# AstraZeneca meets primary endpoint for Enhertu phase II trial

- Link: https://www.directorstalkinterviews.com/astrazeneca-meets-primary-endpoint-for-enhertu-phase-ii-trial/412804017
- Published: 2020-01-27T07:20:58+00:00
- Author: Amilia Stone

High-level results from the positive registrational Phase II trial DESTINY-Gastric01
showed **AstraZeneca** ([LON:AZN](https://www.directorstalkinterviews.com/ftse-company/astrazeneca/azn.l))
and Daiichi Sankyo Company, Limited’s _Enhertu_, achieved a statistically significant
and clinically meaningful improvement in objective response rate and overall survival
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.
^(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 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.

Share on: