Enhertu additional analyses further reinforce ground-breaking efficacy in patients with HER2-positive metastatic breast cancer

DESTINY-Breast03 data presented at SABCS 2021 showed AstraZeneca and Daiichi Sankyo’s Enhertu demonstrated a similar benefit in patient subgroups, including those with stable brain metastases, when compared to T-DM1

New results from the DESTINY-Breast03 Phase III trial showed that Enhertu (trastuzumab deruxtecan) demonstrated a higher progression-free survival (PFS) and objective response rate (ORR) in pre-specified patient subgroups compared to trastuzumab emtansine (T-DM1) in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane.

Enhertu is a HER2-directed antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo).

A similar PFS and ORR benefit was observed in exploratory analyses in patients defined by stable brain metastases, hormone receptor status, number of prior lines of therapy, prior pertuzumab treatment, or status of visceral metastasis. Results were presented in an oral presentation at the 2021 San Antonio Breast Cancer Symposium (SABCS).

In patients with stable brain metastases at baseline, treatment with Enhertu resulted in higher PFS compared to T-DM1 (PFS by blinded independent central review (BICR) hazard ratio [HR] 0.25; 95% confidence interval [CI] 0.13-0.45). Additionally, in this subgroup, Enhertu improved PFS to a median of 15 months versus 3 months for T-DM1.

Sara Hurvitz, MD, FACP, medical oncologist, professor of medicine, and director of the Breast Cancer Clinical Trials Program in the division of hematology-oncology at the David Geffen School of Medicine at UCLA, and medical director for the Clinical Research Unit at the UCLA Jonsson Comprehensive Cancer Center in Santa Monica, CA, said: “The main goals in the treatment of HER2-positive metastatic breast cancer, including those with stable brain metastases are to improve symptoms, stabilise or reduce the tumour size and improve overall survival. The higher progression-free survival seen in DESTINY-Breast03 in the subgroup of patients with stable brain metastases are encouraging, and underscores the excitement around another potential treatment option for patients who have experienced disease progression on currently available therapies.”

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “More treatment options are needed to delay progression and extend survival for patients with HER2-positive metastatic breast cancer who develop brain metastases. These additional analyses from DESTINY-Breast03 reinforce the potential of Enhertu with similar benefits in the different subgroups.”

Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: “These additional analyses from DESTINY-Breast03 continue to demonstrate the benefit of Enhertu compared to T-DM1 in patient subgroups, including 15-month progression-free survival in those with stable brain metastases, illustrating the potential of this treatment to become the new standard of care in patients with previously treated HER2-positive metastatic breast cancer. These data will support our ongoing conversations with global health authorities to realise our commitment to bring Enhertu to patients with previously treated HER2-positive breast cancer earlier in the metastatic setting.”

Between 30 to 50% of patients with HER2-positive metastatic breast cancer will develop brain metastases, and while increased availability of HER2 therapies has improved systemic disease control, prognosis following the development of brain metastases remains poor.^1-5

Confirmed ORR for patients with stable brain metastases at baseline was 67.4% with Enhertu versus 20.5% with T-DM1. A retrospective, non-prespecified evaluation of intracranial response among patients with stable brain metastases who received scans at baseline provided preliminary evidence that treatment with Enhertu is associated with intracranial tumour response and reduction in Central Nervous System disease with 10 (27.8%) complete responses (CR) and 13 (36.1%) partial responses (PR) compared to one (2.8%) CR and 11 (30.6%) PRs in those treated with T-DM1.

Summary of DESTINY-Breast03 subgroup analyses

CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; NE, not estimable; ORR, objective response rate

a Absolute ORR Difference, % [Enhertu-T-DM1]

b Patients with rapid progression on (neo)adjuvant therapy were included. Line of therapy does not include endocrine therapy.

The safety profile of the most common adverse events with Enhertu in DESTINY-Breast03 remains consistent with previous clinical trials of Enhertu in breast cancer with no new safety concerns identified. Adjudicated drug-related interstitial lung disease or pneumonitis was reported in 27 patients (10.5%) treated with Enhertu and five patients (1.9%) treated with T-DM1 overall, with no Grade 4 or 5 events.

Based on the primary results of DESTINY-Breast03, Enhertu received its fourth Breakthrough Therapy Designation (BTD) in the US 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 in September 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 more than 30 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.

Notes

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 overall survival, objective response rate, duration of response, 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.

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.⁶ More than two million patients with breast cancer were diagnosed in 2020, resulting in nearly 685,000 deaths globally.⁶ Approximately one in five cases of breast cancer are considered HER2-positive.⁷

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 a poor prognosis in breast cancer.⁹

Despite initial treatment with trastuzumab and a taxane, patients with HER2-positive metastatic breast cancer will often experience disease progression.¹ Additionally, it is estimated that 30 to 50% of patients will develop brain metastases, and while increased availability of HER2 therapies has improved systemic disease control, prognosis following development of brain metastases remains poor.^1-5 More treatment options are needed to further delay progression and extend survival.^1-4

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 (5.4 mg/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 two or more prior anti-HER2-based regimens in the metastatic setting based on the results from the DESTINY-Breast01 trial.

Enhertu (6.4 mg/kg) is also approved in several 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.

A Type II Variation is currently under review by the European Medicines Agency (EMA) for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior anti-HER2-based regimen.

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.

Enhertu received its fourth BTD in the US, which was 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.

Daiichi Sankyo collaboration

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 investigational agents next-generation oral SERD and camizestrant.

PARP inhibitor Lynparza (olaparib) is a targeted treatment option for 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 first approval 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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