REG - AstraZeneca PLC - Enhertu combination improved PFS in 1L HER2+ mBC

AstraZenecaAnnouncement

22/04/2025 07:00

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RNS Number : 5592F  AstraZeneca PLC  22 April 2025

This announcement contains inside information

 

22 April 2025

 

Enhertu plus pertuzumab demonstrated highly statistically significant and
clinically meaningful improvement in progression-free survival vs. THP as
1st-line therapy for patients with HER2-positive metastatic breast cancer

 

DESTINY-Breast09 Phase III trial of AstraZeneca and Daiichi Sankyo's Enhertu
is the first trial in more than a decade to demonstrate superior efficacy
across a broad HER2-positive metastatic patient population versus current
1st-line standard of care

 

Positive high-level results from a planned interim analysis of the
DESTINY-Breast09 Phase III trial showed Enhertu (trastuzumab deruxtecan) in
combination with pertuzumab demonstrated a highly statistically significant
and clinically meaningful improvement in progression-free survival (PFS)
compared to a taxane, trastuzumab and pertuzumab (THP) as a 1st-line treatment
for patients with HER2-positive metastatic breast cancer.

 

The PFS improvement was seen across all pre-specified patient subgroups with
Enhertu in combination with pertuzumab. The key secondary endpoint of overall
survival (OS) was not mature at the time of this planned interim analysis;
however, interim OS data showed an early trend favouring the Enhertu
combination compared with THP.

 

The second arm assessing Enhertu monotherapy versus THP remains blinded to
patients and investigators and will continue to the final PFS analysis.

 

HER2-positive metastatic breast cancer is an aggressive disease driven by
overexpression or amplification of HER2 affecting 15-20% of patients with
metastatic breast cancer.(1) While HER2-targeted therapies have improved
outcomes, prognosis remains poor, with most patients experiencing disease
progression within two years of 1st-line treatment with THP, which has been
the standard of care for more than a decade.(2-4) Further, approximately one
in three patients never go on to receive treatment following 1st-line therapy
due to disease progression or death.(5,6)

 

Susan Galbraith, Executive Vice President, Oncology Haematology R&D,
AstraZeneca, said: "This is the first trial in more than a decade to
demonstrate superior efficacy across a broad HER2-positive metastatic breast
cancer patient population compared to the current 1st-line standard of care.
This is a significant milestone for patients and sets the foundation for
Enhertu in combination with pertuzumab as an important treatment option in the
first-line HER2-positive setting."

 

Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: "The results from
DESTINY-Breast09 reinforce the importance of effectively targeting HER2 to
achieve durable disease control early in the treatment of HER2-positive
metastatic breast cancer. Building on the positive results seen with Enhertu
in the second-line setting, these new findings suggest that starting treatment
with Enhertu in combination with pertuzumab at the time of metastatic
diagnosis delays disease progression, postponing the time until additional
treatment may be needed."

 

The safety profile of Enhertu in combination with pertuzumab was consistent
with the known profiles of each individual therapy.

 

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.

 

Data from the combination arm of DESTINY-Breast09 will be presented at an
upcoming medical meeting and shared with regulatory authorities.

 

Enhertu is already approved in more than 75 countries as 2nd-line treatment
for patients with HER2-positive breast cancer based on the results from
the DESTINY-Breast03 trial.

 

Notes

 

(https://clinicaltrials.gov/study/NCT04784715) HER2-positive metastatic breast
cancer

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
about 30% of patients diagnosed with or who progress to metastatic disease are
expected to live five years following diagnosis.(8)

( )

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the
surface of many types of tumours, including breast cancer.(9) HER2 protein
overexpression may occur as a result of HER2 gene amplification and is often
associated with aggressive disease in breast cancer.(1) Approximately one in
five cases of breast cancer are considered HER2-positive.(10)

 

While HER2-targeted therapies have improved outcomes, prognosis remains poor,
with most patients experiencing disease progression within two years of
1st-line treatment with THP, which has been the standard of care for more than
a decade.(2-4) Further, approximately one in three patients never go on to
receive treatment following 1st-line therapy due to disease progression or
death.(5,6)

 

DESTINY-Breast09

DESTINY-Breast09 is a global, multicentre, randomised, open-label, Phase III
trial evaluating the efficacy and safety of Enhertu (5.4mg/kg) either alone or
in combination with pertuzumab versus standard of care THP (a taxane
[docetaxel or paclitaxel], trastuzumab and pertuzumab) as a 1st-line treatment
in patients with HER2-positive metastatic breast cancer.

 

Patients were randomised 1:1:1 to receive either Enhertu monotherapy with a
pertuzumab matching placebo; Enhertu in combination with pertuzumab; or THP.
Randomisation was stratified by prior treatment (de novo metastatic disease
versus progression from early-stage disease), hormone receptor (HR) status and
PIK3CA mutation status.

 

The primary endpoint of DESTINY-Breast09 is PFS as assessed by blinded
independent central review in both the Enhertu monotherapy and Enhertu
combination arms. Secondary endpoints include investigator-assessed PFS,
overall survival, objective response rate, duration of response,
investigator-assessed time to second progression or death, patient-reported
tolerability, pharmacokinetics and safety.

 

DESTINY-Breast09 enrolled 1,157 patients across multiple sites in Africa,
Asia, Europe, North America and South America. For more information about the
trial, visit ClinicalTrials.gov (https://clinicaltrials.gov/study/NCT04784715)
.

 

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 (5.4mg/kg) is approved in more than 30 countries 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 locally or regionally approved
test, that have 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 and other countries 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
(https://gateway.zscalertwo.net/auD?origurl=https:%2f%2fwww.linkedin.com%2fcompany%2fastrazeneca&_ordtok=Mkk3WV5DBDPmQrD4F5MGdGDMZR)
.

 
Contacts

For details on how to contact the Investor Relations Team, please click here
(https://www.astrazeneca.com/investor-relations.html#Contacts) . For Media
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.

 

References

1.   Tarantino P, et al. ESMO expert consensus statements (ECS) on the
definition, diagnosis, and management of HER2-low breast cancer. J An Onc.
2023;34(8):645-659.

2.   Swain SM et al. Pertuzumab, trastuzumab, and docetaxel for
HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from
a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol.
2020;21(4):519-530.

3.   Blumenthal G, et al. First FDA Approval of Dual Anti-HER2 Regimen:
Pertuzumab in Combination with Trastuzumab and Docetaxel for HER2-Positive
Metastatic Breast Cancer. Clin Can Res. 2013;19(18).

4.   Tripathy D, et al. De Novo Versus Recurrent HER2-Positive Metastatic
Breast Cancer: Patient Characteristics, Treatment, and Survival from the
SystHERs Registry. Oncologist. 2020;25(2):e214-e222.

5.   Hall P, et al. Attrition rates from first- to third-line therapy in
HER2+ metastatic breast cancer in Europe. Presented at SABCS Annual Meeting
2023. Poster #PO3-16-11.

6.   Hartkopt AD, et al. Attrition in the First Three Therapy Lines in
Patients with Advanced Breast Cancer in the German Real-World PRAEGNANT
Registry. Geburtshilfe Frauenheilkd. 2024;84(5):459-469.

7.   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;10.3322/caac.21834.

8. National Cancer Institute. SEER Cancer Stat Facts: Female Breast Cancer
Subtypes. Available at:
https://seer.cancer.gov/statfacts/html/breast-subtypes.html
(https://seer.cancer.gov/statfacts/html/breast-subtypes.html) Accessed April
2025.

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

10.  Ahn S, et al. HER2 status in breast cancer: changes in guidelines and
complicating factors for interpretation. J Pathol Transl Med.
2019;54(1):34-44.

Adrian Kemp
Company Secretary
AstraZeneca PLC

 

 

 

 

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