RNS Number : 2205V
08 August 2022
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
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
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
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 w e are thrilled that we can now offer Enhertu to even
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(R) ) 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
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
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 i
mmunohistochemistry (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
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
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 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
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
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
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,
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 (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 .
For details on how to contact the Investor Relations Team,
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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(R) ) for Breast Cancer
V2.2022. (c) 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
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):
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:
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:
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:
Accessed August 2022.
Dr. Modi has financial interests related to AstraZeneca and
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August 08, 2022 02:10 ET (06:10 GMT)
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