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
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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
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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.
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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
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Adrian Kemp
Company Secretary
AstraZeneca PLC