TIDMAZN
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
in the US as well as the Breakthrough Therapy Designation 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 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 .
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 .(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 .
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 (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 , and datopotamab deruxtecan (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 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 and follow the
Company on Twitter @ AstraZeneca .
Contacts
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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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