# AstraZeneca’s Enhertu reduces risk of disease progression by 72%

- Link: https://www.directorstalkinterviews.com/astrazenecas-enhertu-reduces-risk-of-disease-progression-by-72/4121023372
- Published: 2021-09-20T08:42:43+01:00
- Author: Amilia Stone

Detailed positive results from the head-to-head DESTINY-Breast03 Phase III trial
showed that _Enhertu_ (trastuzumab deruxtecan), the **[AstraZeneca plc](https://www.directorstalkinterviews.com/ftse-company/astrazeneca/azn.l)**(
[LON:AZN](https://www.directorstalkinterviews.com/ftse-company/astrazeneca/azn.l))
and Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) HER2-directed antibody
drug conjugate, demonstrated superior progression-free survival versus trastuzumab
emtansine (T-DM1), a HER2-directed ADC currently approved to treat patients with
HER2-positive unresectable and/or metastatic breast cancer previously treated with
trastuzumab and a taxane. Results were presented today in a Presidential Symposium
at the European Society for Medical Oncology Congress 2021.

At a prespecified interim analysis of DESTINY-Breast03, _Enhertu_ demonstrated a
72% reduction in the risk of disease progression or death compared to T-DM1 (hazard
ratio [HR] 0.28; 95% confidence interval [CI] 0.22-0.37; p=7.8×10^(-22)). After 
15.5 and 13.9 months of follow-up in the _Enhertu_ and T-DM1 arms respectively, 
the median PFS for patients treated with _Enhertu_ was not reached (95% CI 18.5-
NE) compared to 6.8 months for T-DM1 (95% CI 5.6-8.2) as assessed by blinded independent
central review (BICR).

In the key secondary endpoint of PFS assessed by investigators, patients treated
with _Enhertu_ experienced a three-fold improvement in PFS of 25.1 months versus
7.2 months for T-DM1 (HR 0.26; 95% CI 0.20-0.35; p=6.5×10^(-24)). A consistent PFS
benefit was observed in key subgroups of patients treated with _Enhertu_, including
those with a history of stable brain metastases.

There was a strong trend towards improved overall survival (OS) with _Enhertu_ (
HR 0.56; 95% CI 0.36-0.86; nominal p=0.007172), however this analysis is not yet
mature and is not statistically significant. Nearly all patients treated with _Enhertu_
were alive at one year (94.1%) compared to 85.9% of patients treated with T-DM1.

Confirmed objective response rate (ORR) more than doubled in the _Enhertu_ arm versus
the T-DM1 arm (79.7% vs. 34.2%). Forty-two (16.1%) complete responses (CR), and 
166 (63.6%) partial responses (PR) were observed in patients treated with _Enhertu_
compared to 23 (8.7%) CRs and 67 (25.5%) PRs in patients treated with T-DM1.

> **Javier Cortés, MD, PhD, Head, International Breast Cancer Center (IBCC), Barcelona,
> said**: “Patients with previously treated HER2-positive metastatic breast cancer
> will typically experience disease progression in less than a year with available
> HER2-directed treatments. The high and consistent benefit seen across efficacy
> endpoints and key subgroups of patients receiving _Enhertu_ in DESTINY-Breast03
> is remarkable and supports the potential of _Enhertu_ to become the new standard
> of care for those who have previously been treated for HER2-positive metastatic
> breast cancer.”

> **Susan Galbraith, Executive Vice President, Oncology R&D, said**: “Today’s results
> are ground-breaking. _Enhertu_ tripled progression-free survival as assessed by
> investigators, and provided a disease control rate exceeding 95% compared to 77%
> for T-DM1 in DESTINY-Breast03. In addition, the safety profile was encouraging
> with no Grade 4 or 5 interstitial lung disease events in this trial. These unprecedented
> data represent a potential paradigm shift in the treatment of HER2-positive metastatic
> breast cancer, and illustrate the potential for _Enhertu_ to transform more patient
> lives in earlier treatment settings.”

> **Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said**: “The early survival
> data, which evaluated _Enhertu_ against another HER2-directed ADC, showed that
> nearly all patients treated with _Enhertu_ were alive after a year and is a positive
> indication of the potential of this medicine to transform the treatment of HER2-
> positive metastatic breast cancer. These landmark data will form the basis of 
> our discussions with global health authorities to potentially bring _Enhertu_ 
> to patients with previously treated HER2-positive metastatic breast cancer as 
> a more effective treatment option as soon as possible.”

The safety profile of the most common adverse events with _Enhertu_ in DESTINY-Breast03
was consistent with previous clinical trials with no new safety concerns identified.
The most common Grade 3 or higher treatment-emergent adverse events in the _Enhertu_
arm were neutropenia (19.1%), thrombocytopenia (7.0%), leukopenia (6.6%) and nausea(
6.6%).

There were 27 cases (10.5%) of treatment-related interstitial lung disease (ILD)
or pneumonitis reported, as determined by an independent adjudication committee.
The majority (9.7%) were low Grade (Grade 1 or Grade 2), with two Grade 3 (0.8%)
events reported. No Grade 4 or Grade 5 ILD or pneumonitis events occurred.

**DESTINY-Breast01 Updated Results**

Updated results from the pivotal DESTINY-Breast01 Phase II trial were also presented
at ESMO and showed that _Enhertu_ (5.4 mg/kg) continued to demonstrate impressive
efficacy and durable responses in patients with HER2-positive metastatic breast 
cancer following two or more prior HER2-based regimens.

With a median duration of follow-up of 26.5 months, a continued increase in response
was seen in patients treated with _Enhertu_ with an updated ORR of 62.0%, including
one additional CR (7.1%). A median duration of response (DoR) of 18.2 months was
also observed.

The median PFS was 19.4 months. In an exploratory analysis of OS with a median follow-
up of 31.1 months, evaluated at a greater maturity (52%), the updated median OS 
was 29.1 months.

The overall safety and tolerability profile seen with _Enhertu_ in DESTINY-Breast01
continues to be consistent with what has been previously observed. There has been
one new case of treatment-related Grade 1 ILD or pneumonitis determined by an independent
adjudication committee as of data cut-off of March 26, 2021.

_Enhertu_ is approved 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 in the US, Japan, the EU and several other countries
based on the results from the DESTINY-Breast01 trial.

_Enhertu_ is being further assessed in a comprehensive clinical development programme
evaluating efficacy and safety across multiple HER2-targetable cancers, including
breast, gastric, lung and colorectal cancers.

Several presentations featured during the ESMO Congress 2021 will showcase the strength
and depth of _Enhertu_ data across multiple tumour types, including gastric, lung
and breast cancers, reinforcing the transformational potential of this medicine 
in the treatment of HER2-targetable cancers.

**HER2-positive breast cancer**

Breast cancer remains the most common cancer and is one of the leading causes of
cancer-related deaths in women worldwide.^(1) More than two million patients with
breast cancer were diagnosed in 2020, resulting in nearly 685,000 deaths globally.
^(1) Approximately one in five cases of breast cancer are considered HER2-positive.
^(2)

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.
^(3) HER2 protein overexpression may occur as a result of HER2 gene amplification
and is often associated with aggressive disease and a poor prognosis in breast cancer.
^(4)

Despite initial treatment with trastuzumab and a taxane, people with HER2-positive
metastatic breast cancer will often experience disease progression.^(5) More effective
options are needed to further delay progression and extend survival.^(5-7)

**DESTINY-Breast03**

DESTINY-Breast03 is a global head-to-head, randomised, open-label, registrational
Phase III trial evaluating the safety and efficacy of _Enhertu_ (5.4mg/kg) versus
T-DM1 in patients with HER2-positive unresectable and/or metastatic breast cancer
previously treated with trastuzumab and a taxane.

The primary efficacy endpoint of DESTINY-Breast03 is PFS based on blinded independent
central review. Secondary efficacy endpoints include OS, objective response rate,
duration of response, clinical benefit rate, PFS based on investigator assessment
and safety.

DESTINY-Breast03 enrolled approximately 500 patients at multiple sites in Asia, 
Europe, North America, Oceania and South America. For more information about the
trial, visit ClinicalTrials.gov.

**DESTINY-Breast01**

DESTINY-Breast01 is a registrational Phase II, single-arm, open-label, global, multi-
centre, two-part trial evaluating the safety and efficacy of _Enhertu_ in patients
with HER2-positive unresectable and/or metastatic breast cancer previously treated
with T-DM1.

The primary endpoint of the trial is ORR, as determined by ICR. Secondary objectives
include DoR, disease control rate, clinical benefit rate, PFS and OS.

DESTINY-Breast01 enrolled 253 patients at multiple sites in Asia, Europe and North
America. 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 Canada, the EU, Israel, Japan, the UK and the
US 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 results from the DESTINY-Breast01 trial.

_Enhertu_ (6.4mg/kg) is also approved in Israel, Japan and the US for the treatment
of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal
junction 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.

_Enhertu_ was highlighted in the Clinical Cancer Advances 2021 report as one of 
two significant advancements in the “ASCO Clinical Advance of the Year: Molecular
Profiling Driving Progress in GI Cancers,” based on data from both the DESTINY-CRC01
and DESTINY-Gastric01 trials, as well as one of the targeted therapy advances of
the year in non-small cell lung cancer (NSCLC), based on the interim results of 
the HER2-mutated cohort of the DESTINY-Lung01 trial.

In May 2020, _Enhertu_ also received Breakthrough Therapy Designation for the treatment
of patients with metastatic NSCLC whose tumours have a HER2-mutation and with disease
progression on or after platinum-based therapy.

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