Enhertu Plus THP Shows Improved Safety and Efficacy Over Standard of Care in Early HER2-Positive Breast Cancer
AstraZeneca and Daiichi Sankyo’s Enhertu (trastuzumab deruxtecan), followed by a regimen of paclitaxel, trastuzumab, and pertuzumab (THP), has shown a significantly improved safety profile and clinical benefit compared to the current standard of care in early-stage HER2-positive breast cancer, according to positive high-level results from the Phase III DESTINY-Breast11 trial.
This marks the first Phase III trial to demonstrate the benefit of Enhertu in early breast cancer. Specifically, the study showed a statistically significant and clinically meaningful improvement in the pathologic complete response (pCR) rate when Enhertu followed by THP was used in the neoadjuvant setting (prior to surgery) compared to the standard neoadjuvant treatment, which includes dose-dense doxorubicin and cyclophosphamide followed by THP (ddAC-THP). pCR is defined as the absence of invasive cancer cells in the breast tissue and lymph nodes removed during surgery after treatment.
While the secondary endpoint of event-free survival (EFS) was not mature at the time of this analysis, early data showed a promising trend favoring Enhertu followed by THP over ddAC-THP. The trial will continue to monitor EFS outcomes.
Approximately one in three patients with early-stage breast cancer are considered high risk for disease recurrence and generally face a poor prognosis. Achieving pCR in this patient group is linked to better long-term outcomes. Current neoadjuvant treatment typically involves combination chemotherapy regimens that often include anthracyclines, which can be difficult for patients to tolerate and carry the risk of long-term cardiovascular effects. Moreover, nearly half of patients receiving neoadjuvant treatment fail to achieve pCR, underscoring the urgent need for new therapeutic approaches.
Susan Galbraith, Executive Vice President, Oncology R&D at AstraZeneca, stated:
“The clinically meaningful improvement in pathologic complete response and favorable safety data seen in DESTINY-Breast11 highlight the potential of Enhertu to redefine the standard of care in early-stage HER2-positive breast cancer. Enhertu is already an important option in the metastatic setting, and these data could enable it to move earlier in the treatment pathway where cure is possible.”
Ken Takeshita, Global Head of R&D at Daiichi Sankyo, added:
“Many patients with early-stage breast cancer do not achieve a pathologic complete response with current neoadjuvant treatments, increasing their risk of recurrence. The DESTINY-Breast11 topline results demonstrate that Enhertu followed by THP could offer these patients a promising new approach before surgery, setting more of them on the path toward a potential cure.”
The study also showed that Enhertu followed by THP had an improved safety profile compared to ddAC-THP. The safety profiles were consistent with the known effects of each drug, with no new safety concerns identified. Notably, rates of interstitial lung disease were similar between the two treatment arms, as confirmed by an independent adjudication committee.
Following the Independent Data Monitoring Committee’s recommendation, enrolment in the trial’s third arm — which evaluated Enhertu alone — was closed after a prior interim efficacy analysis.
Full data from DESTINY-Breast11 will be presented at an upcoming medical conference and shared with global regulatory authorities.
Enhertu is a HER2-directed DXd antibody-drug conjugate (ADC) developed by Daiichi Sankyo and jointly developed and commercialized with AstraZeneca. Enhertu has already demonstrated improved outcomes across six Phase III breast cancer trials, including the recently reported DESTINY-Breast09 trial in the first-line HER2-positive metastatic setting. It is also being studied in other ongoing trials, such as DESTINY-Breast05, which is evaluating its use in the high-risk adjuvant early HER2-positive setting.
HER2-positive early breast cancer
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide.5 More than two million breast cancer cases were diagnosed in 2022, with more than 665,000 deaths globally.5
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours including breast cancer.6 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.7 Approximately one in five cases of breast cancer are considered HER2-positive.8
DESTINY-Breast11
DESTINY-Breast11 is a global, multicentre, randomised, open-label, Phase III trial evaluating the efficacy and safety of neoadjuvant Enhertu (5.4mg/kg) monotherapy or Enhertu followed by THP vs. the standard of care regimen in patients with high-risk (lymph node positive [N1-3] or primary tumour stage T3-4), locally advanced or inflammatory HER2-positive early-stage breast cancer.
Patients were randomised 1:1:1 to receive either eight cycles of Enhertu monotherapy; four cycles of Enhertu followed by four cycles of THP; or four cycles of ddAC (dose-dense doxorubicin and cyclophosphamide) followed by four cycles of THP.
The primary endpoint of DESTINY-Breast11 is pCR (absence of invasive disease in the breast and lymph nodes). Secondary endpoints include EFS, invasive disease-free survival, overall survival and safety.
DESTINY-Breast11 enrolled 927 patients across multiple sites in Asia, Europe, North America and South America. 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 number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.
Enhertu (5.4mg/kg) is approved in more than 75 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC 3+ or in-situ hybridisation [ISH]+) 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-Breast03trial.
Enhertu (5.4mg/kg) is approved in more than 75 countries worldwide 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 from the DESTINY-Breast04 trial.
Enhertu (5.4mg/kg) is approved in more than 30 countries for the treatment of adult patients with unresectable or metastatic hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by a locally or regionally approved test, that have progressed on one or more endocrine therapies in the metastatic setting based on the results from the DESTINY-Breast06 trial.
Enhertu (5.4mg/kg) is approved in more than 50 countries worldwide for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumours have activating HER2 (ERBB2) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 and/or DESTINY-Lung05 trials. Continued approval in China and the US for this indication is contingent upon verification and description of clinical benefit in a confirmatory trial.
Enhertu (6.4mg/kg) is approved in more than 65 countries worldwide for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01, DESTINY-Gastric02 and/or DESTINY-Gastric06 trials. Continued approval in China for this indication will depend on whether a randomised controlled confirmatory clinical trial can demonstrate clinical benefit in this population.
Enhertu (5.4mg/kg) is approved in the US and other countries for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumours who have received prior systemic treatment and have no satisfactory alternative treatment options based on the results from the DESTINY-PanTumor02, DESTINY-Lung01 andDESTINY-CRC02 trials. Continued approval for this indication in the US is contingent upon verification and description of clinical benefit in a confirmatory trial.
Enhertu development programme
A comprehensive global clinical development programme is underway evaluating the efficacy and safety of Enhertu as monotherapy or in combination or sequentially with other anti-cancer therapies across multiple HER2-targetable cancers.
Daiichi Sankyo collaboration
AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise Enhertu in March 2019 and Datroway (datopotamab deruxtecan) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of Enhertu and Datroway.
AstraZeneca in breast cancer
Driven by a growing understanding of breast cancer biology, AstraZeneca is challenging, and redefining, 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, AstraZeneca and Daiichi Sankyo are aiming to improve outcomes in previously treated HER2-positive, HER2-low and HER2-ultralow 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 first-in-class AKT inhibitor, Truqap (capivasertib), the TROP2-directed ADC, Datroway (datopotamab deruxtecan), and next-generation oral SERD and potential new medicine camizestrant.
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. AstraZeneca is also exploring the potential of saruparib, a potent and selective inhibitor of PARP1, in combination with camizestrant in BRCA-mutated, HR-positive, HER2-negative advanced breast cancer.
To bring much-needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is collaborating with Daiichi Sankyo to evaluate the potential of Datroway alone and in combination with immunotherapy Imfinzi (durvalumab).
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’s innovative medicines are sold in more than 125 countries and used by millions of patients worldwide.
