19 July 2022 07:00 BST

Enhertu approved in the EU for patients with HER2-positive metastatic breast cancer treated with one or more prior anti-HER2-based regimens

Approval broadens indication for AstraZeneca and Daiichi Sankyo's Enhertu across Europe to earlier use in HER2-positive metastatic breast cancer

Based on ground-breaking DESTINY-Breast03 results in which Enhertu demonstrated a 72% reduction in the risk of disease progression or death vs. trastuzumab emtansine (T-DM1)

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<0.000001) in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane.

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.

Further details on the financial arrangements were set out in the March 2019 announcement of the collaboration.

HER2-positive breast cancer

Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.⁷ More than two million patients were diagnosed with breast cancer in 2020, with nearly 685,000 deaths globally.⁷ 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

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.⁸ HER2 protein overexpression may occur as a result of HER2 gene amplification and is often associated with aggressive disease and poor prognosis in breast cancer.⁹

Despite initial treatment with trastuzumab, pertuzumab and a taxane, patients with HER2-positive metastatic breast cancer will often experience disease progression.^4,5 More treatment options are needed to further delay progression and extend survival.^4,10,11

DESTINY-Breast03

DESTINY-Breast03 is a global, head-to-head, randomised, open-label, registrational Phase III trial evaluating the efficacy and safety 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. OS is a key secondary efficacy outcome measure. Secondary efficacy endpoints include ORR, duration of response and PFS based on investigator assessment.

DESTINY-Breast03 enrolled 524 patients at multiple sites in Asia, Europe, North America, Oceania and South America. Results from DESTINY-Breast03 have been published in The New England Journal of Medicine.¹ 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 more than 30 countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a (or one or more) prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy, based on the results from the DESTINY-Breast03 trial.

Enhertu (5.4mg/kg) is also approved in several countries 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 results from the DESTINY-Breast01 trial.

Enhertu (6.4mg/kg) is approved in several countries for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) 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.

Regulatory applications for Enhertu are currently under review in China, Japan and several other countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen based on the results from the DESTINY-Breast03 trial.

Enhertu is under review in Europe for the treatment of adult patients with unresectable or metastatic HER2-low (immunohistochemistry (IHC) 1+ or IHC 2+/ in-situ hybridisation (ISH)-negative) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy, based on the results from the DESTINY-Breast04 trial. Patients with hormone receptor (HR) positive breast cancer must additionally have received or be ineligible for endocrine therapy.

Enhertu is also currently under review in the US for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumours have a HER2 (ERBB2) mutation and who have received a prior systemic therapy based on the results of the DESTINY-Lung01 trial, and in Europe for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior anti-HER2-based regimen based on the DESTINY-Gastric01 and DESTINY-Gastric02 trials.

Enhertu was granted Breakthrough Therapy Designation in the US for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-negative) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy, based on the results of the DESTINY-Breast04 trial. Patients with HR-positive breast cancer should additionally have received or be ineligible for endocrine therapy.

Daiichi Sankyo collaboration

Daiichi Sankyo Company, Limited (TSE:4568) [referred to as Daiichi Sankyo] and AstraZeneca entered into a global collaboration to jointly develop and commercialise Enhertu (a HER2-directed ADC) in March 2019, and datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for manufacturing and supply of Enhertu and datopotamab deruxtecan.

AstraZeneca in breast cancer

Driven by a growing understanding of breast cancer biology, AstraZeneca is starting to challenge, and redefine, the current clinical paradigm for how breast cancer is classified and treated to deliver even more effective treatments to patients in need - with the bold ambition to one day eliminate breast cancer as a cause of death.

AstraZeneca has a comprehensive portfolio of approved and promising compounds in development that leverage different mechanisms of action to address the biologically diverse breast cancer tumour environment.

AstraZeneca aims to continue to transform outcomes for HR-positive breast cancer with foundational medicines Faslodex (fulvestrant) and Zoladex (goserelin) and the next-generation oral selective oestrogen receptor degrader (SERD) and potential new medicine camizestrant.

PARP inhibitor Lynparza (olaparib) is a targeted treatment option that has been studied in HER2-negative early and metastatic breast cancer patients with an inherited BRCA mutation. AstraZeneca with MSD (Merck & Co., Inc. in the US and Canada) continue to research Lynparza in metastatic breast cancer patients with an inherited BRCA mutation and are exploring new opportunities to treat these patients earlier in their disease.

Building on the initial approvals of Enhertu, a HER2-directed ADC, in previously treated HER2-positive metastatic breast cancer, AstraZeneca and Daiichi Sankyo are exploring its potential in earlier lines of treatment and in new breast cancer settings.

To bring much needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is testing immunotherapy Imfinzi (durvalumab) in combination with other oncology medicines, including Lynparza and Enhertu, evaluating the potential of AKT kinase inhibitor, capivasertib, in combination with chemotherapy, and collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan.

AstraZeneca in oncology

AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

AstraZeneca

AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including 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.   Cortes J, et al. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med. 2022; 386:1143-1154.

2.   Globocan 2020. Europe Fact Sheets. Available at: https://gco.iarc.fr/today/data/factsheets/populations/908-europe-fact-sheets.pdf. Last accessed: July 2022.

3.   Ahn S, et al. HER2 status in breast cancer: changes in guidelines and complicating factors for interpretation. J Pathol Transl Med. 2020; 54(1): 34-44.

4.   Barok M, et al. Trastuzumab emtansine: mechanism of action and drug resistance. Breast Cancer Res. 2014; 16(2):209.

5.   Nader-Marta G, et al. How we treat patients with metastatic HER2-positive breast cancer. ESMO Open. 2022; 7:1.

6.   Gennari A, et al. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Available at: https://www.annalsofoncology.org/article/S0923-7534(21)04498-7/pdf. Last accessed: July 2022.

7.   Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 10.3322/caac.21660.

8.   Iqbal N, et al. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int. 2014;852748.

9.   Pillai R, et al. HER2 mutations in lung adenocarcinomas: A report from the Lung Cancer Mutation Consortium. Cancer. 2017;1;123(21):4099-4105.

10.  Mounsey L, et al. Changing Natural History of HER2-Positive Breast Cancer Metastatic to the Brain in the Era of New Targeted Therapies. Clin Breast Cancer. 2018; 18(1):29-37.

11.  Martinez-S Sáez O, et al. Current and Future Management of HER2-Positive Metastatic Breast Cancer. JCO Oncol Pract. 2021. 10.1200/OP.21.00172.

Adrian Kemp

Company Secretary

AstraZeneca PLC