NASDAQ : Phase II DESTINY-Gastric01 trial of Enhertu versus chemotherapy met primary endpoint

Phase II DESTINY-Gastric01 trial of Enhertu versus chemotherapy met primary endpoint

27 January 2020 07:00 GMT



Phase II DESTINY-Gastric01 trial of Enhertu versus
chemotherapy met primary endpoint

Trial met primary endpoint of objective response rate and key secondary
endpoint of overall survival in patients with previously treated HER2-positive
metastatic gastric cancer

High-level results from the positive registrational Phase II trial DESTINY
-Gastric01 showed AstraZeneca's and Daiichi Sankyo Company, Limited (Daiichi
Sankyo)'s Enhertu (trastuzumab deruxtecan), achieved a statistically significant
and clinically meaningful improvement in objective response rate (ORR) and
overall survival (OS) in patients with HER2-positive unresectable or metastatic
gastric or gastroesophageal junction cancer that had progressed following two or
more treatment regimens including trastuzumab and chemotherapy.

The trial met its primary endpoint of an improvement in ORR, as assessed by an
independent review committee, in patients treated with Enhertu compared to
investigator's choice of chemotherapy (irinotecan or paclitaxel
monotherapy). Enhertu also showed a statistically significant and clinically
meaningful improvement in OS, a key secondary endpoint.

José Baselga, Executive Vice President, Oncology R&D, said: 'Gastric cancer is
usually diagnosed in the advanced stage and patients face markedly high
mortality rates, making the need for new therapies especially urgent. Given the
previous results seen in our HER2-positive development programme and now in HER2
-positive metastatic gastric cancer, we believe this antibody drug conjugate has
the potential to redefine the treatment of patients with HER2-expressing
cancers.'

Gilles Gallant, Senior Vice President, Global Head, Oncology Development,
Oncology R&D, Daiichi Sankyo, said: 'We are excited to report positive top-line
results from this trial. Our development plan remains on track in gastric
cancer, including an initial regulatory application in Japan where gastric
cancer is highly prevalent, and where SAKIGAKE designation has been granted for
this indication. We are strongly committed to bringing this therapy as rapidly
as possible to patients in need.'

The overall safety and tolerability profile of Enhertu in DESTINY-Gastric01 was
consistent with that seen in the published Phase I trial in which the most
common adverse events (≥30 percent, any grade) were haematologic and
gastrointestinal including neutrophil count decrease, anaemia, nausea and
decreased appetite. There were cases of treatment-related interstitial lung
disease (ILD) and pneumonitis, the majority of which were Grade 1 and 2 with two
Grade 3 and one Grade 4. No ILD-related deaths (Grade 5) occurred in gastric
patients in the Phase I trial or in the DESTINY-Gastric01 trial.

These results confirm activity seen in the non-randomised Phase I trial
of Enhertu in patients with HER2-positive advanced gastric cancer published
in The Lancet
Oncology (https://www.thelancet.com/journals/lanonc/article/PIIS1470
-2045(19)30088-9/fulltext).[1] Data from DESTINY-Gastric01 will be presented at
a forthcoming medical meeting.

In addition to the planned discussion with the Japan Ministry of Health, Labour
and Welfare (MHLW), both companies plan to discuss the data with other health
authorities. Enhertu recently received Accelerated Approval in the
US (https://www.astrazeneca.com/media-centre/press-releases/2019/enhertu
-trastuzumab-deruxtecan-approved-in-the-us-for-her2-positive-unresectable-or
-metastatic-breast-cancer-following-2-or-more-prior-anti-her2-based
-regimens.html) for HER2-positive unresectable or metastatic breast cancer
following two or more prior anti-HER2 based treatment regimens and additional
global regulatory submissions in HER2-positive metastatic breast cancer are
underway.

Enhertu is being jointly developed and commercialised worldwide with AstraZeneca
except in Japan where Daiichi Sankyo maintains exclusive rights.

HER2
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the
surface of many types of tumours including gastric, breast and lung cancers.
HER2 overexpression is often associated with aggressive disease and poorer
prognosis.[2] When a patient is diagnosed with gastric cancer, guidelines
recommend evaluating HER2-expression levels by an immunohistochemistry (IHC)
test.[3] A finding of IHC 3+ is considered positive. A result of IHC 2+ is
considered equivocal, in which case an additional testing method of in situ
hybridisation (ISH) is recommended to confirm HER2 status.

Gastric cancer
Gastric (stomach) cancer is the fifth most common cancer worldwide and the third
leading cause of cancer mortality; there were approximately one million new
cases reported in 2018 and 783,000 deaths.[4] Incidence rates for gastric cancer
are markedly higher in eastern Asia, where approximately half of all cases
occur.[4] South Korea and Japan have the first and third highest incidence rates
of gastric cancer worldwide, respectively; in 2018, the age-standardised rate in
Japan was 27.5 per 100,000 and in South Korea it was 39.6 per 100,000.[5]

Approximately one in five gastric cancers are HER2 positive.[6] Gastric cancer
is usually diagnosed in the advanced stage, but even when diagnosed in earlier
stages of the disease the survival rate remains modest.[7] 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.[8] For gastric cancer that
progresses on trastuzumab, there are no other approved HER2-targeting medicines
and subsequent treatment options are limited.[9]

DESTINY-Gastric01
DESTINY-Gastric01 is a registrational Phase II, open-label, multi-centre trial
assessing the safety and efficacy of Enhertu in 189 patients from Japan and
South Korea with HER2-expressing advanced gastric cancer or gastroesophageal
junction adenocarcinoma (defined as IHC3+ or IHC2+/ISH+) who have progressed on
two or more prior treatment regimens including fluoropyrimidine (5-FU) and
platinum chemotherapy and trastuzumab. Patients were randomised 2:1 to
receive Enhertu or investigator's choice of chemotherapy (paclitaxel or
irinotecan monotherapy). Patients were treated with Enhertu 6.4mg/kg once every
three weeks or chemotherapy given on the same schedule. The primary endpoint of
the trial is ORR. Secondary endpoints include OS, progression-free survival,
duration of response, disease control rate and time to treatment failure as well
as pharmacokinetic and safety endpoints.

Enhertu
Enhertu (fam-trastuzumab deruxtecan-nxki in the US only; trastuzumab deruxtecan
outside the US) is a HER2-directed antibody drug conjugate (ADC) and is the lead
product in the ADC Franchise of the Daiichi Sankyo Cancer Enterprise 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 clinical development
A comprehensive development programme is underway globally with five
registrational trials in HER2-expressing metastatic breast and gastric cancers
including a trial in patients with metastatic breast cancer and low levels of
HER2 expression. Phase II trials are underway for HER2-expressing advanced
colorectal cancer, as well as metastatic non-squamous HER2-overexpressing or
HER2-mutated non-small cell lung cancer. Trials in combination with other
anticancer treatments, such as immunotherapy, are also underway.

Collaboration between AstraZeneca and Daiichi Sankyo
In March 2019, AstraZeneca and Daiichi Sankyo entered into a global
collaboration to jointly develop and commercialise Enhertu worldwide, except in
Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is solely
responsible for manufacturing and supply.

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 at least six new medicines to be 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. In addition
to AstraZeneca's main capabilities, the Company is actively pursuing innovative
partnerships and investments that accelerate the delivery of our strategy, as
illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms - Immuno-Oncology, Tumour
Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates - 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/NYSE: 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 and Metabolism, and Respiratory.
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).



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References

      1.   Shitara K et al. Lancet Oncol. 2019; S1470-2045 (19):30088-9.
2.   Iqbal and Iqbal. Mol Biol Int. 2014; 2014: 852748.
3.   NCCN Guidelines® Gastric Cancer. Version 4.2019. December 20, 2019: GAST-B
3.
4.   Bray F et al. GLOBOCAN CA CANCER J CLIN 2018;68:394-424.
5.  World Cancer Research Fund International. Stomach Cancer Statistics. 2018.
Accessed 25 January 2020: https://www.wcrf.org/dietandcancer/cancer
-trends/stomach-cancer-statistics.
6.   American Cancer Society. Tests for Stomach Cancer. 2017. Accessed 25
January 2020: https://www.cancer.org/cancer/stomach-cancer/treating/targeted
-therapies.html.
7.   Curea et al. Cancer Biotherapy & Radiopharmaceuticals. 2017;32 (10):
Review.
8.   NCCN Guidelines® Gastric Cancer. Version 4.2019. December 20, 2019: MS-22.
9.   NCCN Guidelines® Gastric Cancer. Version 4.2019. December 20, 2019: MS-36.

Adrian Kemp
Company Secretary
AstraZeneca PLC

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