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Highest reported pathologic complete response rate seen in a Phase III registrational trial for HER2-positive early breast cancer with favourable safety profile vs. standard treatment. DESTINY-Breast11 presented in ESMO Presidential Symposium alongside DESTINY-Breast05 reinforce potential for AstraZeneca and Daiichi Sankyo's Enhertu to become a foundational treatment in curative-intent early breast cancer setting.
Positive results from the DESTINY-Breast11 Phase III trial showed Enhertu (trastuzumab deruxtecan) followed by paclitaxel, trastuzumab and pertuzumab (THP) in the neoadjuvant setting (before surgery) demonstrated a statistically significant and clinically meaningful improvement in the pathologic complete response (pCR) rate. The trial compared Enhertu followed by THP with dose-dense doxorubicin and cyclophosphamide followed by THP (ddAC-THP) in patients with high-risk, locally advanced HER2-positive early-stage breast cancer. Pathologic complete response is defined as no evidence of invasive cancer cells in the removed breast tissue and lymph nodes following treatment.
In DESTINY-Breast11, Enhertu followed by THP resulted in a pCR rate of 67.3% compared with 56.3% for ddAC-THP, representing a pCR rate improvement of 11.2%. Improvement in pCR rates was observed across both hormone receptor (HR)-positive and HR-negative subgroups (HR-positive: 61.4% versus 52.3%; HR-negative: 83.1% versus 67.1%). Additionally, after surgery, 81.3% of patients who received neoadjuvant treatment in the Enhertu followed by THP arm had no or minimal residual invasive cancer (residual cancer burden [RCB] 0+I) detected in the resected breast or lymph node tissue compared to 69.1% of patients in the comparator arm.
The secondary endpoint of event-free survival (EFS) was not mature at the time of this analysis (4.5% maturity at data cutoff); however, an early analysis showed a trend favouring Enhertu followed by THP versus ddAC-THP (hazard ratio 0.56; 95% CI 0.26-1.17).
Nadia Harbeck, MD, PhD, Director of Breast Center, Cancer Department of OB&GYN and CCC Munich, LMU University Hospital, Germany and principal investigator for the trial, said: "For patients with early breast cancer who are at high risk of disease recurrence, using the most effective treatment option at the earliest opportunity is critical to prevent recurrence, optimise safety and improve the potential for cure. In the DESTINY-Breast11 trial, more than two thirds of patients had a pathologic complete response with trastuzumab deruxtecan followed by THP, suggesting a potential new standard of care in the neoadjuvant setting for patients with high-risk, HER2-positive early breast cancer."
Susan Galbraith, Executive Vice President, Oncology Haematology R&D, AstraZeneca, said: "The goal of treatment in the early breast cancer setting is to provide patients with the best possible chance for cure whilst optimising the tolerability of the treatment regimen. The impressive pathologic response rates and favourable safety profile seen with Enhertu followed by THP in DESTINY-Breast11 have the potential to transform treatment in the neoadjuvant setting and underscore the importance of bringing Enhertu into earlier stages of HER2-positive disease."
Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: "While achieving a pathologic complete response in HER2-positive early-stage breast cancer is critical for reducing disease recurrence and improving long-term prognosis, approximately half of patients still show evidence of residual disease following surgery with currently available neoadjuvant treatment options. The results from DESTINY-Breast11 show that treatment with Enhertu followed by THP prior to surgery resulted in no evidence of residual invasive disease in two thirds of patients, illustrating the first treatment regimen in more than a decade to significantly improve outcomes in the earliest treatment setting for HER2-positive breast cancer."
Summary of Results: DESTINY-Breast11i,ii
| Efficacy Measure | Enhertu (5.4 mg/kg; 4 cycles) followed by THP (4 cycles) (n=321) | ddAC (4 cycles) followed by THP (4 cycles) (n=320) |
| pCR | ||
| pCR rate, %iii | 67.3 | 56.3 |
| ΔpCR,% (95% CI)iii,iv | 11.2 (4.0-18.3) | |
| p=0.003 | ||
| HR-positive subgroup pCR rate, %iii | 61.4 | 52.3 |
| ΔpCR, % (95% CI) | 9.1 (0.2-17.9) | |
| HR-negative subgroup pCR rate, % iii | 83.1 | 67.1 |
| ΔpCR, % (95% CI) | 16.1 (3.0-28.8) | |
| RCB (0+I)v | ||
| RCB (0+I rate), % | 81.3 | 69.1 |
| ΔRCB, % | 12.2 | |
| RCB-I rate, % | 68.8 | 57.5 |
| RCB-0 rate, % | 12.5 | 11.6 |
| HR-positive subgroup RCB (0+I) rate, % | 78.0 | 64.7 |
| ΔRCB, % (95% CI) | 13.3 | |
| HR-positive RCB-I rate, % | 63.1 | 52.8 |
| HR-positive RCB-0 rate, % | 14.8 | 11.9 |
| HR-negative subgroup RCB (0+I) rate, %v | 90.4 | 81.2 |
| ΔpCR, % (95% CI) | 9.2 | |
| HR-negative RCB-I rate, % | 84.3 | 70.6 |
| HR-negative RCB-0 rate, % | 6.0 | 10.6 |
| EFSvi | ||
| 2-year EFS, % Hazard ratio (95% CI) | 96.9 | 93.1 |
| 0.56 (0.26, 1.17) | ||
THP, paclitaxel, trastuzumab and pertuzumab; ddAC, dose-dense doxorubicin and cyclophosphamide; pCR, pathologic complete response; HR, hormone receptor; CI, confidence interval; RCB (0+I), residual cancer burden; EFS, event-free survival
i Data cut-off 12 March 2025; median duration of follow up was 24.2 months with Enhertu followed by THP and 23.6 months with ddAC-THP
ii Based on blinded central review
iii pCR responders were defined as patients who only received randomised study treatment (at least one dose) and had pCR
iv Stratified Miettinen & Nurminen method; p value crossed the 0.03 prespecified boundary
v RCB is based on raw data and is not corrected for non-starters, or any bridging/off study neoadjuvant treatment; therefore, there may be differences between pCR and RCB-0
vi EFS was 4.5% mature at interim analysis
The safety profile of Enhertu followed by THP in DESTINY-Breast11 was consistent with the known profiles of each individual therapy with no new safety concerns identified.
Enhertu followed by THP showed a favourable safety profile compared with ddAC-THP with reduced rates of Grade 3 or higher adverse events (AEs) (37.5% versus 55.8%), serious AEs (10.6% versus 20.2%), treatment interruptions (37.8% versus 54.5%) and left ventricular dysfunction (1.3% versus 6.1%).
Rates of interstitial lung disease (ILD) were low and similar between arms with ILD events occurring in 4.4% of patients in the Enhertu followed by THP arm compared with 5.1% in the ddAC-THP arm. The majority of ILD events were low Grade (Grade 1 and 2). There was one Grade 3/4 event in the Enhertu followed by THP arm and five Grade 3/4 events in the ddAC-THP arm. There was one Grade 5 ILD event in each arm as determined by an independent adjudication committee.
DESTINY-Breast11 results (abstract #291O) will be presented today during Presidential Symposium I, alongside the results from the DESTINY-Breast05 Phase III trial (abstract #LBA1) at the European Society for Medical Oncology (ESMO) 2025 Congress in Berlin, Germany. The DESTINY-Breast11 results will also be published in the Annals of Oncology in parallel with ESMO.
A supplemental Biologics License Application for Enhertu followed by THP based on the results from DESTINY-Breast11 is currently under review by the US Food and Drug Administration (FDA).
Enhertu is a specifically engineered HER2-directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed and commercialised by Daiichi Sankyo and AstraZeneca.
Notes
HER2-positive early breast cancer
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide.1 More than two million breast cancer cases were diagnosed in 2022, with more than 665,000 deaths globally.1
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours, including breast cancer.2 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.2 Approximately one in five cases of breast cancer are considered HER2-positive.3
Approximately one in three patients with HER2-positive early breast cancer are considered high-risk, meaning they are more likely to experience disease recurrence and have a poor prognosis.4 For patients with HER2-positive early breast cancer, achieving pCR with neoadjuvant treatment is the earliest indicator of improved long-term survival.5 However, approximately half of patients who receive neoadjuvant treatment do not reach pCR.6-10
The current standard of care in the HER2-positive neoadjuvant setting in many regions of the world consists of combination chemotherapy regimens.11 These regimens often include anthracyclines, which can be challenging for patients to tolerate and may result in long-term cardiotoxicity, reinforcing the need for new treatment options.11-13
DESTINY-Breast11
DESTINY-Breast11 is a global, multicentre, randomised, open-label, Phase III trial evaluating the efficacy and safety of neoadjuvant Enhertu (5.4 mg/kg) monotherapy or Enhertu followed by THP (paclitaxel, trastuzumab and pertuzumab) versus ddAC-THP 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 followed by four cycles of THP.
The Enhertu monotherapy arm was closed early following a recommendation from the Independent Data Monitoring Committee (IDMC). The recommendation was based on multiple factors including a lower pCR rate, low likelihood that Enhertu alone would be superior to ddAC-THP, and timing of surgery. The recommendation was not related to safety.
The primary endpoint of DESTINY-Breast11 is rate of 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 (5.4 mg/kg) is approved in more than 85 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+ or in-situ hybridization (ISH)+) breast cancer who have received a 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 85 countries/regions 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 (5.4 mg/kg) is approved in more than 45 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic 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 (5.4 mg/kg) is approved in more than 60 countries/regions 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 may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Enhertu (6.4 mg/kg) is approved in more than 70 countries/regions worldwide for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 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 may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Enhertu (5.4 mg/kg) is approved in more than 10 countries/regions worldwide 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 efficacy results from the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02 trials. Continued approval for this indication may be 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 a monotherapy or in combination or sequentially with other cancer medicines 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. 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 (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. Please visit astrazeneca.com and follow the Company on Social Media @AstraZeneca.
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References
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