AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) has been approved in China 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 China's National Medical Products Administration (NMPA) is based on the results of the DESTINY-Breast03 Phase III trial, where Enhertu demonstrated a 72% reduction in the risk of disease progression or death compared to 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 China, breast cancer is the most common cancer in women, with more than 415,000 patients diagnosed in 2020.[1] There were nearly 120,000 breast cancer deaths in China in 2020, representing approximately 18% of global breast cancer deaths.[1] Approximately one in five cases of breast cancer are considered HER2-positive.[2]

Binghe Xu, MD, Professor and Director of the Department of Medical Oncology, Cancer Hospital and Institute Cancer Hospital, Chinese Academy of Medical Sciences, said: "This approval marks an important day for the breast cancer community in China as patients with HER2-positive metastatic breast cancer continue to need additional treatment options. Despite initial treatment, patients with HER2-positive metastatic breast cancer will often experience disease progression, demonstrating the importance of early systemic disease control and the potential for Enhertu to help eligible patients with metastatic breast cancer."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: "This first approval of Enhertu in China represents a significant advance in the treatment of HER2-targetable tumours and provides the opportunity for patients with previously treated HER2-positive metastatic breast cancer to benefit from this important medicine as a second line therapy. The approval underscores our commitment to patients in China, where there has been an increased incidence rate of breast cancer, as we continue to explore the potential benefits of Enhertu earlier in the treatment of HER2-directed metastatic breast cancer and across HER2-targetable cancers."

Kiminori Nagao, Head of the Asia, South and Central America (ASCA) Business Unit, Daiichi Sankyo, said: "Enhertu is extending the time before disease progression or death and helping to redefine outcomes for patients with previously treated HER2-positive metastatic breast cancer, and now physicians in China will have this important medicine as an option for their patients. With this approval, Enhertu has the potential to become a new standard of care in China in the second-line setting for patients with HER2-positive metastatic breast cancer."

The safety profile of Enhertu in DESTINY-Breast03 was evaluated in 257 patients with unresectable or metastatic HER2-positive breast cancer and was consistent with previous clinical trials with no new safety concerns identified. The most common adverse reactions were nausea (75.9%), fatigue (49.4%), vomiting (49.0%), neutropenia (42.8%) and alopecia (37.0%).

This approval follows the Breakthrough Therapy Designation and Priority Review granted to Enhertu by China's NMPA in this type of breast cancer in 2022.

Financial considerations
Sales of Enhertu in China are recognised by AstraZeneca and will be recorded as product sales on the profit and loss statement. Further details on the financial arrangements were set out in the March 2019 announcement (https://www.astrazeneca.com/media-centre/press-releases/2019/astrazeneca-and-daiichi-sankyo-enter-collaboration-for-novel-her-2-targeting-antibody-drug-conjugate.html) of the collaboration.

Notes

Breast cancer and HER2 expression
Breast cancer is the most common cancer and one of the leading causes of cancer-related deaths worldwide.[3] More than two million patients were diagnosed with breast cancer in 2020, with nearly 685,000 deaths globally.[3] In China, breast cancer is the most common cancer in women, with more than 415,000 patients diagnosed in 2020.[1] There were nearly 120,000 breast cancer deaths in China in 2020, representing approximately 18% of global breast cancer deaths.[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.[4] 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.[5]

Despite initial treatment with trastuzumab and a taxane, patients with HER2-positive metastatic breast cancer will often experience disease progression.[6,7]

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 progression-free survival (PFS) based on blinded independent central review (BICR). Overall survival (OS) is a key secondary efficacy outcome measure. Other secondary efficacy endpoints include objective response rate (ORR), duration of response, PFS based on investigator assessment and safety. Primary results from DESTINY-Breast03 were published in The New England Journal of Medicine (https://www.nejm.org/doi/full/10.1056/NEJMoa2115022?query=featured_home),[8 ]with updated PFS and OS results published in The Lancet (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02420-5/fulltext).[9]

DESTINY-Breast03 enrolled 524 patients at multiple sites in Asia, Europe, North America, Oceania and South America. For more information about the trial, visit ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03529110).

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 40 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 approved in more than 30 countries for the treatment of adult patients with unresectable or metastatic HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in-situ hybridisation [ISH]-) 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.

Enhertu (5.4mg/kg) is approved under accelerated approval in the US for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer whose tumours have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (6.4mg/kg) is approved in more than 30 countries 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 and/or DESTINY-Gastric02 trial.

Enhertu development programme
A comprehensive global development programme is underway 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.

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 (https://www.astrazeneca.com/media-centre/press-releases/2019/astrazeneca-and-daiichi-sankyo-enter-collaboration-for-novel-her-2-targeting-antibody-drug-conjugate.html), and datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in July 2020 (https://www.astrazeneca.com/media-centre/press-releases/2020/astrazeneca-and-daiichi-sankyo-enter-collaboration-to-develop-and-commercialise-new-antibody-drug-conjugate.html), except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for the 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.

With Enhertu (trastuzumab deruxtecan), a HER2-directed ADC, AstraZeneca and Daiichi Sankyo are aiming to improve outcomes in previously treated HER2-positive and HER2-low metastatic breast cancer and are exploring its potential in earlier lines of treatment and in new breast cancer settings.

In HR-positive breast cancer, AstraZeneca continues to improve outcomes with foundational medicines Faslodex (fulvestrant) and Zoladex (goserelin) and aims to reshape the HR-positive space with next-generation SERD and potential new medicine camizestrant as well as a potential first-in-class AKT kinase inhibitor, capivasertib. AstraZeneca is also collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan, in this setting.

PARP inhibitor Lynparza (olaparib) is a targeted treatment option that has been studied in 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 these settings and to explore its potential in earlier disease.

To bring much-needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is evaluating the potential of datopotamab deruxtecan alone and in combination with immunotherapy Imfinzi (durvalumab), capivasertib in combination with chemotherapy, and Imfinzi in combination with other oncology medicines, including Lynparza and Enhertu.

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 (http://www.astrazeneca.com/) and follow the Company on Twitter @AstraZeneca (https://twitter.com/AstraZeneca).

Contacts
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References

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3. 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.
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5. Pillai R, et al. HER2 mutations in lung adenocarcinomas: A report from the Lung Cancer Mutation Consortium. Cancer. 2017;1;123(21):4099-4105.
6. Barok M, et al. Trastuzumab emtansine: mechanism of action and drug resistance. Breast Cancer Res. 2014; 16(2):209.
7. Nader-Marta G, et al. How we treat patients with metastatic HER2-positive breast cancer. ESMO Open. 2022; 7:1.
8. Cortes J, et al. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med. 2022; 386:1143-1154.
9. Hurvitz S, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2022 Dec 6;S0140-6736(22)02420-5.