REG - AstraZeneca PLC - Enhertu recommended in EU in post-ET breast cancer

AstraZenecaAnnouncement

28/02/2025 13:00

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RNS Number : 9298Y  AstraZeneca PLC  28 February 2025

28 February 2025

 

Enhertu recommended for approval in the EU by CHMP for patients with HER2-low
or HER2-ultralow metastatic breast cancer following at least one endocrine
therapy

Recommendation 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

AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) has been
recommended for approval in the European Union (EU) as a monotherapy for the
treatment of adult patients with unresectable or metastatic hormone receptor
(HR)-positive, HER2-low or HER2-ultralow breast cancer who have received at
least one endocrine therapy in the metastatic setting and who are not
considered suitable for endocrine therapy as the next line of treatment.

 

The Committee for Medicinal Products for Human Use (CHMP) of the European
Medicines Agency (EMA) based its positive opinion on the 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 (http://www.nejm.org) .

 

In the trial, Enhertu showed a 38% reduction in the risk of disease
progression or death versus chemotherapy (hazard ratio  HR  0.62; confidence
interval  CI  0.52-0.75; p<0.0001) in patients with chemotherapy-naïve
HR-positive, HER2-low metastatic breast cancer with a median progression-free
survival (PFS) of 13.2 months versus 8.1 months.

 

In the overall trial population (patients with HER2-low or HER2-ultralow
metastatic breast cancer), the median PFS was 13.2 months in patients
randomised to Enhertu compared to 8.1 months in those randomised to
chemotherapy (HR 0.64; 95% CI 0.54-0.76; p<0.0001). In an exploratory
analysis, results were seen to be consistent between patients with HER2-low
expression and HER2-ultralow expression.

 

Susan Galbraith, Executive Vice President, Oncology Haematology R&D,
AstraZeneca, said: "Endocrine therapy is typically used in the initial
treatment of HR-positive metastatic breast cancer but as the disease
progresses the benefit of continued endocrine therapy is limited, and
subsequent standard-of-care chemotherapy is associated with poor outcomes.
Enhertu has the potential to be the first HER2-directed treatment for patients
in the EU with HR-positive, HER2-low or HER2-ultralow metastatic breast cancer
directly following endocrine therapy, which would mark an important shift in
how patients in this setting are treated."

 

Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: "Enhertu is the
first HER2-directed treatment and antibody drug conjugate to show a
progression-free survival of more than one year in patients with HER2-low or
HER2-ultralow metastatic breast cancer following endocrine therapy. The CHMP
recommendation is encouraging and supports our goal of further developing and
advancing the way breast cancer is classified and treated."

 

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 be HER2-low or
HER2-ultralow.(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 was recently approved in the US
(https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-approved-in-us-for-breast-cancer-post-et.html)
for patients with HR-positive, HER2-low or HER2-ultralow metastatic breast
cancer that has progressed on one or more endocrine therapies in the
metastatic setting. In addition to the EU, regulatory applications are under
review in Japan and several other countries based on the DESTINY-Breast06
results.

 

Enhertu is already approved in more than 75 countries, including the EU, for
patients with HER2-low metastatic breast cancer who have received 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.

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
Europe, approximately 557,000 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) In the DESTINY-Breast06 trial,
approximately 85-90% of patients with HR-positive, HER2-negative metastatic
breast cancer were determined to be HER2-low or HER2-ultralow.(1)

 

Prior to the approval of Enhertu in HER2-low metastatic breast cancer based
on the DESTINY-Breast04 trial, there were no targeted therapies specifically
approved for patients with HER2-low expression. There are no targeted
therapies specifically approved in the EU for patients with HER2-ultralow
expression.(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
objective response rate, 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
(https://clinicaltrials.gov/study/NCT04494425) .

 

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
(https://clinicaltrials.gov/ct2/show/NCT03529110)  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 (https://clinicaltrials.gov/ct2/show/NCT03734029)
 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
(https://clinicaltrials.gov/study/NCT04494425) 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
(https://www.clinicaltrials.gov/study/NCT04644237?term=DESTINY-Lung02&rank=1)
 and/or DESTINY-Lung05 (https://clinicaltrials.gov/study/NCT05246514)
 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 (https://clinicaltrials.gov/ct2/show/NCT03329690)
, DESTINY-Gastric02 (https://clinicaltrials.gov/ct2/show/NCT04014075)
 and/or DESTINY-Gastric06 (https://clinicaltrials.gov/study/NCT04989816)
 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
(https://classic.clinicaltrials.gov/ct2/show/NCT04482309) , DESTINY-Lung01
(https://clinicaltrials.gov/study/NCT03505710)  and DESTINY-CRC02
(https://www.clinicaltrials.gov/study/NCT04744831?term=DESTINY-CRC02&rank=1)
 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
(https://www.astrazeneca.com/media-centre/press-releases/2019/astrazeneca-and-daiichi-sankyo-enter-collaboration-for-novel-her-2-targeting-antibody-drug-conjugate.html)
 and Datroway (datopotamab deruxtecan) in July 2020
(https://www.astrazeneca.com/media-centre/press-releases/2020/astrazeneca-and-daiichi-sankyo-enter-collaboration-to-develop-and-commercialise-new-antibody-drug-conjugate.html#!)
, 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
challenging, and redefining, 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, AstraZeneca and Daiichi Sankyo are aiming to improve outcomes in
previously treated HER2-positive, HER2-low and HER2-ultralow 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), the TROP-2-directed ADC, Datroway (datopotamab
deruxtecan) and next-generation oral SERD and potential new medicine
camizestrant.

 

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. AstraZeneca is also exploring the potential of
saruparib, a potent and selective inhibitor of PARP1, in combination with
camizestrant in BRCA-mutated, HR-positive, HER2-negative advanced breast
cancer.

 

To bring much-needed treatment options to patients with triple-negative breast
cancer, an aggressive form of breast cancer, AstraZeneca is collaborating with
Daiichi Sankyo to evaluate the potential of Datroway alone and in combination
with immunotherapy Imfinzi (durvalumab).

 

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 (http://www.astrazeneca.com/)  and follow the
Company on social media @AstraZeneca
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References

1.   Salgado RF, et al. LBA21 - Human epidermal growth factor receptor 2
(HER2)-low and HER2-ultralow status determination in tumors of patients (pts)
with hormone receptor-positive (HR+) metastatic breast cancer (mBC) in
DESTINY-Breast06 (DB-06). Annals of Oncology. (2024) 35 (suppl_2): 1-72.
10.1016/annonc/annonc1623.

2.   Bray F, et al. Global cancer statistics 2022: GLOBOCAN estimates of
incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer
J Clin. 2024 Apr 4. doi: 10.3322/caac.21834.

3.     WHO. International Agency of Cancer Research. Cancer Today. Breast.
2022. Available at:
https://gco.iarc.who.int/media/globocan/factsheets/cancers/20-breast-fact-sheet.pdf.
Accessed February 2025.

4.   National Cancer Institute. Surveillance, Epidemiology and End Results
Program. Available
at: https://seer.cancer.gov/statfacts/html/breast-subtypes.html. Accessed
February 2025.

5.   Iqbal N, et al. Human Epidermal Growth Factor Receptor 2 (HER2) in
Cancers: Overexpression and Therapeutic Implications. Mol Biol Int.
2014;852748.

6.   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.

7.   Sajjadi E, et al. Improving HER2 testing reproducibility in HER2-low
breast cancer. Cancer Drug Resist. 2022;5(4):882-888.

8.   Manohar P, et al. Updates in endocrine therapy for metastatic breast
cancer. Cancer Biol Med. 2022 Feb 15; 19(2):202-212.

9.   Cortes J, et al. Eribulin monotherapy versus treatment of physician's
choice in patients with metastatic breast cancer (EMBRACE): a phase 3
open-label randomised study. Lancet. 2011;377:914-923.

10.  Yuan P, et al. Eribulin mesilate versus vinorelbine in women with
locally recurrent or metastatic breast cancer: A randomised clinical
trial. Eur J Cancer. 2019;112:57-65.

11.  Jerusalem G, et al. Everolimus Plus Exemestane vs Everolimus or
Capecitabine Monotherapy for Estrogen Receptor-Positive, HER2-Negative
Advanced Breast Cancer. JAMA Oncol. 2018;4(10):1367-1374.

12.  Modi S, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low
Advanced Breast Cancer. N Engl J Med. 2022;387:9-20.

13.  Bardia A, et al. Trastuzumab Deruxtecan after Endocrine Therapy in
Metastatic Breast Cancer. N Eng J Med. 2024; 391:2110-2122.

 

Adrian Kemp

Company Secretary

AstraZeneca PLC

 

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