a2207v
FORM 6-K
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
Report
of Foreign Issuer
Pursuant
to Rule 13a-16 or 15d-16 of
the
Securities Exchange Act of 1934
For the
month of August 2022
Commission
File Number: 001-11960
AstraZeneca PLC
1
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AstraZeneca PLC
INDEX
TO EXHIBITS
1.
Enhertu approved in the US for HER2-low mBC
08 August 2022 07:00 BST
Enhertu approved
in the US as the first HER2-directed therapy for patients with
HER2-low metastatic breast cancer
Based on DESTINY-Breast04 results which showed AstraZeneca and
Daiichi Sankyo's Enhertu reduced risk of disease progression or
death by 50% and
increased overall survival by more than six months versus
chemotherapy
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-low (IHC 1+ or IHC 2+/ISH-) breast
cancer who have received a 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 approval by the Food and Drug Administration (FDA) was based on
the results from the DESTINY-Breast04 Phase
III trial. In the
trial, Enhertu reduced
the risk of disease progression or death by 50% versus physician's
choice of chemotherapy in patients with HER2-low metastatic breast
cancer with hormone receptor (HR)-positive disease or HR-negative
disease (median progression-free survival [PFS] 9.9 versus 5.1
months; hazard ratio [HR]
0.50; 95% confidence interval [CI] 0.40-0.63;
p<0.0001). A median overall
survival (OS) of 23.4 months was seen in patients treated
with Enhertu versus
16.8 months in those treated with chemotherapy, a 36% reduction in
the risk of death (HR 0.64; 95% CI 0.49-0.84;
p=0.001).
Shanu Modi, MD, Medical Oncologist, Memorial Sloan Kettering Cancer
Center, US, said: "Approximately half of all patients with
breast cancer have tumours that are HER2-low, which have previously
been classified as HER2-negative and have not had effective
treatment options with HER2-targeted medicines. Based on the
promising results of the DESTINY-Breast04 trial, clinicians are
starting to differentiate levels of HER2 expression and redefine
how metastatic breast cancer is classified with a distinct HER2-low
patient population that may be eligible for trastuzumab
deruxtecan."
Dave Fredrickson, Executive Vice President, Oncology Business Unit,
AstraZeneca, said: "The rapid approval of Enhertu in HER2-low metastatic breast cancer by the
FDA underscores the urgency to bring this transformational medicine
to patients as quickly as possible. Patients with HER2-low tumours,
who are identified through existing HER2 testing methods, will now
have the opportunity to be treated based upon their HER2
status."
Ken Keller, Global Head of Oncology Business and President and CEO,
Daiichi Sankyo, Inc, said: "Today's FDA approval marks a monumental
moment in breast cancer treatment as Enhertu is the first-ever HER2-directed
medicine to be approved for the treatment of patients with HER2-low
metastatic breast cancer. With the ground-breaking survival
benefit seen in the DESTINY-Breast04 trial, this milestone
confirms the importance of targeting lower levels of HER2
expression in the treatment of metastatic breast cancer and we are
thrilled that we can now
offer Enhertu to
even more patients."
The approval was granted under the FDA's Real-Time Oncology Review
programme after securing Priority
Review and Breakthrough Therapy
Designation of Enhertu in the US in this setting. The expanded
approval for Enhertu in the US, following its previous approval
in 2nd-line HER2-positive metastatic breast cancer, enables its use
across a wide spectrum of HER2-expressing breast cancer, including
patients with HER2-low disease.
The DESTINY-Breast04 Phase III trial results were presented at the
presidential plenary session of the 2022 American Society of
Clinical Oncology Annual meeting and simultaneously
published in The
New England Journal of Medicine (NEJM).1
The safety profile
of Enhertu was consistent with previous clinical trials
with no new safety concerns identified. Interstitial lung disease
(ILD) or pneumonitis rates were consistent with those observed in
late-line HER2-positive breast cancer trials
of Enhertu. Overall, 12% of patients had confirmed ILD or
pneumonitis related to treatment as determined by an independent
adjudication committee. The majority of ILD events were Grade 1 or
2 (10%), with five Grade 3 (1.3%) and no Grade 4 events
reported. There were three (0.8%) ILD-related deaths (Grade
5).
In June 2022, fam-trastuzumab
deruxtecan-nxki (Enhertu) was added to the NCCN Clinical Practical
Guidelines in Oncology (NCCN Guidelines®)
as the Category 1 preferred regimen for patients with tumours that
are HER2 IHC 1+ or 2+ and ISH- who have received at least one
prior line of chemotherapy for metastatic disease and, if tumour is
HR-positive, are refractory to endocrine therapy, based on the data
from DESTINY-Breast04.2
The US regulatory submission for DESTINY-Breast04 was reviewed
under Project Orbis, which provides a framework for concurrent
submission and review of oncology medicines among participating
international partners. As part of Project
Orbis, Enhertu is also under regulatory review for the same
indication by the Australian Therapeutic Goods Administration, the
Brazilian Health Regulatory Agency (ANVISA), Health Canada and
Switzerland's Swissmedic.
Regulatory applications for Enhertu are also currently under review in Europe,
Japan and several other countries based on the DESTINY-Breast04
results.
Notes
Financial considerations
Following this approval for Enhertu in the US, an amount of $200m is due from
AstraZeneca to Daiichi Sankyo as a milestone payment for the
HER2-low breast cancer post chemotherapy indication. 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 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.
Further details on the financial arrangements were set out in
the March 2019
announcement of the
collaboration.
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.3,4 More
than two million patients with breast cancer were diagnosed in 2020
resulting in nearly 685,000 deaths
globally.3 In
the US, more than 290,000 patients are expected to be diagnosed in
2022, resulting in more than 43,000 deaths.5
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.6
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.6,7 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-.6 However,
approximately half of all breast cancers are HER2-low, defined as
an HER2 score of IHC 1+ or IHC 2+/ISH-.8-10 HER2-low
occurs in both HR-positive and HR-negative
disease.11
Previously, patients with HR-positive metastatic breast cancer and
HER2-low disease had limited effective treatment options following
progression on endocrine (hormone) therapy.9,12 Additionally,
few targeted options were available for those with HR-negative
disease.13 Now
with the approval of Enhertu, patients with HER2-low tumours may be eligible
for HER2-directed therapy.
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 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 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.
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
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 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 chemotherapy 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.
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 in breast, gastric and non-small cell lung
cancer are currently under review in several other countries based
on the DESTINY-Breast01, DESTINY-Breast03, DESTINY-Breast04,
DESTINY-Gastric01, DESTINY-Gastric02 and DESTINY-Lung01 trials,
respectively.
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 the manufacturing and supply
of Enhertu and datopotamab
deruxtecan.
AstraZeneca in breast cancer
Driven by a growing understanding of breast cancer biology,
AstraZeneca is challenging and redefining the current clinical
paradigm for how breast cancer is classified and treated to deliver
even more 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. Modi S, et al. Trastuzumab
Deruxtecan in Previously Treated HER2-Low Advanced Breast
Cancer. N Engl J
Med. 2022;
387:9-20.
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 August 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/. Accessed August
2022.
5.
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.
Accessed August 2022.
6. Iqbal N, et al. Human
Epidermal Growth Factor Receptor 2 (HER2) in Cancers:
Overexpression and Therapeutic
Implications. Mol Biol
Int. 2014;
852748.
7.
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.
8. 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.
9. 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.
10. 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.
11. 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.
12. Matutino A, et
al. Current
Oncology. Hormone
receptor-positive, HER2-negative metastatic breast cancer:
redrawing the lines. 2018; 25(S1):S131-S141.
13.
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 August 2022.
Dr. Modi has financial interests related to AstraZeneca and Daiichi
Sankyo.
Adrian Kemp
Company Secretary
AstraZeneca PLC
SIGNATURES
Pursuant
to the requirements of the Securities Exchange Act of 1934, the
Registrant has duly caused this report to be signed on its behalf
by the undersigned, thereunto duly authorized.
Date:
8 August
2022
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By: /s/
Adrian Kemp
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|
Name:
Adrian Kemp
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|
Title:
Company Secretary
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