REG - AstraZeneca PLC - Enhertu approved in the US for HER2-low mBC

AstraZenecaAnnouncement

08/08/2022 07:15

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RNS Number : 2205V  AstraZeneca PLC  08 August 2022

08 August 2022 07:00 BST

 

Enhertu approved in the US as the first HER2-directed therapy for patients
with HER2-low metastatic breast cancer

 

Based on DESTINY-Breast04 results which showed AstraZeneca and Daiichi
Sankyo's Enhertu reduced risk of disease progression or death by 50% and

increased overall survival by more than six months versus chemotherapy

 

AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) has been
approved in the US 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 chemotherapy in the metastatic setting or developed disease recurrence
during or within six months of completing adjuvant chemotherapy.

 

Enhertu is a specifically engineered HER2-directed antibody drug conjugate
(ADC) being jointly developed and commercialised by AstraZeneca and Daiichi
Sankyo.

 

The approval by the Food and Drug Administration (FDA) was based on the
results from the DESTINY-Breast04
(https://www.astrazeneca.com/media-centre/press-releases/2022/enhertu-efficacy-results-in-her2-low-breast-cancer.html)
Phase III trial. In the trial, Enhertu reduced the risk of disease progression
or death by 50% versus physician's choice of chemotherapy in patients with
HER2-low metastatic breast cancer with hormone receptor (HR)-positive disease
or HR-negative disease (median progression-free survival  PFS  9.9 versus 5.1
months; hazard ratio  HR  0.50; 95% confidence interval  CI  0.40-0.63;
p<0.0001). A median overall survival (OS) of 23.4 months was seen in
patients treated with Enhertu versus 16.8 months in those treated with
chemotherapy, a 36% reduction in the risk of death (HR 0.64; 95% CI 0.49-0.84;
p=0.001).

 

Shanu Modi, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center,
US, said: "Approximately half of all patients with breast cancer have tumours
that are HER2-low, which have previously been classified as HER2-negative and
have not had effective treatment options with HER2-targeted medicines. Based
on the promising results of the DESTINY-Breast04 trial, clinicians are
starting to differentiate levels of HER2 expression and redefine how
metastatic breast cancer is classified with a distinct HER2-low patient
population that may be eligible for trastuzumab deruxtecan."

 

Dave Fredrickson, Executive Vice President, Oncology Business Unit,
AstraZeneca, said: "The rapid approval of Enhertu in HER2-low metastatic
breast cancer by the FDA underscores the urgency to bring this
transformational medicine to patients as quickly as possible. Patients with
HER2-low tumours, who are identified through existing HER2 testing methods,
will now have the opportunity to be treated based upon their HER2 status."

 

Ken Keller, Global Head of Oncology Business and President and CEO, Daiichi
Sankyo, Inc, said: "Today's FDA approval marks a monumental moment in breast
cancer treatment as Enhertu is the first-ever HER2-directed medicine to be
approved for the treatment of patients with HER2-low metastatic breast cancer.
With the ground-breaking survival benefit seen in the DESTINY-Breast04 trial,
this milestone confirms the importance of targeting lower levels of HER2
expression in the treatment of metastatic breast cancer and we are thrilled
that we can now offer Enhertu to even more patients."

 

The approval was granted under the FDA's Real-Time Oncology Review programme
after securing Priority Review
(https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2022/enhertu-granted-priority-review-for-her2-low-mbc.html)
and Breakthrough Therapy Designation
(https://www.astrazeneca.com/media-centre/press-releases/2022/enhertu-granted-btd-her2-low-breast-cancer.html#:~:text=AstraZeneca%20and%20Daiichi%20Sankyo's%20Enhertu%20(trastuzumab%20deruxtecan)%20has%20been%20granted,systemic%20therapy%20in%20the%20metastatic)
of Enhertu in the US in this setting. The expanded approval for Enhertu in the
US, following its previous approval in 2nd-line HER2-positive metastatic
breast cancer, enables its use across a wide spectrum of HER2-expressing
breast cancer, including patients with HER2-low disease.

 

The DESTINY-Breast04 Phase III trial results were presented at the
presidential plenary session of the 2022 American Society of Clinical Oncology
Annual meeting and simultaneously published in The New England Journal of
Medicine (NEJM)
(https://www.nejm.org/doi/10.1056/NEJMoa2203690?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed)
.(1)

 

The safety profile of Enhertu was consistent with previous clinical trials
with no new safety concerns identified. Interstitial lung disease (ILD) or
pneumonitis rates were consistent with those observed in late-line
HER2-positive breast cancer trials of Enhertu. Overall, 12% of patients had
confirmed ILD or pneumonitis related to treatment as determined by an
independent adjudication committee. The majority of ILD events were Grade 1 or
2 (10%), with five Grade 3 (1.3%) and no Grade 4 events reported. There were
three (0.8%) ILD-related deaths (Grade 5).

 

In June 2022, fam-trastuzumab deruxtecan-nxki (Enhertu) was added to the NCCN
Clinical Practical Guidelines in Oncology (NCCN Guidelines(®)) as the
Category 1 preferred regimen for patients with tumours that are HER2 IHC 1+ or
2+ and ISH- who have received at least one prior line of chemotherapy for
metastatic disease and, if tumour is HR-positive, are refractory to endocrine
therapy, based on the data from DESTINY-Breast04.(2)

 

The US regulatory submission for DESTINY-Breast04 was reviewed under Project
Orbis, which provides a framework for concurrent submission and review of
oncology medicines among participating international partners. As part of
Project Orbis, Enhertu is also under regulatory review for the same indication
by the Australian Therapeutic Goods Administration, the Brazilian Health
Regulatory Agency (ANVISA), Health Canada and Switzerland's Swissmedic.

 

Regulatory applications for Enhertu are also currently under review in Europe,
Japan and several other countries based on the DESTINY-Breast04 results.

 

Notes

 

Financial considerations

Following this approval for Enhertu in the US, an amount of $200m is due from
AstraZeneca to Daiichi Sankyo as a milestone payment for the HER2-low breast
cancer post chemotherapy 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
collaboration 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.

 

Breast cancer and HER2 expression

Breast cancer is the most common cancer and is one of the leading causes of
cancer-related deaths worldwide and in the US.(3,4) More than two million
patients with breast cancer were diagnosed in 2020 resulting in nearly 685,000
deaths globally.(3) In the US, more than 290,000 patients are expected to be
diagnosed in 2022, resulting in more than 43,000 deaths.(5)

 

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the
surface of many types of tumours including breast, gastric, lung and
colorectal cancers, and is one of many biomarkers expressed in breast cancer
tumours.(6)

 

HER2 expression is currently determined by an immunohistochemistry (IHC) test
which estimates the amount of HER2 protein on a cancer cell, and/or an in-situ
hybridisation (ISH) test, which counts the copies of the HER2 gene in cancer
cells.(6,7) HER2 tests provide IHC and ISH scores across the full HER2
spectrum and are routinely used to determine appropriate treatment options for
patients with metastatic breast cancer.

 

HER2-positive cancers are currently defined as HER2 expression measured as IHC
3+ or IHC 2+/ISH+, and HER2-negative cancers are defined as HER2 expression
measured as IHC 0, IHC 1+ or IHC 2+/ISH-.(6) However, approximately half of
all breast cancers are HER2-low, defined as an HER2 score of IHC 1+ or IHC
2+/ISH-.(8-10) HER2-low occurs in both HR-positive and HR-negative
disease.(11)

 

Previously, patients with HR-positive metastatic breast cancer and HER2-low
disease had limited effective treatment options following progression on
endocrine (hormone) therapy.(9,12) Additionally, few targeted options were
available for those with HR-negative disease.(13) Now with the approval of
Enhertu, patients with HER2-low tumours may be eligible for HER2-directed
therapy.

 

DESTINY-Breast04

DESTINY-Breast04 is a global, randomised, open-label, Phase III trial
evaluating the efficacy and safety of Enhertu (5.4mg/kg) versus physician's
choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel or
nab-paclitaxel) in patients with HR-positive or HR-negative, HER2-low
unresectable and/or metastatic breast cancer previously treated with one or
two prior lines of chemotherapy. Patients were randomised 2:1 to receive
either Enhertu or chemotherapy.

 

The primary endpoint of DESTINY-Breast04 is PFS in patients with HR-positive
disease based on blinded independent central review (BICR). Key secondary
endpoints include PFS based on BICR in all randomised patients (HR-positive
and HR-negative disease), OS in patients with HR-positive disease and OS in
all randomised patients (HR-positive and HR-negative disease). Other secondary
endpoints include PFS based on investigator assessment, objective response
rate based on BICR and on investigator assessment, duration of response based
on BICR and safety.

 

DESTINY-Breast04 enrolled 557 patients at multiple sites in Asia, Europe and
North America. For more information about the trial, visit ClinicalTrials.gov
(https://clinicaltrials.gov/ct2/show/NCT03734029) .

 

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
topoisomerase I inhibitor payload, an exatecan derivative, via a stable
tetrapeptide-based cleavable linker.

 

Enhertu (5.4mg/kg) is approved in more than 30 countries for the treatment of
adult patients with unresectable or metastatic HER2-positive 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 several countries for the treatment of adult
patients with unresectable or metastatic HER2-positive breast cancer who have
received two or more prior anti-HER2-based regimens based on the results from
the DESTINY-Breast01 trial.

 

Enhertu (5.4mg/kg) is approved in the US 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 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.

 

Enhertu (6.4mg/kg) is approved in several countries for the treatment of adult
patients with locally advanced or metastatic HER2-positive gastric or
gastroesophageal junction adenocarcinoma who have received a prior
trastuzumab-based regimen based on the results from the DESTINY-Gastric01
trial.

 

Enhertu development programme

A comprehensive development programme is underway globally, evaluating the
efficacy and safety of Enhertu monotherapy across multiple HER2-targetable
cancers, including breast, gastric, lung and colorectal cancers. Trials in
combination with other anticancer treatments, such as immunotherapy, are also
underway.

 

Regulatory applications for Enhertu in breast, gastric and non-small cell lung
cancer are currently under review in several other countries based on the
DESTINY-Breast01, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Gastric01,
DESTINY-Gastric02 and DESTINY-Lung01 trials, respectively.

 

Daiichi Sankyo collaboration

Daiichi Sankyo Company, Limited (TSE: 4568) [referred to as Daiichi Sankyo]
and AstraZeneca entered into a global collaboration to jointly develop and
commercialise Enhertu (a HER2-directed ADC) 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 datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) 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. 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
challenging and redefining the current clinical paradigm for how breast cancer
is classified and treated to deliver even more 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.

 

AstraZeneca aims to continue to transform outcomes for HR-positive breast
cancer with foundational medicines Faslodex (fulvestrant)
and Zoladex (goserelin) and the next-generation oral selective oestrogen
receptor degrader (SERD) and potential new medicine camizestrant.

 

PARP inhibitor Lynparza (olaparib) is a targeted treatment option that has
been studied in HER2-negative 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 metastatic breast cancer
patients with an inherited BRCA mutation and are exploring new opportunities
to treat these patients earlier in their disease.

 

Building on the initial approvals of Enhertu, a HER2-directed ADC, in
previously treated HER2-positive metastatic breast cancer, AstraZeneca and
Daiichi Sankyo are exploring its potential in earlier lines of treatment and
in new breast cancer settings.

 

To bring much needed treatment options to patients with triple-negative breast
cancer, an aggressive form of breast cancer, AstraZeneca is testing
immunotherapy Imfinzi (durvalumab) in combination with other oncology
medicines, including Lynparza and Enhertu, evaluating the potential of AKT
kinase inhibitor, capivasertib, in combination with chemotherapy, and
collaborating with Daiichi Sankyo to explore the potential of TROP2-directed
ADC, datopotamab deruxtecan.

 

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 (http://www.astrazeneca.com/)  and follow the
Company on Twitter @AstraZeneca (https://twitter.com/AstraZeneca) .

 

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

 

References

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

2.   Referenced with permission from the NCCN Clinical Practice Guidelines
in Oncology (NCCN Guidelines(®)) for Breast Cancer V2.2022. © National
Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed August
2022. To view the most recent and complete version of the guideline, go online
to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their
content, use or application and disclaims any responsibility for their
application or use in any way.

3.   Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of
Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J
Clin. 2021; 10.3322/caac.21660.

4.   Centers for Disease Control and Prevention. Available at:
https://gis.cdc.gov/Cancer/USCS/#/AtAGlance/. Accessed August 2022.

5.   American Cancer Society. Cancer Facts & Figures 2022. Available at:
https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2022.html.
Accessed August 2022.

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

7.   Wolff A, et al. Human Epidermal Growth Factor Receptor 2 Testing in
Breast Cancer: American Society of Clinical Oncology/College of American
Pathologists Clinical Practice Guideline Focused Update. Arch Pathol Lab Med.
2018; 142(11): 1364-1382.

8.   Schalper K, et al. A retrospective population-based comparison of HER2
immunohistochemistry and fluorescence in situ hybridization in breast
carcinomas. Arch Pathol Lab Med. 2014; 138: 213-219.

9.   Schettini F, et al. Clinical, pathological, and PAM50 gene expression
features of HER2-low breast cancer. npj Breast Cancer. 2021; 7:1;
https://doi.org/10.1038/s41523-020-00208-2.

10.  Denkert C, et al. Clinical and molecular characteristics of
HER2-low-positive breast cancer: pooled analysis of individual patient data
from four prospective, neoadjuvant clinical trials. 2021. Lancet Oncol; 22:
1151-61.

11.  Miglietta F, et al. Evolution of HER2-low expression from primary to
recurrent breast cancer. NPJ Breast Cancer. 2021; 7: 137;
10.1038/s41523-021-00343-4.

12.  Matutino A, et al. Current Oncology. Hormone receptor-positive,
HER2-negative metastatic breast cancer: redrawing the lines. 2018;
25(S1):S131-S141.

13.  American Cancer Society. Breast Cancer Hormone Receptor Status.
Available at:
https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-hormone-receptor-status.html.
Accessed August 2022.

 

Dr. Modi has financial interests related to AstraZeneca and Daiichi Sankyo.

 

Adrian Kemp

Company Secretary

AstraZeneca PLC

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