TIDMAZN
RNS Number : 9823L
AstraZeneca PLC
18 January 2021
18 January 2021 07:00 GMT
Enhertu approved in the US for the treatment of patients
with
previously treated HER2-positive advanced gastric cancer
First HER2-directed medicine approved for patients with gastric
cancer in a decade
AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi
Sankyo)'s Enhertu (trastuzumab deruxtecan) has been approved in the
US 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
.
In the US, gastric cancer is most frequently diagnosed in the
advanced stage, with only approximately 5% of patients surviving
beyond five years.(1,2) Approximately one in five gastric cancers
are HER2 positive.(3)
The approval by the Food and Drug Administration (FDA) was based
on the positive results from the randomised DESTINY-Gastric01 Phase
II trial conducted in Japan and South Korea. In the trial, Enhertu
demonstrated a statistically significant and clinically meaningful
improvement in overall survival (OS) and objective response rate
(ORR) versus chemotherapy (irinotecan or paclitaxel) in patients
with advanced gastric cancer or GEJ adenocarcinoma who had
progressed on at least two or more prior regimens including
trastuzumab plus a fluoropyrimidine- and platinum-based
chemotherapy combination.(4)
Ronan Kelly, MD, MBA, Director of the Charles A. Sammons Cancer
Center and the W.W. Caruth, Jr. Chair of Immunology at Baylor
University Medical Center, Dallas, Texas, US, said: "Patients with
metastatic HER2-positive gastric cancer with progression following
1st-line treatment have historically faced poor outcomes, including
low response to treatment and rapid disease progression. This
approval represents the first time a HER2-directed medicine has
demonstrated a significant improvement in survival compared to
chemotherapy following initial treatment in the metastatic setting,
and it has the potential to become the new standard of care for
this patient population."
Dave Fredrickson, Executive Vice President, Oncology Business
Unit, said: "Today's approval of Enhertu represents the first
HER2-directed medicine approved in a decade for patients with
HER2-positive metastatic gastric cancer. The results from the
DESTINY-Gastric01 trial highlight the potential to change clinical
practice, showing a 41 per cent improvement in survival and a
response rate more than three times higher with Enhertu compared to
chemotherapy. We are thrilled to bring this important medicine to
more patients and physicians in the US."
Antoine Yver, Executive Vice President and Global Head, Oncology
Research and Development, Daiichi Sankyo, said: "Enhertu is the
first antibody drug conjugate to receive approval in the US for the
treatment of patients with metastatic gastric cancer, and
represents a major advance in managing this difficult-to-treat
disease. This second indication in the US represents an important
step forward in our ambitious plan to accelerate the development of
Enhertu across a broad range of HER2-targetable cancers."
In a pre-specified interim analysis from the DESTINY-Gastric01
trial, patients treated with Enhertu had a 41% reduction in the
risk of death versus patients treated with chemotherapy (based on a
hazard ratio [HR] of 0.59; 95% confidence interval [CI] 0.39-0.88;
p=0.0097) with a median OS of 12.5 months versus 8.4 months.(3)
Confirmed ORR, assessed by independent central review was a
major efficacy outcome. Results showed a confirmed ORR of 40.5% in
patients treated with Enhertu (n=126) compared to 11.3% in patients
treated with chemotherapy (n=62). Patients treated with Enhertu had
a 7.9% complete response rate and a 32.5% partial response rate
compared to a complete response rate of 0% and a partial response
rate of 11.3% for patients treated with chemotherapy .(4)
Enhertu demonstrated a median progression-free survival (PFS) of
5.6 months compared to 3.5 months with chemotherapy (HR=0.47; 95%
CI 0.31-0.71). Additionally, Enhertu showed a median duration of
response (DoR) of 11.3 months versus 3.9 months with
chemotherapy.(4)
Results from the DESTINY-Gastric01 trial were published in The
New England Journal of Medicine in June 2020 .(5)
The most common adverse reactions, including laboratory
abnormalities, of any grade (greater than or equal to 20%) for
patients treated with Enhertu (n=125) in the DESTINY-Gastric01
trial were anaemia, leukopenia, neutropenia, lymphocytopenia,
thrombocytopenia, nausea, decreased appetite, increased aspartate
aminotransferase, fatigue, increased blood alkaline phosphatase,
increased alanine aminotransferase, diarrhoea, hypokalaemia,
vomiting, constipation, increased blood bilirubin, pyrexia and
alopecia. Interstitial lung disease or pneumonitis occurred in 10%
of patients.(4)
This is the second indication approved for Enhertu in the US
following the accelerated approval for adult patients with
unresectable or metastatic HER2-positive breast cancer who have
received two or more prior anti-HER2-based regimens in the
metastatic setting based on the DESTINY-Breast01 trial.
Enhertu was previously granted Priority Review , Breakthrough
Therapy Designation (BTD) in HER2-positive metastatic gastric
cancer and Orphan Drug Designation for gastric cancer by the FDA.
Two additional Phase II trials, DESTINY-Gastric02 and
DESTINY-Gastric03, are underway, further evaluating treatment with
Enhertu in patients with HER2-positive metastatic gastric
cancer.
Financial considerations
Following US approval, an amount of $115m is due from
AstraZeneca to Daiichi Sankyo as a combined 2nd-line and 3rd-line
milestone payment in HER2-positive gastric cancer. In AstraZeneca,
the milestones paid will be capitalised as an addition to the
upfront payment made in 2019 and subsequent capitalised milestones
and amortised through the profit and loss.
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. For further details on the financial arrangements,
please consult the collaboration agreement from March 2019.
Gastric cancer
Gastric (stomach) cancer is the fifth most common cancer
worldwide and the third leading cause of cancer mortality with a
five-year survival rate of 5% for metastatic disease; there were
approximately one million new cases reported in 2020 and more than
768,000 deaths.(6) In the US, it is estimated that 27,600 new cases
of gastric cancer were diagnosed in 2020 and more than 11,000
people died from the disease.(7)
Approximately one in five gastric cancers are HER2 positive.(1)
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. Gastric cancer is usually
diagnosed in the advanced stage, but even when diagnosed in earlier
stages of the disease the survival rate remains modest.(2)
Recommended 1st-line treatment for HER2-positive advanced or
metastatic gastric cancer is combination chemotherapy plus
trastuzumab, an anti-HER2 medicine, which has been shown to improve
survival outcomes when added to chemotherapy. For patients with
metastatic gastric cancer that progresses following initial
treatment with a trastuzumab-based regimen, there were previously
no other approved HER2-targeted medicines prior to the approval of
Enhertu.(8)
DESTINY-Gastric01
DESTINY-Gastric01 is a Phase II, open-label, multi-centre,
randomised controlled trial testing the safety and efficacy of
Enhertu (6.4 mg/kg) versus investigator's choice of chemotherapy in
a primary cohort of patients from Japan and South Korea with
HER2-positive (defined as IHC3+ or IHC2+/ISH+), locally advanced or
metastatic gastric cancer or GEJ adenocarcinoma who have progressed
on at least two or more prior regimens including trastuzumab plus a
fluoropyrimidine- and platinum-based chemotherapy combination.
Patients (n=188) were randomised 2:1 to receive Enhertu or
physician's choice of chemotherapy (paclitaxel or irinotecan
monotherapy). Patients were treated with Enhertu 6.4mg/kg once
every three weeks or chemotherapy.
The main efficacy outcome measures were ORR, assessed by
independent central review, and OS. Additional efficacy outcome
measures were PFS and DoR.(4)
Enhertu
Enhertu (trastuzumab deruxtecan; fam-trastuzuab deruxtecan-nxki
in the US) is a HER2-directed antibody drug conjugate (ADC). It is
the lead ADC in the oncology portfolio of Daiichi Sankyo and the
most advanced programme in AstraZeneca's ADC scientific
platform.
ADCs are targeted cancer medicines that deliver cytotoxic
chemotherapy ('payload') to cancer cells via a linker attached to a
monoclonal antibody that binds to a specific target expressed on
cancer cells. Enhertu is comprised of a humanised anti-HER2 IgG1
monoclonal antibody with the same amino acid sequence as
trastuzumab attached to a topoisomerase I inhibitor payload, an
exatecan derivative, via a tetrapeptide-based cleavable linker.
Enhertu (5.4mg/kg) is approved in the US under accelerated
approval, and in Japan under the conditional early approval system,
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 in the metastatic setting based on the
DESTINY-Breast01 trial. In addition to the US, Enhertu (6.4mg/kg)
is also approved in Japan for patients with HER2-positive
unresectable advanced or recurrent gastric cancer that progressed
after chemotherapy based on the DESTINY-Gastric01 trial.
Development programme
A comprehensive development programme is underway globally, with
nine registrational trials evaluating the efficacy and safety of
Enhertu monotherapy across multiple HER2 cancers, including breast,
gastric and lung cancers. Trials in combination with other
anticancer treatments, such as immunotherapy, are also
underway.
In May 2020, Enhertu received a BTD for the treatment of
patients with metastatic non-small cell lung cancer whose tumours
have a HER2 mutation and with disease progression on or after
platinum-based therapy.
Daiichi Sankyo collaboration
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 manufacturing and supply of Enhertu and datopotamab
deruxtecan.
AstraZeneca in gastrointestinal cancers
AstraZeneca has a broad development programme for the treatment
of gastrointestinal (GI) cancers across several medicines spanning
a variety of tumour types and stages of disease. In 2020, GI
cancers collectively represented over five million new cancer cases
leading to more than 3.5 million deaths.(6) Within this programme,
the Company is committed to improving outcomes in gastric, liver,
oesophageal, pancreatic, and colorectal cancers.
The Company aims to understand the potential of Enhertu in the
two most common GI cancers, colorectal and gastric cancers. Imfinzi
(durvalumab) is being assessed as both as monotherapy and in
combinations including with tremelimumab across the two main types
of liver cancer, hepatocellular carcinoma and biliary tract cancer,
and in oesophageal and gastric cancers. Lynparza (olaparib) is a
first-in-class PARP inhibitor with a broad and advanced clinical
trial programme across multiple GI tumour types including
pancreatic and colorectal cancers. Lynparza is developed and
commercialised in collaboration with MSD (Merck & Co., Inc.
inside the US and Canada).
AstraZeneca in oncology
AstraZeneca has a deep-rooted heritage in oncology and offers a
quickly growing portfolio of new medicines that has the potential
to transform patients' lives and the Company's future. With seven
new medicines launched between 2014 and 2020, and a broad pipeline
of small molecules and biologics in development, the Company is
committed to advance oncology as a key growth driver for
AstraZeneca focused on lung, ovarian, breast and blood cancers.
By harnessing the power of six scientific platforms -
Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage
Response, Antibody Drug Conjugates, Epigenetics, and Cell Therapies
- and by championing the development of personalised combinations,
AstraZeneca has the vision to redefine cancer treatment 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,
primarily for the treatment of diseases in three therapy areas -
Oncology, 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
For details on how to contact the Investor Relations Team,
please click here . For Media contacts, click here .
References
1. Curea F.G, et al. Current Targeted Therapies in HER2-Positive
Gastric Adenocarcinoma. Cancer Biotherapy &
Radiopharmaceuticals. 2017;32 (10).
2. American Cancer Society. Stomach Cancer: Early Detection,
Diagnosis, and Staging. Available at:
https://www.cancer.org/cancer/stomach-cancer/detection-diagnosis-staging/survival-rates.html
.
3. American Cancer Society. Stomach Cancer: Treating Stomach Cancer. Available at: https://www.cancer.org/cancer/stomach-cancer/treating/targeted-therapies.html .
4. ENHERTU(R) [fam-trastuzumab deruxtecan-nxki] US prescribing information; 2021.
5. Shitara, K et al. Trastuzumab Deruxtecan in Previously
Treated HER2-Positive Gastric Cancer. N Engl J Med.
2020;382(25):2419-2430. DOI: 10.1056/NEJMoa2004413.
6. Global Cancer Observatory. Cancer Today. Lyon, France:
International Agency for Research on Cancer. Available at:
https://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.pdf
.
7. American Cancer Society. Stomach Cancer: About Stomach Cancer. Available at: https://www.cancer.org/cancer/stomach-cancer/about/key-statistics.html .
8. NCCN Guidelines(R) Gastric Cancer. Version 4.2019. December 20, 2019: MS-22-36.
Adrian Kemp
Company Secretary
AstraZeneca PLC
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