First HER2-low metastatic breast cancer Phase III results for
Positive high-level results from the pivotal DESTINY-Breast04 Phase III trial showed Enhertu (trastuzumab deruxtecan) demonstrated a statistically significant and clinically meaningful improvement in both progression-free survival (PFS) and overall survival (OS) in patients with HER2-low unresectable and/or metastatic breast cancer regardless of hormone receptor (HR) status versus physician's choice of chemotherapy.
Enhertu is a HER2-directed antibody drug conjugate (ADC) being jointly developed by
All patients in the trial received a HER2 test, and the results were centrally confirmed. HER2-low status was defined as an immunohistochemistry (IHC) score of 1+ or IHC 2+ with a negative in-situ hybridisation (ISH) score.
Up to 55% of all patients with breast cancer have tumours with a HER2 IHC score of 1+, or 2+ in combination with a negative ISH test, a level of HER2 expression not currently eligible for HER2-targeted therapy.1,2 HER2-low expression occurs in both HR-positive and HR-negative disease.3
HER2 testing is well established to determine an appropriate treatment strategy in metastatic breast cancer. Targeting the lower range of HER2 expression may offer another approach to delay disease progression and extend survival in patients with metastatic breast cancer.4 Currently, chemotherapy remains the only treatment option both for patients with HR-positive tumours following progression on endocrine (hormone) therapy, and for those who are HR-negative.5
DESTINY-Breast04 met its primary endpoint, where Enhertu demonstrated superior PFS in previously treated patients with HR-positive HER2-low metastatic breast cancer compared to the standard-of-care chemotherapy. The trial met the key secondary endpoint of PFS in patients with HER2-low metastatic breast cancer regardless of HR status (HR-positive or HR-negative). The trial also met the key secondary endpoints of OS in patients with HR-positive disease and in patients regardless of HR status at interim analysis.
The safety profile of Enhertu was consistent with previous clinical trials, with no new safety concerns identified. Overall interstitial lung disease (ILD) rates were consistent with that observed in late-line HER2-positive breast cancer trials of Enhertu, with a lower rate of Grade 5 ILD observed as determined by an independent adjudication committee.
The data will be presented at a forthcoming medical meeting and shared with global health authorities.
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 two or more prior anti-HER2-based regimens 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
Breast cancer and HER2 expression
Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.6 More than two million cases of breast cancer were diagnosed in 2020 resulting in nearly 685,000 deaths globally.6
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, and is one of many biomarkers expressed in breast cancer tumours.7 HER2 expression is currently defined as either positive or negative, and is determined by an IHC test which measures the amount of HER2 protein in a cancer cell, and/or an ISH test which counts the copies of the HER2 gene in cancer cells.7,8 HER2-positive cancers are defined as IHC 3+ or IHC 2+/ISH+, and HER2-negative cancers are currently defined as IHC 0, IHC 1+ or IHC 2+/ISH-.7
DESTINY-Breast04
DESTINY-Breast04 is a global, randomised, open-label, registrational Phase III trial evaluating the efficacy and safety of Enhertu (5.4 mg/kg) versus physician's choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel) in patients with HR-positive (n=480) or HR-negative (n=60) HER2-low unresectable and/or metastatic breast cancer previously treated with one or two prior lines of chemotherapy. Patients were randomised 2:1 to receive either Enhertu or chemotherapy.
The primary endpoint of DESTINY-Breast04 is PFS in patients with HR-positive disease based on blinded independent central review (BICR). Key secondary endpoints include PFS based on BICR in all randomised patients (regardless of HR status), OS in patients with HR-positive disease and OS in all randomised patients (regardless of HR status). Other secondary endpoints include PFS based on BICR and investigator assessment, duration of response based on BICR and safety.
DESTINY-Breast04 enrolled approximately 540 patients at multiple sites in
Enhertu
Enhertu is a HER2-directed ADC. Designed using
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 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
Enhertu also is currently under review in
Driven by a growing understanding of breast cancer biology,
PARP inhibitor Lynparza (olaparib) is a targeted treatment option for metastatic breast cancer patients with an inherited BRCA mutation. Lynparza has also demonstrated a statistically significant and clinically meaningful improvement in invasive disease-free survival versus placebo in the adjuvant treatment of patients with germline BRCA-mutated HER2-negative early breast cancer.
Building on the first approval of Enhertu, in previously treated HER2-positive metastatic breast cancer,
To bring much needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer,
The Company's focus is on some of the most challenging cancers. It is through persistent innovation that
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References
1. Tarantino P, et al. HER2-Low Breast Cancer: Pathological and Clinical Landscape. J Clin Oncol. 2020;38(17):1951-1962.
2. 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.
3. Miglietta F, et al. Evolution of HER2-low expression from primary to recurrent breast cancer. NPJ Breast Cancer. 2021; 7:137; 10.1038/s41523-021-00343-4.
4. Eiger D, et al. The Exciting New Field of HER2-Low Breast Cancer Treatment. Cancers. 2021; 10.3390/cancers13051015.
5. Matutino A, et al. Hormone receptor-positive, HER2-negative metastatic breast cancer: redrawing the lines. Current Oncology. 2018; 25(S1):S131-S141.
6. 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.
7. Iqbal N, et al. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int. 2014;852748.
8. Wolff A, et al. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer:
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