ENHERTU® Approved in the EU as the First HER2 Directed Therapy for Patients with HER2 Low Metastatic Breast Cancer
Approval based on DESTINY-Breast04 results where
Daiichi Sankyoand AstraZeneca’s ENHERTU reduced the risk of disease progression or death by 50% and increased median overall survival by more than six months versus chemotherapy
ENHERTU is a specifically engineered HER2 directed antibody drug conjugate (ADC) being jointly developed and commercialized by
The approval by the
In DESTINY-Breast04, ENHERTU significantly reduced the risk of disease progression or death by 50% versus physician’s choice of chemotherapy (hazard ratio [HR]=0.50; 95% confidence interval [CI]: 0.40-0.63; p<0.0001) in patients with HER2 low metastatic breast cancer with hormone receptor (HR) positive or HR negative disease. A median progression-free survival (PFS) of 9.9 months (95% CI: 9.0-11.3) was seen with ENHERTU versus 5.1 months (95% CI: 4.2-6.8) in those treated with chemotherapy as assessed by blinded independent central review (BICR). A 36% reduction in the risk of death (HR=0.64; 95% CI: 0.49-0.84; p=0.001) also was seen with ENHERTU compared to chemotherapy with a median overall survival (OS) of 23.4 months (95% CI: 20.0-24.8) in patients treated with ENHERTU versus 16.8 months (95% CI: 14.5-20.0) in those treated with chemotherapy.
“The European approval of ENHERTU in the HER2 low metastatic breast cancer population marks the first time we will have the opportunity to treat patients with lower levels of HER2 expression with a HER2 directed therapy,” said Javier Cortés, MD, PhD, Head,
“The approval of ENHERTU in HER2 low metastatic breast cancer represents a significant clinical advance for patients in
“Historically, patients with breast cancer who have tumors with low levels of HER2 expression have been classified as HER2 negative, giving them limited treatment options beyond chemotherapy,” said
In DESTINY-Breast04, the safety profile of ENHERTU was consistent with previous clinical trials with no new safety concerns identified. Grade 3 or grade 4 treatment-related adverse events from a pooled safety analysis of patients treated with ENHERTU (5.4 mg/kg) across multiple tumor types in clinical studies included neutropenia (16.3%), anemia (9.2%), fatigue (7.5%), leukopenia (6.3%), thrombocytopenia (5.9%), nausea (5.6%), lymphopenia (4.8%), transaminases increased (3.9%), hypokalemia (3.5%), vomiting (2.2%), pneumonia (1.9%), diarrhea (1.8%), decreased appetite (1.7%), febrile neutropenia (1.2%), dyspnea (1.2%), blood bilirubin increased (1.1%), ejection fraction decreased (1.1%), and musculoskeletal pain (1.1%). Grade 5 adverse reactions occurred in 1.5% of patients, including interstitial lung disease (1.2%).
Following approval in the EU, an amount of
DESTINY-Breast04 is a global, randomized, open-label, pivotal phase 3 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 or HR negative, HER2 low unresectable and/or metastatic breast cancer previously treated with one or two prior lines of chemotherapy. Patients were randomized 2:1 to receive either ENHERTU or chemotherapy.
The primary endpoint of DESTINY-Breast04 is PFS in patients with HR positive disease based on BICR. Key secondary endpoints include PFS based on BICR in all randomized patients (HR positive and HR negative disease), OS in patients with HR positive disease and OS in all randomized patients (HR positive and HR negative disease). Other secondary endpoints include PFS based on investigator assessment, objective response rate based on BICR and on investigator assessment, duration of response based on BICR and safety. DESTINY-Breast04 enrolled 557 patients at multiple sites in
About Breast Cancer and HER2 Expression
Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.1 More than two million cases of breast cancer were diagnosed in 2020 with nearly 685,000 deaths globally.1 In
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast, gastric, lung and colorectal cancers, and is one of many biomarkers expressed in breast cancer tumors.3
HER2 expression is currently determined by an immunohistochemistry (IHC) test which estimates the amount of HER2 protein on a cancer cell, and/or an in-situ hybridization (ISH) test, which counts the copies of the HER2 gene in cancer cells.3,4 HER2 tests provide IHC and ISH scores across the full HER2 spectrum and are routinely used to determine appropriate treatment options for patients with metastatic breast cancer. HER2 positive cancers are currently defined as HER2 expression measured as IHC 3+ or IHC 2+/ISH+, and HER2 negative cancers are defined as HER2 expression measured as IHC 0, IHC 1+ or IHC 2+/ISH-.3 However, approximately half of all breast cancers are HER2 low, defined as a HER2 score of IHC 1+ or IHC 2+/ISH-.5,6,7 HER2 low occurs in both HR positive and HR negative disease.8
Currently, patients with HR positive metastatic breast cancer and HER2 low disease have limited effective treatment options following progression on endocrine (hormone) therapy.9 Additionally, few targeted options are available for those with HR negative disease.10
ENHERTU (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the
ENHERTU (5.4 mg/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 (5.4 mg/kg) is approved in more than 30 countries for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/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 of the DESTINY-Breast04 trial.
ENHERTU (5.4 mg/kg) is approved under accelerated approval in the
ENHERTU (6.4 mg/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 (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 and/or DESTINY-Gastric02 trials.
About the ENHERTU Clinical Development Program
A comprehensive global development program 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, also are underway.
About the DXd ADC Portfolio of
The DXd ADC portfolio of
Designed using Daiichi Sankyo’s proprietary DXd ADC technology, each ADC targets and delivers a cytotoxic payload inside cancer cells that express a specific cell surface antigen. Each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.
Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan and DS-6000 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.
1 Sung H, et al. CA Cancer J Clin. 2021;10.3322/caac.21660.
2 Globocan 2020. Breast Cancer. Accessed
3 Iqbal N, et al. Mol Biol Int. 2014;852748.
4 Wolff A, et al. Arch Pathol Lab Med. 2018;142(11):1364–1382.
5 Schalper K, et al. Arch Pathol Lab Med. 2014;138:213-219.
6 Schettini F, et al. NPJ Breast Cancer. 2021;7:1.
7 Denkert C, et al. Lancet Oncol. 2021;22:1151-61.
8 Miglietta F, et al. NPJ Breast Cancer. 2021;7:137.
9 Matutino A, et al. Current Oncology. 2018;25(S1):S131-S141.
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