REG - AstraZeneca PLC - Enhertu approved in US for HER2-mutant NSCLC

AstraZenecaAnnouncement

12/08/2022 07:00

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RNS Number : 8362V  AstraZeneca PLC  12 August 2022

12 August 2022 07:00 BST

 

Enhertu approved in the US as the first HER2-directed therapy for patients
with previously treated HER2-mutant metastatic non-small cell lung cancer

 

Based on DESTINY-Lung02 results which showed AstraZeneca and Daiichi Sankyo's
Enhertu reported a confirmed objective response rate of 57.7% in patients with
HER2-mutant 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 non-small cell lung cancer (NSCLC) whose tumours have activating
HER2 (ERBB2) mutations, as detected by a Food and Drug Administration
(FDA)-approved test, and who have received a prior systemic therapy.

 

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) being jointly developed and commercialised by AstraZeneca and Daiichi
Sankyo.

 

The accelerated approval by the FDA was based on the results from the
DESTINY-Lung02 Phase II trial. An interim efficacy analysis in a pre-specified
patient cohort showed Enhertu (5.4mg/kg) demonstrated a confirmed ORR of 57.7%
(n=52; 95% confidence interval  CI  43.2-71.3), as assessed by blinded
independent central review (BICR), in patients with previously treated
unresectable or metastatic non-squamous HER2-mutant (HER2m) NSCLC. Complete
responses (CR) were seen in 1.9% of patients and partial responses (PR) in
55.8% of patients with a median DoR of 8.7 months (95% CI 7.1-NE). Results
from the DESTINY-Lung02 trial will be presented at an upcoming medical
meeting.

 

Bob T. Li, MD, PhD, MPH, Medical Oncologist and Physician-Scientist, Memorial
Sloan Kettering Cancer Center, US, said: "The approval of trastuzumab
deruxtecan in non-small cell lung cancer is an important milestone for
patients and the oncology community. After two decades of research into the
role of targeting HER2 in lung cancer, the approval of the first HER2-directed
treatment option validates HER2 as an actionable target in lung cancer and
marks an important step forward for treating this patient population with
unmet medical needs."

 

Dave Fredrickson, Executive Vice President, Oncology Business Unit,
AstraZeneca, said: "HER2-mutant non-small cell lung cancer is an aggressive
form of disease which commonly affects young patients who have faced limited
treatment options and a poor prognosis to date. Today's news provides these
patients with the opportunity to benefit from a targeted therapy and
highlights the importance of testing for predictive markers, including HER2 in
lung cancer, at the time of diagnosis to ensure patients receive the most
appropriate treatment for their specific disease."

 

Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi
Sankyo, Inc, said: "We are excited that the FDA has granted accelerated
approval for Enhertu for patients with HER2-mutant metastatic non-small cell
lung cancer. Enhertu has now been approved in three different tumour types,
underscoring its significant potential across several HER2-targetable tumours.
We are continuing to evaluate the efficacy and safety of Enhertu versus
standard chemotherapy in our DESTINY clinical trials in lung cancer."

 

The safety of Enhertu was evaluated in an analysis of 101 patients with
unresectable or metastatic HER2m NSCLC who received at least one dose of
Enhertu (5.4mg/kg) in the DESTINY-Lung02 trial. In the analysis, the safety
profile of Enhertu was consistent with previous clinical trials with no new
safety concerns identified.

 

Concurrently with this approval, the FDA also approved companion diagnostic
tests to detect HER2 mutations in lung tumour tissue and plasma. This is the
third tumour type approved by the FDA for Enhertu in three years, following
approval in breast and gastric cancers. The approval follows the recently
received Priority Review
(https://www.astrazeneca.com/media-centre/press-releases/2022/enhertu-granted-priority-review-for-her2m-nsclc.html)
in the US as well as the Breakthrough Therapy Designation
(https://www.astrazeneca.com/media-centre/press-releases/2020/enhertu-granted-breakthrough-therapy-designation-in-the-us-for-her2-mutant-metastatic-non-small-cell-lung-cancer.html)
granted in 2020 by the FDA for this specific type of lung cancer based on the
results of the DESTINY-Lung01 trial.

 

Notes

 

Financial considerations

Following US approval, an amount of $125m is due from AstraZeneca to Daiichi
Sankyo as a milestone payment for the HER2-mutant metastatic NSCLC 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.

 

HER2m NSCLC

Lung cancer is the second most common form of cancer globally, with more than
two million patients diagnosed in 2020.(1) In the US, lung cancer is the
second most commonly diagnosed cancer, with more than 236,000 patients
expected to be diagnosed in 2022.(2) For patients with metastatic NSCLC,
prognosis is particularly poor, as only approximately 8% will live beyond five
years after diagnosis.(3)

 

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the
surface of many types of tumours, including lung, breast, gastric and
colorectal cancers. Certain HER2 gene alterations (called HER2 mutations) have
been identified in patients with non-squamous NSCLC as a distinct molecular
target, and occur in approximately 2-4% of patients with this type of lung
cancer.(4,5) Next-generation sequencing is used to identify HER2 (ERBB2)
mutations.(6)

 

While HER2 gene mutations can occur in a range of patients, they are more
commonly found in patients with NSCLC who are younger, female and have never
smoked.(7) HER2 gene mutations have been independently associated with cancer
cell growth and poor prognosis, with an increased incidence of brain
metastases.(8) Although the role of anti-HER2 treatment is well established in
breast and gastric cancers, there were no approved HER2-directed therapies in
NSCLC prior to the accelerated approval of Enhertu in unresectable or
metastatic NSCLC.(8,9)

 

DESTINY-Lung02

DESTINY-Lung02 is a global Phase II trial evaluating the safety and efficacy
of two doses (5.4mg/kg or 6.4mg/kg) of Enhertu in patients with HER2m
metastatic NSCLC with disease recurrence or progression during or after at
least one regimen of prior anticancer therapy that must have contained a
platinum-based chemotherapy.

 

The primary endpoint of the trial is ORR as assessed by BICR. Secondary
endpoints include disease control rate (DCR), DoR, progression-free survival
(PFS), investigator-assessed ORR, overall survival (OS) and safety.

 

DESTINY-Lung02 enrolled 152 patients at multiple sites, including Asia, Europe
and North America. For more information about the trial, visit
ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT04644237) .

 

DESTINY-Lung01

DESTINY-Lung01 is a global Phase II, open-label, two-cohort trial evaluating
the safety and efficacy of Enhertu in patients with HER2m (6.4mg/kg) or
HER2-overexpressing (defined as IHC 3+ or IHC 2+) [6.4mg/kg and 5.4mg/kg]
unresectable and/or metastatic non-squamous NSCLC who had progressed after one
or more systemic therapies. The primary endpoint is confirmed ORR by
independent central review (ICR). Key secondary endpoints include DoR, DCR,
PFS, OS and safety. DESTINY-Lung01 enrolled 181 patients at multiple sites,
including Asia, Europe and North America.

 

Data from the DESTINY-Lung01 Phase II trial was published in The New England
Journal of Medicine (https://www.nejm.org/doi/full/10.1056/NEJMoa2112431)
.(10) Primary results from previously-treated patients with HER2-mutations
(cohort 2) of DESTINY-Lung01 demonstrated an ORR of 54.9% (95% CI 44.2-65.4)
in patients treated with Enhertu (6.4mg/kg) as assessed by ICR. One (1.1%) CR
and 49 (53.8%) PRs were observed. A confirmed DCR of 92.3% was seen with a
reduction in tumour size observed in most patients. After a median follow-up
of 13.1 months, the median DoR for Enhertu was 9.3 months. The median PFS was
8.2 months and the median OS was 17.8 months.

 

The safety profile of the most common adverse events with Enhertu in
DESTINY-Lung01 was consistent with previous clinical trials with no new safety
concerns identified. For more information about the trial, visit
ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03505710) .

 

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
(https://clinicaltrials.gov/ct2/show/NCT03734029) trial.

 

Enhertu (5.4mg/kg) is approved in the US for the treatment of adult patients
with unresectable or metastatic NSCLC whose tumours have activating HER2
(ERBB2) mutations, as detected by an FDA-approved test, and who have received
a prior systemic therapy based on the results from the DESTINY-Lung02 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 (GEJ) 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 and gastric cancer are currently
under review in several countries based on the DESTINY-Breast01,
DESTINY-Breast03, DESTINY-Breast04, DESTINY-Gastric01 and DESTINY-Gastric02
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 (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 lung cancer

AstraZeneca is working to bring patients with lung cancer closer to cure
through the detection and treatment of early-stage disease, while also pushing
the boundaries of science to improve outcomes in the resistant and advanced
settings. By defining new therapeutic targets and investigating innovative
approaches, the Company aims to match medicines to the patients who can
benefit most.

 

The Company's comprehensive portfolio includes leading lung cancer medicines
and the next wave of innovations, including Tagrisso (osimertinib) and Iressa
(gefitinib); Imfinzi (durvalumab) and tremelimumab; Enhertu (trastuzumab
deruxtecan) and datopotamab deruxtecan in collaboration with Daiichi Sankyo;
Orpathys (savolitinib) in collaboration with HUTCHMED; as well as a pipeline
of potential new medicines and combinations across diverse mechanisms of
action.

 

AstraZeneca is a founding member of the Lung Ambition Alliance, a global
coalition working to accelerate innovation and deliver meaningful improvements
for people with lung cancer, including and beyond treatment.

 

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.   WHO. International Agency of Cancer Research. Cancer Today. 2020.
Available at: https://gco.iarc.fr/today/home. Accessed August 2022.

2.   American Cancer Society. Key Statistics for Lung Cancer. Available at:
https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html. Accessed
August 2022.

3.   American Cancer Society. Lung Cancer Survival Rates. Available at:
https://www.cancer.org/cancer/lung-cancer/detection-diagnosis-staging/survival-rates.html.
Accessed August 2022.

4.   Liu S, et al. Targeting HER2 Aberrations in Non-Small Cell Lung Cancer
with Osimertinib. Clin Cancer Res. 2018;24(11):2594-2604.

5.   Riudavets M, et al. Targeting HER2 in non-small-cell lung cancer
(NSCLC): a glimpse of hope? An updated review on therapeutic strategies in
NSCLC harbouring HER2 alterations. ESMO Open. 2021;6(5):100260.

6.   Hechtman, J, et al. The Past, Present, and Future of HER2 (ERBB2) in
Cancer: Approaches to Molecular Testing and an Evolving Role in Targeted
Therapy. Cancer Cyto. 2019;127(7):428-431.

7.   Pillai RN, et al. HER2 mutations in lung adenocarcinomas: A report from
the Lung Cancer Mutation Consortium. Cancer. 2017;123:4099-105.

8.   Offin M, et al. Frequency and Outcomes of Brain Metastases in Patients
With HER2-Mutant Lung Cancers. Cancer. 2019;125:4380-7.

9.   Zhou J, et al. Clinical outcomes of patients with HER2-mutant advanced
lung cancer: chemotherapies versus HER2-directed therapies. Ther Adv Med
Oncol. 2020;12.

10.  Li B T, et al. Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung
Cancer. NEJM. 2022; 386:241-251.

 

Dr. Li has provided uncompensated advisory services to AstraZeneca and Daiichi
Sankyo.

 

Adrian Kemp

Company Secretary

AstraZeneca PLC

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