January 20, 2021: “AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo)’s Enhertu (trastuzumab deruxtecan) has been granted conditional approval in the European Union (EU) as a monotherapy 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 Europe, approximately 531,000 cases of breast cancer in women are diagnosed annually, with an estimated one in five cases being HER2-positive.
The impact of the disease is significant, with breast cancer responsible for more than 141,000 deaths per year in Europe.
The approval by the European Commission was based on positive results from the single-arm DESTINY-Breast01 Phase II trial, in which Enhertu showed clinically meaningful and durable antitumour activity in patients with HER2-positive metastatic breast cancer who had received two or more prior anti-HER2-based regimens.
It follows the December 2020 recommendation for approval by the Committee for Medicinal Products for Human Use of the European Medicines Agency, which reviewed the application under its accelerated assessment procedure.
Professor Fabrice André, Head of Research, Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France, said: “One in five women with breast cancer have HER2-positive disease and those with previously treated metastatic disease often progress quickly.
Related News: Phase II DESTINY-Gastric01 trial of Enhertu (trastuzumab deruxtecan) versus chemotherapy met primary endpoint
Trastuzumab deruxtecan (DS-8201), accomplished the tumour response rate of 60.9% in pivotal Phase II HER2-positive metastatic breast cancer trial
One of the biggest challenges in this setting has been identifying treatments that produce a durable response.
The DESTINY-Breast01 trial showed a breadth, depth and durability of response not previously seen in this patient population.”
Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: “Enhertu is already transforming outcomes for patients with HER2-positive metastatic breast cancer in the US and Japan, and this approval enables us to bring the benefits of this medicine to patients in the EU.
We will continue to explore the potential of Enhertu in this setting, as well as in earlier lines of treatment and stages of disease, with the ambition of improving the lives of patients with HER2-targetable breast cancer.”
Gilles Gallant, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo, said: “This expedited review underscores the practice-changing potential of Enhertu for patients in the metastatic setting.
Enhertu is the first-ever new medicine to be approved in breast cancer in Europe on the basis of Phase II single-arm data, and one of the fastest accelerated assessment procedures for an application in oncology.”
In the DESTINY-Breast01 Phase II trial, after a median follow-up of 20.5 months, Enhertu showed a confirmed objective response rate (ORR) of 61.4%, including a 6.5% complete response rate and a 54.9% partial response rate, and an estimated median duration of response (DoR) of 20.8 months for patients with HER2-positive metastatic breast cancer who had received at least two previous lines of therapy.
The analysis was presented during the 2020 San Antonio Breast Cancer Symposium. An earlier analysis with a median follow-up of 11.1 months was published in The New England Journal of Medicine in February 2020.
The safety of Enhertu has been evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of Enhertu 5.4mg/kg in clinical trials.
The most common adverse reactions were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anaemia, neutropenia, diarrhoea, thrombocytopenia, cough, leukopenia and headache.
Cases of interstitial lung disease (ILD) or pneumonitis, were reported in 15.0% of patients, and in 2.6% of patients, ILD led to death.
Enhertu (5.4mg/kg) is approvedin 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 Phase II trial.
It is also approved in the US and Japan for the treatment of patients with HER2-positive unresectable advanced or recurrent gastric cancer that has progressed after a trastuzumab-containing regimen based on the DESTINY-Gastric01 Phase II trial.
Enhertu is being further assessed in several ongoing Phase III breast cancer trials as part of a broad development programme, including DESTINY-Breast02, a confirmatory trial in 3rd-line HER2-positive metastatic breast cancer, and DESTINY-Breast03, as a 2nd-line treatment.
DESTINY-Breast04 is testing Enhertu in patients with metastatic breast cancer and low expression of HER2; and DESTINY-Breast05 is evaluating Enhertu as an adjuvant treatment of patients with high-risk HER2-positive early breast cancer.
Additional ongoing trials are testing Enhertu in combination with other anti-cancer medicines in HER2-positive and HER2-low metastatic breast cancer.
Financial considerations
Following EU approval, an amount of $75m is due from AstraZeneca to Daiichi Sankyo as a milestone payment for HER2-positive breast 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 most EU territories are recognised by Daiichi Sankyo. AstraZeneca reports its share of gross profit margin from Enhertu sales in those territories as collaboration revenue in the Company’s financial statements.
AstraZeneca will record product sales in respect of sales made in territories where AstraZeneca is the selling party.
For further details on the financial arrangements, please consult the collaboration agreement from March 2019.
HER2-positive breast cancer
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours, including breast cancer.
HER2 overexpression may be associated with a specific HER2 gene alteration known as HER2 amplification and is often associated with aggressive disease and a poor prognosis in breast cancer.
There remain significant unmet clinical needs for patients with HER2-positive metastatic breast cancer.
The disease remains incurable with patients eventually progressing after currently available treatment options.
DESTINY-Breast01
DESTINY-Breast01 was a single-arm, open-label, global, multicentre, two-part Phase II trial testing the safety and efficacy of Enhertu in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine.
The primary endpoint of the trial was ORR, as determined by independent central review. Secondary objectives included DoR, disease control rate, clinical benefit rate, progression-free survival and overall survival.
Enhertu
Enhertu (trastuzumab deruxtecan; fam-trastuzumab 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 by a tetrapeptide-based cleavable linker.
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 also received a Breakthrough Therapy Designation 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.”
