment
with trastuzumab, pertuzumab and a taxane, patients with
HER2-positive metastatic breast cancer will often experience
disease progression.(4,5)
Javier Cortés, MD, PhD, Head, International Breast Cancer Center
(IBCC), Barcelona, Spain, said: "This approval is an important
milestone for patients and clinicians in Europe, since previously
treated patients with HER2-positive metastatic breast cancer
typically experience disease progression in less than a year with
historical standard of care treatment. In the DESTINY-Breast03
trial, the time to progression was extended well beyond a year for
patients receiving Enhertu, illustrating the potential for this
medicine to set a new benchmark in the treatment of HER2-positive
metastatic breast cancer."
Dave Fredrickson, Executive Vice President, Oncology Business
Unit, AstraZeneca , said: "With this approval, patients across
Europe with HER2-positive metastatic breast cancer will have the
opportunity to be treated with Enhertu even earlier in the
treatment of their disease, improving their chance for better
outcomes beyond what we can already offer patients treated in
later-line settings. Today's news is a further step in achieving
our vision to continuously bring the transformative potential of
Enhertu to patients as early as possible in their treatment to
improve cancer outcomes."
Ken Keller, Global Head of Oncology Business, and President and
CEO, Daiichi Sankyo, Inc., said: "We believe there is a significant
need to transform outcomes for patients with HER2-positive
metastatic breast cancer in Europe. In DESTINY-Breast03, treatment
with Enhertu demonstrated superior progression-free survival and a
doubling of the response rate compared to another HER2-directed
ADC. With this approval we are now able to offer patients with
HER2-positive metastatic breast cancer another option earlier in
their treatment."
Additional results from the DESTINY-Breast03 Phase III trial
showed that in the secondary endpoint of overall survival (OS),
there was a strong trend towards improved OS with Enhertu (HR 0.55;
95% CI 0.36-0.86), however this analysis is not yet mature and
further follow-up is ongoing. Nearly all patients (96.1%) treated
with Enhertu were alive at nine months compared to 91.3% of
patients treated with T-DM1. Confirmed objective response rate
(ORR) was more than doubled in the Enhertu arm versus the T-DM1 arm
(79.7% vs. 34.2%).
The safety of Enhertu has been evaluated in a pooled analysis of
573 patients across multiple tumour types who had received at least
one dose of Enhertu (5.4 mg/kg) in clinical trials. The most common
adverse reactions were nausea (77.0%), fatigue (57.2%), vomiting
(46.8%), alopecia (38.0%) and neutropenia (34.6%). Cases of
interstitial lung disease (ILD) or pneumonitis were reported in
12.0% of patients. Most ILD cases were Grade 1 (2.6%) and Grade 2
(7.3%). Grade 3 cases occurred in 0.7% of patients, no Grade 4
cases occurred, and Grade 5 cases occurred in 1.4% of patients.
Based on the results of DESTINY-Breast03, the European Society
for Medical Oncology Clinical Practice Guidelines were updated in
October 2021 to recommend Enhertu for use as the preferred
second-line therapy for patients with HER2-positive metastatic
breast cancer following progression with a taxane and
trastuzumab.(6)
As part of this approval, the EC has also extended the market
protection period for Enhertu in this setting by one extra year
based on the significant clinical benefit compared to existing
approved therapies.
Notes
Financial considerations
Following EU approval, an amount of $75m is due from AstraZeneca
to Daiichi Sankyo as a milestone payment in 2nd-line HER2-positive
metastatic breast cancer. The milestone will be capitalised as an
addition to the upfront payment made by AstraZeneca to Daiichi
Sankyo in 2019 and subsequent capitalised milestones, and will be
amortised through the profit and loss statement.
Sales of Enhertu in most EU territories are recognised by
Daiichi Sankyo. AstraZeneca reports its share of gross profit
margin from Enhertu sales in those territories as collaboration
revenue in the Company's financial statements. AstraZeneca will
record product sales in respect of sales made in territories where
AstraZeneca is the selling party.
Further details on the financial arrangements were set out in
the March 2019 announcement of the collaboration.
HER2-positive breast cancer
Breast cancer is the most common cancer and is one of the
leading causes of cancer-related deaths worldwide.(7) More than two
million patients were diagnosed with breast cancer in 2020, with
nearly 685,000 deaths globally.(7) In Europe, more than 530,000
patients are diagnosed with breast cancer each year.(2)
Approximately one in five patients with breast cancer are
considered HER2-positive.(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.(8) 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.(9)
Despite initial treatment with trastuzumab, pertuzumab and a
taxane, patients with HER2-positive metastatic breast cancer will
often experience disease progression.(4,5) More treatment options
are needed to further delay progression and extend
survival.(4,10,11)
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 PFS based
on blinded independent central review. OS is a key secondary
efficacy outcome measure. Secondary efficacy endpoints include ORR,
duration of response and PFS based on investigator assessment.
DESTINY-Breast03 enrolled 524 patients at multiple sites in
Asia, Europe, North America, Oceania and South America. Results
from DESTINY-Breast03 have been published in The New England
Journal of Medicine .(1) For more information about the trial,
visit ClinicalTrials.gov .
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 (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 (5.4mg/kg) is also 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 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 under review in Europe for the treatment of adult
patients with unresectable or metastatic HER2-low (
immunohistochemistry (IHC) 1+ or IHC 2+/ in-situ hybridisation (
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 from the DESTINY-Breast04 trial. Patients with
hormone receptor (HR) positive breast cancer must 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 results of 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.
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 HR-positive breast cancer
should additionally have received or be ineligible for endocrine
therapy.
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 initial approvals 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 and follow the
Company on Twitter @AstraZeneca .
Contacts
For details on how to contact the Investor Relations Team,
please click here . For Media contacts, click here .
References
1. Cortes J, et al. Trastuzumab Deruxtecan versus Trastuzumab
Emtansine for Breast Cancer. N Engl J Med. 2022; 386:1143-1154.
2. Globocan 2020. Europe Fact Sheets. Available at: https://gco.iarc.fr/today/data/factsheets/populations/908-europe-fact-sheets.pdf . Last accessed: July 2022.
3. 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.
4. Barok M, et al. Trastuzumab emtansine: mechanism of action
and drug resistance. Breast Cancer Res. 2014; 16(2):209.
5. Nader-Marta G, et al. How we treat patients with metastatic
HER2-positive breast cancer. ESMO Open. 2022; 7:1.
6. Gennari A, et al. ESMO Clinical Practice Guideline for the
diagnosis, staging and treatment of patients with metastatic breast
cancer. Available at:
https://www.annalsofoncology.org/article/S0923-7534(21)04498-7/pdf.
Last accessed: July 2022.
7. 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.
8. Iqbal N, et al. Human Epidermal Growth Factor Receptor 2
(HER2) in Cancers: Overexpression and Therapeutic Implications. Mol
Biol Int. 2014;852748.
9. Pillai R, et al. HER2 mutations in lung adenocarcinomas: A
report from the Lung Cancer Mutation Consortium. Cancer.
2017;1;123(21):4099-4105.
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. Martinez-S 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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