TIDMAZN
RNS Number : 3949O
AstraZeneca PLC
29 May 2020
29 May 2020 13:00 BST
Enhertu significantly improved tumour response rate and overall
survival in HER2-positive metastatic gastric cancer in Phase II
DESTINY-Gastric01 trial
First HER2-directed medicine to show an improvement in overall
survival for previously treated metastatic gastric cancer with a
41% reduction in the risk of death vs. chemotherapy
Breakthrough Therapy Designation recently granted in the US
for Enhertu in this setting
Detailed results from the positive, registrational, randomised
controlled Phase II DESTINY-Gastric01 trial showed AstraZeneca and
Daiichi Sankyo Company, Limited (Daiichi Sankyo)'s Enhertu
(trastuzumab deruxtecan) demonstrated a statistically significant
and clinically meaningful improvement in objective response rate
(ORR) and overall survival (OS), a key secondary endpoint, versus
chemotherapy.
The trial evaluated patients with HER2-positive unresectable or
metastatic gastric or gastroesophageal junction adenocarcinoma that
had progressed following two or more treatment regimens including
trastuzumab and chemotherapy.
Gastric cancer is the third leading cause of cancer mortality
with a five-year survival rate of 5% for metastatic disease.(1,2)
Approximately one in five gastric cancers are considered HER2
positive.(3,4)
The confirmed ORR, assessed by independent central review, was
42.9% with Enhertu monotherapy (6.4mg/kg) compared to 12.5% with
investigator's choice of chemotherapy (paclitaxel or irinotecan).
Ten complete responses (CRs) and 41 partial responses (PRs) were
seen in patients treated with Enhertu versus no CRs and seven PRs
seen in patients treated with chemotherapy.
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) at a pre-specified interim analysis. The median OS was
12.5 months versus 8.4 months with chemotherapy. The estimated OS
rate at one year in the Enhertu arm was 52.1% and 28.9% with the
chemotherapy arm.
Kohei Shitara, MD, Chief of Department of Gastrointestinal
Oncology, National Cancer Center Hospital East, Chiba, Japan and
principal investigator in the Phase II DESTINY-Gastric01 trial,
said: "Once patients with HER2-positive metastatic gastric cancer
progress following initial treatment with an anti-HER2 regimen,
there are limited options and no approved HER2-targeted therapies.
Based on the compelling results of the DESTINY-Gastric01 trial,
Enhertu has the potential to become a new standard of care for
these patients."
José Baselga, Executive Vice President, R&D Oncology, said:
"In DESTINY-Gastric01, the response rate was more than three times
higher with Enhertu versus chemotherapy. Additionally, more than
half of patients treated with Enhertu were alive at one year
compared to less than a third with chemotherapy. In addition to the
impressive results we saw in HER2-positive metastatic breast cancer
in DESTINY-Breast01, these results in gastric cancer may help
further define the role of Enhertu in transforming patient outcomes
across multiple HER2-targetable cancers."
Antoine Yver Executive Vice President and Global Head, Oncology
Research and Development, Daiichi Sankyo, said: "Enhertu is the
first HER2-directed therapy to show an improvement in overall
survival for patients with previously treated HER2-positive
metastatic gastric cancer. These data are encouraging and
meaningful since patients with advanced gastric cancer have limited
therapeutic options once they progress and face markedly high
mortality rates. We are working with regulatory authorities to
bring Enhertu to patients with metastatic gastric cancer as quickly
as possible."
Enhertu showed a confirmed disease control rate (DCR) of 85.7%
versus 62.5% and a median confirmed duration of response (DoR) of
11.3 months versus 3.9 months with chemotherapy.
Summary of results:(i)
Enhertu monotherapy(ii) Investigator's choice
of chemotherapy
(paclitaxel or irinotecan)
n=119 n=56
------------------------ ----------------------------
Confirmed ORR (%)(iii,iv,v) 42.9 12.5
(95% CI) (33.8-52.3; p<0.0001 (5.2-24.1)
)
------------------------ ----------------------------
CR (%) 8.4 0
------------------------ ----------------------------
PR (%) 34.5 12.5
------------------------ ----------------------------
SD (%) 42.9 50.0
------------------------ ----------------------------
Confirmed DCR (%)(vi) 85.7 62.5
(95% CI) (78.1-91.5) (48.5-75.1)
------------------------ ----------------------------
Confirmed median DoR (months) 11.3 3.9
(95% CI) (5.6-NE) (3.0-4.9)
------------------------ ----------------------------
SD, stable disease
i. Data cut-off was 8 November 2019.
ii. Enhertu 6.4mg/kg.
iii. As assessed by independent central review.
iv. ORR is (CR + PR).
v. Confirmed ORR represents responses confirmed by a follow-up
scan >=four weeks after initial CR/PR; unconfirmed ORR is the
primary endpoint of the trial (51.3% [95% CI 41.9-60.5] versus
14.3% [95% CI 6.4-26.2]; p<0.0001). Both confirmed and
unconfirmed ORR were assessed by independent central review.
vi. DCR is (CR + PR + SD).
The safety and tolerability profile of Enhertu in
DESTINY-Gastric01 was consistent with that observed in the Phase I
gastric cancer trial and previously reported Enhertu trials.(5) The
most common Grade 3 or higher treatment-emergent adverse events
were decreased neutrophil count (51.2%), anaemia (37.6%), decreased
white blood cell count (20.8%) and decreased appetite (16.8%).
There were 12 cases (9.6%) of confirmed treatment-related
interstitial lung disease (ILD) and pneumonitis as determined by an
independent review. The majority were Grade 1 or 2 with two Grade
3, one Grade 4 and no Grade 5 (ILD-related deaths).
The results were presented during the 2020 American Society of
Clinical Oncology ASCO20 Virtual Scientific Program and
simultaneously published online in The New England Journal of
Medicine.(6)
Enhertu was recently granted Breakthrough Therapy Designation
(BTD) in the US for the treatment of patients with HER2-positive
unresectable or metastatic gastric cancer based on data from
DESTINY-Gastric01 trial and Orphan Drug Designation (ODD) for
patients with gastric cancer, including gastroesophageal junction
cancer.
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 2018 and 783,000
deaths.(1,2)
Approximately one in five gastric cancers are HER2
positive.(3,4) 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.(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. For gastric cancer
that progresses on 1st-line treatment, there are no other approved
HER2-targeted medicines.(8)
DESTINY-Gastric01
DESTINY-Gastric01 is a registrational Phase II, open-label,
multi-centre, randomised controlled trial testing the safety and
efficacy of Enhertu versus investigator's choice of chemotherapy in
a primary cohort of 188 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 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.
The primary endpoint of the trial is ORR, as assessed by
independent central review. ORR, or tumour response rate,
represents the percentage of patients whose disease decreased
and/or disappears. OS was a key secondary endpoint to be
statistically evaluated hierarchically at a prespecified interim
analysis if the primary endpoint was statistically significant.
Other secondary endpoints include progression-free survival, DoR,
DCR and confirmed ORR assessed in those responses confirmed by a
follow-up scan of at least four weeks after initial independent
central review.(9)
Enhertu
Enhertu (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki
in the US) is a HER2-directed antibody drug conjugate (ADC) and 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 (5.4mg/kg) is approved in the US and Japan 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 DESTINY-Breast01 trial.
Enhertu clinical development
A comprehensive development programme is underway globally with
six registrational trials evaluating the efficacy and safety of
Enhertu monotherapy across multiple HER2-targetable 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 BTD from the US FDA for the
treatment of patients with HER2-positive unresectable or metastatic
gastric or gastroesophageal junction adenocarcinoma who have
received two or more prior regimens including trastuzumab and ODD
for patients with gastric cancer, including gastroesophageal
junction cancer. In March 2018, Enhertu received a SAKIGAKE
designation for potential use in the same HER2-positive gastric
cancer patient population and a supplemental New Drug Application
was recently submitted to the Japan Ministry of Health, Labour and
Welfare.
In May 2020, Enhertu also 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.
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 six 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. In
addition to AstraZeneca's main capabilities, the Company is
actively pursuing innovative partnerships and investment 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 ADCs - 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 & 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 .
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References
1. Bray F, et al. Global cancer statistics 2018: GLOBOCAN
estimates of incidence and mortality worldwide for 36 cancers in
185 countries. CA Cancer J. Clin. 2018; 68:394-424.
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. Iqbal N. et al. Human Epidermal Growth Factor Receptor 2
(HER2) in Cancers: Overexpression and Therapeutic Implications. Mol
Biol Int. 2014;2014:852748. doi:10.1155/2014/852748.
5. Shitara, K, et al. Trastuzumab deruxtecan (DS-8201a) in
patients with advanced HER2-positive gastric cancer: a
dose-expansion, phase 1 study. Lancet Oncol. 2019; 20:827-36.
6. Shitara, K et al. Trastuzumab Deruxtecan in Previously
Treated HER2-Positive Gastric Cancer. N Engl J Med. DOI:
10.1056/NEJMoa2004413.
7. Curea F.G, et al. Current Targeted Therapies in HER2-Positive
Gastric Adenocarcinoma. Cancer Biotherapy &
Radiopharmaceuticals. 2017;32 (10).
8. NCCN Guidelines(R) Gastric Cancer. Version 4.2019. December 20, 2019: MS-22-36.
9. ClinicalTrials.Gov. NCT03329690. Available at:
https://www.clinicaltrials.gov/ct2/show/NCT03329690
Adrian Kemp
Company Secretary
AstraZeneca PLC
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