astrazenecaplc-5918j
FORM 6-K
SECURITIES
AND EXCHANGE COMMISSION
Washington,
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Report
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AstraZeneca PLC
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AstraZeneca PLC
INDEX
TO EXHIBITS
1.
Enhertu approved in US for HER2+ solid tumours
08 April 2024
Enhertu approved
in the US as first tumour-agnostic HER2-directed
therapy
for previously treated patients with metastatic HER2-positive solid
tumours
Based on three Phase II trials of AstraZeneca and Daiichi Sankyo's
Enhertu which showed
clinically meaningful responses across a broad range of
tumours
Enhertu now has five approved indications with
the latest in HER2-expressing
(IHC 3+) metastatic cancers
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-positive (IHC 3+) solid tumours who have received
prior systemic treatment and have no satisfactory alternative
treatment options.
This indication is approved under accelerated approval based on
objective response rate (ORR) and duration of response (DoR).
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in a confirmatory
trial.
Enhertu is
a specifically engineered HER2-directed antibody drug conjugate
(ADC) discovered by Daiichi Sankyo and being jointly developed and
commercialised by AstraZeneca and Daiichi
Sankyo.
The first tumour-agnostic approval of a HER2-directed therapy and
ADC by the Food and Drug Administration (FDA) was based on results
from the subgroup of patients with HER2-positive IHC 3+ tumours in
each of the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02 Phase
II trials.
Funda Meric-Bernstam, MD, Chair of Investigational Cancer
Therapeutics at The University of Texas MD Anderson Cancer Center,
US, said: "Until the approval of trastuzumab deruxtecan, patients
with metastatic HER2-positive solid tumours have had limited
treatment options. Based on the clinically meaningful response
rates seen across clinical trials, this tumour-agnostic approval
means that patients may now be treated with a HER2-directed
medicine."
Dave Fredrickson, Executive Vice President, Oncology Business Unit,
AstraZeneca, said: "As the first antibody drug conjugate to be
granted a tumour-agnostic indication, Enhertu is truly delivering on its potential across
metastatic HER2-targetable tumours. This approval also elevates the
importance of testing for biomarkers, including HER2, across a
broad range of tumours to ensure these patients with advanced
cancer who have few options know whether a targeted medicine might
be right for them."
Ken Keller, Global Head of Oncology Business, and President and
CEO, Daiichi Sankyo, Inc., said: "This fifth indication in the US
is a significant milestone as eligible patients with previously
treated metastatic HER2-positive solid tumours may now be treated
with Enhertu. The accelerated approval by the FDA for this
tumour-agnostic indication is based on the clinically meaningful
efficacy seen with Enhertu across numerous types of metastatic
cancers."
In the DESTINY-PanTumor02 Phase II trial, patients with centrally
or locally assessed HER2-positive (IHC 3+) solid tumours including
either biliary tract, bladder, cervical, endometrial, ovarian,
pancreatic or other tumours treated with Enhertu showed
a confirmed ORR of 51.4% (95%
confidence interval [CI] 41.7-61.0) and
a median DoR range of 19.4 months (range 1.3-27.9+ [+ denotes
ongoing responses at data cutoff]). In DESTINY-Lung01, patients
with centrally confirmed HER2-positive (IHC 3+) non-small cell lung
cancer (NSCLC) treated with Enhertu showed
a confirmed ORR of 52.9% (95%
CI 27.8-77.0) and
median DoR range of 6.9 months (range 4.0-11.7+). A confirmed ORR
of 46.9% (95%
CI 34.3-59.8) and
median DoR range of 5.5 months (range 1.3+-9.7+) was seen in
patients with centrally confirmed HER2-positive (IHC 3+) colorectal
cancer in the DESTINY-CRC02 trial.
The safety of Enhertu was evaluated in 347 patients with
unresectable or metastatic HER2-positive (IHC 3+) solid tumours in
the DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01 and
DESTINY-CRC02 trials. The safety profile observed across the trials
was consistent with previous clinical trials
of Enhertu with no new safety concerns
identified.
Based on these results, fam-trastuzumab
deruxtecan-nxki (Enhertu) has been included in the NCCN Clinical Practice
Guidelines in Oncology (NCCN Guidelines®)
as a treatment option for multiple metastatic tumours. See NCCN
Guidelines® for
detailed recommendations.1
This approval was granted under the FDA's Real-Time Oncology Review
programme after securing Priority
Review and Breakthrough
Therapy Designation for Enhertu in
the US in this setting.
The US regulatory submission 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 regulatory authorities in Australia, Brazil and
Singapore.
Financial considerations
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 of the
collaboration.
Notes
HER2 expression in solid tumours
HER2 is a tyrosine kinase receptor growth-promoting protein
expressed on the surface of various tissue cells throughout the
body and is involved in normal cell growth.2,3 In
some cancers, HER2 expression is amplified or the cells have
activating mutations.2,4 HER2
protein overexpression may occur as a result of HER2 gene
amplification and is often associated with aggressive disease and
poor prognosis.5
HER2-directed therapies have been used to treat breast, gastric,
lung and colorectal cancers for a number of
years.3,6,7 Although
HER2 is expressed in solid tumour types including biliary tract,
bladder, cervical, endometrial, ovarian and pancreatic cancers,
testing is not routinely performed in these additional tumour types
and as a result, available literature is
limited.4 In
these solid tumours, HER2-positive expression, classified as
immunohistochemistry (IHC) 3+, has been observed at rates from 1%
to 28%.8,9 Approximately
1% to 5% of patients with NSCLC have tumours with HER2
overexpression (IHC 3+), however, the levels of protein expression
reported vary in the literature.8,10 Approximately
1% to 4% of patients with metastatic colorectal cancer have tumours
which are HER2 overexpressing
(IHC 3+).8,11,12
DESTINY-PanTumor02
DESTINY-PanTumor02 is a global, multicentre, multi-cohort,
open-label Phase II trial evaluating the efficacy and safety
of Enhertu (5.4mg/kg) for the treatment of previously
treated HER2-expressing tumours, including biliary tract cancer,
bladder cancer, cervical cancer, endometrial cancer, ovarian
cancer, pancreatic cancer or other tumours.
The primary efficacy endpoint of DESTINY-PanTumor02 is confirmed
ORR as assessed by investigator. Secondary endpoints include DoR,
disease control rate (DCR), progression-free survival (PFS),
overall survival (OS), safety, tolerability and
pharmacokinetics.
DESTINY-PanTumor02 has enrolled 267 patients, including 111
HER2-positive (IHC 3+) adult patients, at multiple sites in Asia,
Europe and North America, and is to be expanded to recruit more
patients with metastatic HER2-positive IHC 1+, IHC 2+ and IHC
3+ tumours. For more information about the trial,
visit ClinicalTrials.gov.
DESTINY-Lung01
DESTINY-Lung01 is a global Phase II, open-label, two-cohort trial
evaluating the efficacy and safety of Enhertu (5.4mg/kg or 6.4mg/kg) in patients with
HER2-mutant (cohort 2, n=91) or HER2-overexpressing (defined as IHC
3+ or IHC 2+) [cohort 1 and 1a, n=90] unresectable or metastatic
non-squamous NSCLC who had progressed after one or more systemic
therapies.
The primary endpoint is confirmed ORR by independent central
review. Key secondary endpoints include DoR, DCR, PFS, OS and
safety.
DESTINY-Lung01 enrolled 181 patients, including 17 HER2-positive
(IHC 3+) adult patients, at multiple sites, including Asia, Europe
and North America. For more information about the trial,
visit ClinicalTrials.gov.
DESTINY-CRC02
DESTINY-CRC02 is a global, randomised, two arm, parallel,
multicentre Phase II trial evaluating the efficacy and safety of
two doses (5.4mg/kg or 6.4mg/kg) of Enhertu in patients with locally advanced,
unresectable or metastatic HER2-positive colorectal cancer of BRAF
wild-type, RAS wild-type or RAS mutant tumour types previously
treated with standard therapy.
The trial was conducted in two stages. In the first stage, patients
(n=80) were randomised 1:1 to receive either 5.4mg/kg or 6.4mg/kg
of Enhertu. In the second stage, additional patients (n=42)
were enrolled in the 5.4mg/kg arm.
The primary endpoint is confirmed ORR as assessed by blinded
independent central review. Secondary endpoints include DoR, DCR,
investigator-assessed confirmed ORR, clinical benefit ratio, PFS,
OS and safety.
DESTINY-CRC02 enrolled 122 patients, including 64 HER2-positive
(IHC 3+) adult patients, at multiple sites in Asia, Europe and
North America. For more information about the trial,
visit ClinicalTrials.gov.
DESTINY-Breast01
DESTINY-Breast01 is a global, single-arm, open-label, two-part
multi-centre Phase II trial evaluating the safety and efficacy
of Enhertu in patients with HER2-positive unresectable
and/or metastatic breast cancer previously treated with trastuzumab
emtansine (T-DM1).
The primary endpoint of the trial is ORR, as determined by
independent central review. Secondary objectives include DoR, DCR,
clinical benefit rate, PFS and OS.
DESTINY-Breast01 enrolled 253 patients at multiple sites in Asia,
Europe and North America. For more information about the trial,
visit ClinicalTrials.gov.
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 60 countries for the treatment of adult
patients with unresectable or metastatic HER2-positive (IHC 3+
or in-situ hybridization [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 (5.4mg/kg) is
approved in more than 55 countries 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 trial.
Enhertu (5.4mg/kg) is
approved in more than 35 countries worldwide for the treatment of
adult patients with unresectable or metastatic non-small cell lung
cancer 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 (6.4mg/kg) is
approved in more than 45 countries for the treatment of adult
patients with locally advanced or metastatic HER2-positive (IHC 3+
or IHC 2+/ISH+) gastric or gastroesophageal junction (GEJ)
adenocarcinoma who have received a prior trastuzumab-based regimen
based on the results from the DESTINY-Gastric01 trial and/or
DESTINY-Gastric02 trial.
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 have no satisfactory
alternative treatment options based on the results from the
DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02 trials.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in a confirmatory
trial.
Enhertu development
programme
A comprehensive clinical development programme is underway
globally, evaluating the efficacy and safety
of Enhertu monotherapy across multiple HER2-targetable
cancers. Trials in combination with other anticancer treatments,
such as immunotherapy, are also underway.
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, and datopotamab
deruxtecan (DS-1062; a TROP2-directed ADC)
in July
2020, 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 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.
Contacts
For details on how to contact the Investor Relations Team, please
click here.
For Media contacts, click here.
References
1.
Referenced with permission from the NCCN
Guidelines. © National Comprehensive Cancer
Network® 2024.
All rights reserved. Accessed March 2024. To view the most recent
and complete version of the guidelines, 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.
2.
ASCO. Breast Cancer. Available
at: https://www.cancer.net/sites/cancer.net/files/asco_answers_guide_breast.pdf.
Accessed April 2024.
3.
Iqbal N, et al. Human Epidermal Growth Factor
Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic
Implications. Mol Biol
Int. 2014;
852748.
4.
Omar N, et al. HER2-an emerging biomarker in
non-breast and non-gastric cancers. Pathogenesis.
2015;2(3):1-9.
5.
Pillai R, et al. HER2 mutations in lung
adenocarcinomas: A report from the Lung Cancer Mutation
Consortium. Cancer. 2017;1;123(21): 4099-4105.
6.
National Cancer Institute.
Enhertu Marks First Targeted Therapy for HER2-Mutant Lung
Cancer. Available
at: https://www.cancer.gov/news-events/cancer-currents-blog/2022/fda-lung-cancer-enhertu-her2. Accessed April
2024.
7.
Siena S, et al. Targeting the Human Epidermal
Growth Factor Receptor 2 (HER2) Oncogene in Colorectal
Cancer. Ann Oncol. 2018 May; 29(5):1108-1119.
8.
Yan M, et al. HER2 expression status in diverse
cancers: review of results from 37,992
patients. Cancer Metastasis
Rev. 2015
Mar;34(1):157-64.
9.
Buza N, et al. Toward standard HER2 testing of
endometrial serous carcinoma: 4-year experience at a large academic
center and recommendations for clinical
practice. Modern
Pathology. 2013
Dec;26(12):1605-12.
10.
Zinner R, et al. Trastuzumab in combination with
cisplatin and gemcitabine in patients with Her2-overexpressing,
untreated, advanced non-small cell lung cancer: report of a phase
II trial and findings regarding optimal identification of patients
with Her2-overexpressing disease. Lung Cancer. 2004; Apr;44(1):99-110.
11.
Cecchi F, et al. The HORIZON III
retrospective exploratory analysis: HER2 expression amplification
in colorectal cancer. J
Clin Oncol.
2023;Jan;41(4).
12.
Valtora E, et al. Assessment of a HER2 scoring
system for colorectal cancer: results from a validation
study. Mod Pathol. 2015 Nov;28(11):1481-91.
Adrian Kemp
Company Secretary
AstraZeneca PLC
SIGNATURES
Pursuant
to the requirements of the Securities Exchange Act of 1934, the
Registrant has duly caused this report to be signed on its behalf
by the undersigned, thereunto duly authorized.
Date:
08 April 2024
|
By: /s/
Adrian Kemp
|
|
Name:
Adrian Kemp
|
|
Title:
Company Secretary
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