REG - AstraZeneca PLC - Enhertu approved in US for breast cancer post ET

AstraZenecaAnnouncement

28/01/2025 07:00

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RNS Number : 9331U  AstraZeneca PLC  28 January 2025

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 (http://www.nejm.org) .

 

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
(https://www.astrazeneca.com/media-centre/press-releases/2019/astrazeneca-and-daiichi-sankyo-enter-collaboration-for-novel-her-2-targeting-antibody-drug-conjugate.html)
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
(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
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 (http://www.astrazeneca.com/)  and follow the
Company on social media @AstraZeneca
(https://gateway.zscalertwo.net/auD?origurl=https:%2f%2fwww.linkedin.com%2fcompany%2fastrazeneca&_ordtok=Mkk3WV5DBDPmQrD4F5MGdGDMZR)
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Contacts

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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.   American Cancer Society. Key Statistics for Breast Cancer. Available
at:
https://www.cancer.org/cancer/types/breast-cancer/about/how-common-is-breast-cancer.html
(https://www.cancer.org/cancer/types/breast-cancer/about/how-common-is-breast-cancer.html)
. Accessed January 2025.

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