29 April 2024
Enhertu
demonstrated
statistically significant and clinically meaningful improvement in
progression-free survival in HR-positive, HER2-low metastatic
breast cancer following one or more lines of endocrine therapy in
DESTINY-Breast06 Phase III trial
AstraZeneca and Daiichi
Sankyo's Enhertu also demonstrated
a clinically meaningful progression-free
survival improvement
in patients with HER2-ultralow
expression
Positive high-level results from the
DESTINY-Breast06 Phase III trial showed that Enhertu (trastuzumab deruxtecan)
demonstrated a statistically significant
and clinically meaningful improvement in progression-free survival
(PFS) compared to standard-of-care chemotherapy in the primary
trial population of patients with HR-positive,
HER2-low (IHC 1+ or 2+/ISH-) metastatic breast cancer following one
or more lines of endocrine therapy.
A statistically significant and
clinically meaningful improvement in PFS was also observed in the
overall trial population (patients with HER2-low and HER2-ultralow
[defined as IHC 0 with membrane staining; IHC >0<1+]
metastatic breast cancer). A prespecified subgroup
analysis showed the clinically meaningful
improvement was consistent between patients with HER2-low and
HER2-ultralow expression.
Overall survival (OS) data were not
mature at the time of the analysis; however, Enhertu showed an early trend towards
an OS improvement versus standard-of-care chemotherapy in patients
with HER2-low metastatic breast cancer and in the overall trial
population. The trial will continue as planned to further assess OS
and other secondary endpoints.
Susan Galbraith, Executive Vice
President, Oncology R&D, AstraZeneca, said:
"DESTINY-Breast06 shows that Enhertu could become a new standard of
care for patients with HER2-low and HER2-ultralow metastatic breast
cancer following one or more lines of endocrine therapy.
These data underscore the potential for treatment
with Enhertu across the
spectrum of HR-positive breast cancer, further redefining the
treatment of metastatic breast cancer."
Ken Takeshita, Global Head, R&D, Daiichi
Sankyo, said: "The topline results from DESTINY-Breast06 highlight
the importance of continuing to challenge current
treatment paradigms and established breast cancer
classifications to evolve how we treat patients with HR-positive,
HER2-expressing metastatic breast cancer. Building
on the practice-changing data seen in DESTINY-Breast04, these
results reinforce the potential for use of Enhertu earlier in the treatment
landscape and in an even broader patient
population."
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.
It is estimated that approximately 60-65% of
HR-positive, HER2-negative breast cancers are HER2-low and
potentially an additional 25% may be
HER2-ultralow.1,2 Endocrine therapies
are widely used in the early lines of treatment for
HR-positive metastatic breast cancer; however after two lines of treatment, further efficacy from
endocrine therapy is often limited.3
The current
standard of care following endocrine therapy is chemotherapy, which
is associated with poor response rates and
outcomes.3-6
The safety profile of Enhertu was consistent with previous
breast cancer clinical trials with no new safety signals
identified.
The data will be presented at a forthcoming
medical meeting and shared with global regulatory
authorities.
Notes
DESTINY-Breast06
DESTINY-Breast06 is a global, randomised,
open-label, Phase III trial evaluating the efficacy and safety of
Enhertu (5.4 mg/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 (defined as IHC 0
with membrane staining; IHC >0<1+)
advanced or metastatic breast cancer. Patients in the trial had no
prior chemotherapy for advanced or metastatic disease and
either experienced disease progression within 6 months
of starting 1st-line treatment with an endocrine therapy combined
with a CDK4/6 inhibitor or received at
least two previous lines of endocrine therapies in the
metastatic setting.
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 OS in
patients with HER2-low expression and PFS by BICR and OS in the
overall trial population (HER2-low and HER2-ultralow). Other
secondary endpoints include objective response rate, duration of
response, time to first subsequent treatment or death, time to
second subsequent treatment or death and safety. Analysis of the
HER2-ultralow subgroup was not powered to demonstrate statistical
significance.
DESTINY-Breast06 enrolled 866 patients (n=713
for HER2-low and n=153 for HER2-ultralow) at multiple sites in
Asia, Europe, North America and South America. For more information
about the trial, visit ClinicalTrials.gov.
Breast cancer
and HER2 expression
Breast cancer is the second most common cancer
and one of the leading causes of cancer-related deaths
worldwide.7 More than two million breast cancer cases
were diagnosed in 2022 with more than 665,000 deaths
globally.7 While survival rates are high for those
diagnosed with early breast cancer, only approximately 30% of
patients who are diagnosed with or progress to metastatic disease
are expected to live five years after their
diagnosis.8
HR-positive, HER2-negative is the most common
breast cancer subtype, accounting for approximately 70% of all
breast cancers.8 HER2 is a tyrosine kinase receptor
growth-promoting protein expressed on the surface of many types of
tumours, including breast cancer.9 Patients with high
levels of HER2 expression (IHC 3+ or 2+/ISH+) are classified as
HER2-positive and treated with HER2-targeted therapies,
representing approximately 15-20% of all breast cancers.10 Historically, tumours that were not classified
as HER2-positive were classified as HER2-negative; however, many of
these tumours still carry some level of HER2
expression.11 It is estimated that approximately 60-65%
of HR-positive, HER2-negative breast cancers are HER2-low and
potentially an additional 25% may be
HER2-ultralow.1,2
Prior to the approval of Enhertu in HER2-low metastatic breast
cancer post chemotherapy based on the DESTINY-Breast04 trial, there
were no targeted therapies approved specifically for patients with
HER2-low expression.12 There are no targeted therapies
specifically approved for patients with HER2-ultralow
expression.
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 (5.4
mg/kg) is approved in more than 60 countries for the
treatment of adult patients with unresectable or metastatic
HER2-positive (IHC 3+ or 2+/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 (5.4 mg/kg)
is approved in more than 60 countries for the treatment of adult
patients with unresectable or metastatic HER2-low (IHC 1+ or
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 more than 35 countries for
the treatment of adult patients with unresectable or metastatic
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 trial. Continued approval in the US for this
indication may be contingent upon verification and description of
clinical benefit in a confirmatory trial.
Enhertu (6.4 mg/kg)
is approved in more than 40 countries 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
and/or DESTINY-Gastric02
trials.
Enhertu (5.4 mg/kg)
is approved in the US for the treatment of adult patients with
unresectable or metastatic HER2-positive (IHC 3+) solid tumours who
have received prior systemic treatment and who have no satisfactory
alternative treatment options based on results from the DESTINY-PanTumor02,
DESTINY-Lung01
and DESTINY-CRC02
trials.
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 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 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.
With Enhertu (trastuzumab deruxtecan), a
HER2-directed antibody drug conjugate (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 and Zoladex (goserelin) and aims to
reshape the HR-positive space with first-in-class AKT inhibitor,
Truqap, and
next-generation SERD and potential new medicine camizestrant.
AstraZeneca is also collaborating with Daiichi Sankyo to explore
the potential of TROP2-directed ADC, datopotamab deruxtecan, 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
datopotamab deruxtecan 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 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 social media @AstraZeneca.
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References
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Clinical and molecular characteristics of HER2-low-positive breast
cancer: pooled analysis of individual patient data from four
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2. Chen Z, et al. Is
HER2 ultra‑low
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3. Manohar P, et al.
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Accessed April 2024
9. Iqbal N, et al. Human
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12. Modi S, et al. Trastuzumab
Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer.
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2022;387:9-20.
Adrian Kemp
Company
Secretary
AstraZeneca
PLC