AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) has been approved 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 one or more prior anti-HER2-based regimens.
Enhertu is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.
The approval by the European Commission (EC) follows the positive opinion of the Committee for Medicinal Products for Human Use and is based on results from the DESTINY-Breast03 Phase III trial, which were published in The New England Journal of Medicine.1 In the trial, Enhertu reduced the risk of disease progression or death by 72% versus trastuzumab emtansine (T-DM1) (hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.22-0.37; p
In Europe, more than 530,000 patients are diagnosed with breast cancer each year.2 Approximately one in five patients with breast cancer are considered HER2-positive.3 Despite initial treatment with trastuzumab, pertuzumab and a taxane, patients with HER2-positive metastatic breast cancer will often experience disease progression.4,5
Javier Cortés, MD, PhD, Head, International Breast Cancer Center (IBCC), Barcelona, Spain, said: "This approval is an important milestone for patients and clinicians in Europe, since previously treated patients with HER2-positive metastatic breast cancer typically experience disease progression in less than a year with historical standard of care treatment. In the DESTINY-Breast03 trial, the time to progression was extended well beyond a year for patients receiving Enhertu, illustrating the potential for this medicine to set a new benchmark in the treatment of HER2-positive metastatic breast cancer."
Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: "With this approval, patients across Europe with HER2-positive metastatic breast cancer will have the opportunity to be treated with Enhertu even earlier in the treatment of their disease, improving their chance for better outcomes beyond what we can already offer patients treated in later-line settings. Today's news is a further step in achieving our vision to continuously bring the transformative potential of Enhertu to patients as early as possible in their treatment to improve cancer outcomes."
Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi Sankyo, Inc., said: "We believe there is a significant need to transform outcomes for patients with HER2-positive metastatic breast cancer in Europe. In DESTINY-Breast03, treatment with Enhertu demonstrated superior progression-free survival and a doubling of the response rate compared to another HER2-directed ADC. With this approval we are now able to offer patients with HER2-positive metastatic breast cancer another option earlier in their treatment."
Additional results from the DESTINY-Breast03 Phase III trial showed that in the secondary endpoint of overall survival (OS), there was a strong trend towards improved OS with Enhertu (HR 0.55; 95% CI 0.36-0.86), however this analysis is not yet mature and further follow-up is ongoing. Nearly all patients (96.1%) treated with Enhertu were alive at nine months compared to 91.3% of patients treated with T-DM1. Confirmed objective response rate (ORR) was more than doubled in the Enhertu arm versus the T-DM1 arm (79.7% vs. 34.2%).
The safety of Enhertu has been evaluated in a pooled analysis of 573 patients across multiple tumour types who had received at least one dose of Enhertu (5.4 mg/kg) in clinical trials. The most common adverse reactions were nausea (77.0%), fatigue (57.2%), vomiting (46.8%), alopecia (38.0%) and neutropenia (34.6%). Cases of interstitial lung disease (ILD) or pneumonitis were reported in 12.0% of patients. Most ILD cases were Grade 1 (2.6%) and Grade 2 (7.3%). Grade 3 cases occurred in 0.7% of patients, no Grade 4 cases occurred, and Grade 5 cases occurred in 1.4% of patients.
Based on the results of DESTINY-Breast03, the European Society for Medical Oncology Clinical Practice Guidelines were updated in October 2021 to recommend Enhertu for use as the preferred second-line therapy for patients with HER2-positive metastatic breast cancer following progression with a taxane and trastuzumab.6
As part of this approval, the EC has also extended the market protection period for Enhertu in this setting by one extra year based on the significant clinical benefit compared to existing approved therapies.
Notes
Financial considerations
Following EU approval, an amount of $75m is due from AstraZeneca to Daiichi Sankyo as a milestone payment in 2nd-line HER2-positive metastatic breast cancer. The milestone will be capitalised as an addition to the upfront payment made by AstraZeneca to Daiichi Sankyo in 2019 and subsequent capitalised milestones, and will be amortised through the profit and loss statement.
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.
