28 January
2025
Enhertu
approved in the US as first
HER2-directed therapy for patients with HER2-low or HER2-ultralow
metastatic breast cancer following disease progression after one or
more endocrine therapies
Based on DESTINY-Breast06 Phase III trial
results which showed Enhertu demonstrated superiority vs. chemotherapy with a median
progression-free survival of more than one year
Approval brings AstraZeneca and Daiichi
Sankyo's Enhertu to an earlier HR-positive treatment setting and
broadens the patient population eligible for treatment with a
HER2-directed therapy to those with HER2-ultralow
disease
AstraZeneca and
Daiichi Sankyo's Enhertu
(trastuzumab deruxtecan) has
been approved in the US for the treatment of
adult patients with unresectable
or metastatic hormone receptor (HR)-positive, HER2-low (IHC 1+
or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane
staining) breast cancer, as determined by a Food and Drug
Administration (FDA)-approved test, that has progressed on one or
more endocrine therapies in the metastatic setting.
The approval was
granted by the FDA after securing Priority Review and Breakthrough
Therapy Designation and was based on results from the
DESTINY-Breast06 Phase III trial, which were presented at the 2024
American Society of Clinical Oncology (ASCO) Meeting and published
in The New England Journal of
Medicine.
Aditya Bardia,
MD,
MPH, Program
Director of
Breast Oncology and Director of
Translational
Research Integration, UCLA Health Jonsson Comprehensive Cancer Center, US, and
investigator in the DESTINY-Breast06 trial, said: "Endocrine
therapy is typically used in the initial treatment of HR-positive
metastatic breast cancer and following progression, subsequent
chemotherapy is associated with poor outcomes. With a median progression-free
survival exceeding one year and a response rate of more than 60 per
cent, trastuzumab deruxtecan offers a potential new standard of
care for
patients with HR-positive, HER2-low or HER2-ultralow
metastatic breast cancer following endocrine
therapy."
Dave Fredrickson,
Executive Vice President, Oncology Haematology Business Unit,
AstraZeneca, said: "Building on the practice-changing
previous approvals for Enhertu,
this new approval brings this
important medicine to an earlier treatment setting and a broader
patient population with HER2-expressing metastatic breast cancer.
The approval also highlights the importance of testing
metastatic breast cancer tumours for detectable staining with a
standard IHC test to identify those who may be eligible for
treatment with Enhertu following
endocrine therapy."
Ken Keller, Global
Head of Oncology Business, and President and CEO, Daiichi Sankyo,
said: "Enhertu
continues to redefine the
classification and treatment of HR-positive metastatic breast
cancer with important new data across the spectrum of HER2
expression. Today's approval underscores our ongoing commitment to
realising the full potential of this innovative antibody drug
conjugate and represents another paradigm shift in how certain breast cancers can
be treated."
Krissa Smith, Vice
President, Education, Susan G. Komen, said: "We are excited to see
more treatment options for these patients which enable more
personalised care. It is critical for patients to understand the
HER2 status of their metastatic breast cancer to help them make
informed treatment decisions. Patients with tumours that are
HER2-low or HER2-ultralow now have more options to consider with
their healthcare team."
In the
trial, Enhertu
showed a 36% reduction in the
risk of disease progression or death versus chemotherapy (hazard
ratio [HR] 0.64; 95% confidence interval [CI]: 0.54-0.76;
p<0.0001) in the overall trial population of patients with
chemotherapy-naïve HER2-low or HER2-ultralow metastatic breast
cancer. A median progression-free survival (PFS) of 13.2 months was
seen in patients randomised to Enhertu
compared to 8.1 months in those
randomised to chemotherapy. The confirmed objective response rate
(ORR) in the overall trial population was 62.6% for
Enhertu
versus 34.4% for
chemotherapy.
In an exploratory
analysis of patients with HER2-ultralow expression, results
were seen to be consistent between patients with HER2-low
expression and HER2-ultralow expression.
HER2
status in the trial was confirmed by a central laboratory and was
performed on a tumour sample obtained at the time of initial
metastatic diagnosis or later. Approximately 85-90% of patients
with HR-positive, HER2-negative metastatic breast cancer
were determined to have actionable levels of
HER2-expression.1 Further, nearly two-thirds of patients
previously assessed as IHC 0 at a local laboratory were classified
as HER2-low or HER2-ultralow upon central analysis of the tumour
sample.1
The safety profile
of Enhertu in
DESTINY-Breast06 was consistent with previous clinical trials
of Enhertu in
breast cancer with no new safety concerns identified.
Enhertu is
a specifically engineered HER2-directed DXd antibody drug conjugate
(ADC) discovered by Daiichi Sankyo and being jointly developed and
commercialised by AstraZeneca and Daiichi Sankyo.
Enhertu is
already approved in more than 70 countries, including the US, for
patients with HER2-low metastatic 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. Regulatory applications are under review in
the EU, Japan and several other countries based on the
DESTINY-Breast06 results.
Financial
considerations
Following this approval
for Enhertu in
the US, an
amount of $175m is due from AstraZeneca to Daiichi Sankyo as a
milestone payment for the HER2-low and HER2-ultralow
chemotherapy-naïve breast cancer 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 Alliance Revenue in the Company's financial
statements.
Further
details on the financial arrangements were set out in
the March
2019 announcement of the collaboration.
Notes
Breast cancer and HER2
expression
Breast cancer is the second most common
cancer and one of the leading causes of cancer-related deaths
worldwide.2 More than two million breast cancer
cases were diagnosed in 2022 with more than 665,000 deaths
globally.2 In the US, more than 300,000 cases of breast
cancer are diagnosed annually.3 While survival rates are high for
those diagnosed with early breast cancer, only about 30% of
patients diagnosed with or who progress to metastatic disease are
expected to live five years following
diagnosis.4
HER2 is
a tyrosine kinase receptor growth-promoting protein expressed on
the surface of many types of tumours, including breast
cancer.5 Patients with high levels of HER2
expression (IHC 3+ or 2+/ISH+) are classified as HER2-positive and
treated with HER2-directed therapies, representing approximately
15-20% of all breast cancers.6 Historically,
tumours that were not classified as HER2-positive were classified
as HER2-negative.7
HR-positive, HER2-negative is the most
common breast cancer subtype, accounting for approximately 70% of
all breast cancers.4 Endocrine therapies are widely
given consecutively in the early lines of treatment for HR-positive
metastatic breast cancer. However, after initial treatment, further
efficacy from endocrine therapy is often
limited.8 The current standard of care following
endocrine therapy is chemotherapy, which is associated with poor
response rates and outcomes.8-11
Despite being classified as HER2-negative,
many of these tumours may still carry some level of HER2
expression.7 Prior to the approvals of
Enhertu
in HER2-low or HER2-ultralow
metastatic breast cancer based on the DESTINY-Breast04 and
DESTINY-Breast06 trials, there were no targeted therapies
specifically approved for these patient
populations.12,13
DESTINY-Breast06
DESTINY-Breast06 is a global, randomised,
open-label, Phase III trial evaluating the efficacy and safety
of Enhertu (5.4mg/kg)
versus investigator's choice of chemotherapy (capecitabine,
paclitaxel or nab-paclitaxel) in patients with HR-positive,
HER2-low (IHC 1+ or 2+/ISH-) or HER2-ultralow (IHC 0 with membrane
staining) advanced or metastatic breast cancer. Patients in the
trial had no prior chemotherapy for advanced or metastatic disease
and received at least two lines of prior endocrine therapy in the
metastatic setting. Patients were also eligible if they had
received one prior line of endocrine therapy combined with a CDK4/6
inhibitor in the metastatic setting and experienced disease
progression within six months of starting 1st-line treatment or
received endocrine therapy as an adjuvant treatment and experienced
disease recurrence within 24 months.
The
primary endpoint is PFS in the HR-positive, HER2-low patient
population as measured by blinded independent central review
(BICR). Key secondary endpoints include PFS by BICR in the overall
trial population (HER2-low and HER2-ultralow), overall survival
(OS) in the HER2-low patient population and OS in the overall trial
population. Other secondary endpoints include ORR, duration of
response, time to first subsequent treatment or death, time to
second subsequent treatment or death and safety.
DESTINY-Breast06 enrolled 866 patients
(n=713 for HER2-low and n=153 for HER2-ultralow) in Asia, Europe,
Australia, North America and South 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 number of topoisomerase
I inhibitor payloads (an exatecan derivative, DXd) via
tetrapeptide-based cleavable linkers.
Enhertu (5.4mg/kg) is approved in more
than 75 countries worldwide for the treatment of adult patients
with unresectable or metastatic HER2-positive (immunohistochemistry
[IHC 3+ or in-situ hybridisation [ISH]+) 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 more
than 75 countries worldwide 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 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.
Enhertu
(5.4 mg/kg) is approved in the
US for adult
patients with unresectable or metastatic HR-positive, HER2-low
(IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with
membrane staining) breast cancer, as determined by an FDA-approved
test, that has progressed on one or more endocrine therapies in the
metastatic setting based on the results from the DESTINY-Breast06
trial.
Enhertu (5.4mg/kg) is
approved in more than 50 countries worldwide for the treatment of
adult patients with unresectable or metastatic non-small cell lung
cancer (NSCLC) whose tumours have
activating HER2 (ERBB2) mutations, as detected by a locally or
regionally approved test, and who have received a prior systemic
therapy based on the results from the
DESTINY-Lung02 and/or DESTINY-Lung05 trials. Continued approval in
China and the US for this indication may be contingent upon
verification and description of clinical benefit in a confirmatory
trial.
Enhertu (6.4mg/kg) is approved in more
than 65 countries worldwide for the treatment of adult patients
with locally advanced or metastatic HER2-positive (IHC 3+ or
2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma
who have received a prior trastuzumab-based regimen based on the
results from the DESTINY-Gastric01, DESTINY-Gastric02 and/or DESTINY-Gastric06 trials. Continued approval in
China for this indication will depend on whether a randomised
controlled confirmatory clinical trial can demonstrate clinical
benefit in this population.
Enhertu (5.4mg/kg) is approved in the
US, Russia, Israel and Brazil for the treatment of adult patients
with unresectable or metastatic HER2-positive (IHC 3+) solid
tumours who have received prior systemic treatment and have no
satisfactory alternative treatment options based on the results
from the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02 trials. Continued approval for
this indication in the US may be contingent upon verification and
description of clinical benefit in a confirmatory trial.
Enhertu development
programme
A comprehensive global clinical development
programme is underway evaluating the efficacy and safety
of Enhertu monotherapy
across multiple HER2-targetable cancers. Trials in combination with
other anti-cancer treatments, such as immunotherapy, also are
underway.
Daiichi Sankyo collaboration
AstraZeneca and
Daiichi Sankyo entered into a global collaboration to jointly
develop and commercialise Enhertu in
March 2019 and Datroway
(datopotamab deruxtecan)
in July
2020, except in Japan where Daiichi Sankyo
maintains exclusive rights for each ADC. Daiichi Sankyo is
responsible for the manufacturing and supply
of Enhertu and
Datroway.
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.
With Enhertu,
a HER2-directed ADC, AstraZeneca and Daiichi Sankyo are aiming to
improve outcomes in previously treated HER2-positive and HER2-low
metastatic breast cancer and are exploring its potential in earlier
lines of treatment and in new breast cancer settings.
In HR-positive
breast cancer, AstraZeneca continues to improve outcomes with
foundational medicines Faslodex
(fulvestrant) and Zoladex (goserelin)
and aims to reshape the HR-positive space with first-in-class AKT
inhibitor, Truqap
(capivasertib), and
next-generation SERD and potential new medicine camizestrant.
AstraZeneca is also collaborating with Daiichi Sankyo to explore
the potential of TROP2-directed ADC, Datroway,
in this setting.
PARP
inhibitor Lynparza (olaparib)
is a targeted treatment option that has been studied in 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
these settings and to explore its potential in earlier
disease.
To bring
much-needed treatment options to patients with triple-negative
breast cancer, an aggressive form of breast cancer, AstraZeneca is
evaluating the potential of Datroway
alone and in combination with
immunotherapy Imfinzi (durvalumab), Truqap in
combination with chemotherapy, and Imfinzi
in combination with other
oncology medicines, including Lynparza and Enhertu.
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's innovative
medicines are sold in more than 125 countries and used by millions
of patients worldwide. Please visit astrazeneca.com and follow the Company on social
media @AstraZeneca.
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References
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https://www.cancer.org/cancer/types/breast-cancer/about/how-common-is-breast-cancer.html. Accessed January 2025.
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Adrian
Kemp
Company
Secretary
AstraZeneca PLC