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Euhyde, jointly developed by AstraZeneca and Daiichi Sankyo, also demonstrated a clinically meaningful improvement in progression-free survival in patients with ultralow HER2 expression
The high-level results of the DESTINY-Breast06 Phase III trial demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with standard chemotherapy in the primary trial population of patients with HR-positive, HER2-low (IHC 1+ or 2+/ISH-) metastatic breast cancer after first- or second-line endocrine therapy.
Statistically significant and clinically significant improvements in PFS were also observed in the entire trial population (HER2-low and HER2-ultralow [defined as membrane staining IHC 0 with membrane staining: i.e., patients with IHC >0<1+] metastatic breast cancer). Pre-specified subgroup analyses showed consistent clinically meaningful improvements between patients with HER2 low expression and HER2 ultralow expression.
At the time of analysis, overall survival (OS) data were immature, however, trastuzumab compared with standard chemotherapy had shown an early trend towards improved OS compared to standard chemotherapy in patients with HER2-low metastatic breast cancer and in the overall trial population. The trial will continue as planned to further assess OS and other secondary endpoints.
Susan Galbraith, Executive Vice President and Head of Oncology R&D at AstraZeneca, said: "DESTINY-Breast06 demonstrates that trastuzumab could become a new standard of care for patients with HER2-low and HER2 ultralow metastatic breast cancer following first- or second-line endocrine therapy. These data underscore the potential of trastuzumab in the treatment of a wide range of HR-positive breast cancers, further redefining the treatment of metastatic breast cancer. ”
Ken Takeshita, Global Head of Daiichi Sankyo's Oncology Business, President and CEO, said, "The key results of DESTINY-Breast06 underscore the importance of continuing to challenge current treatment paradigms and established traditional breast cancer classifications to improve the way we treat patients with HR-positive, HER2-expressing metastatic breast cancer. Building on the clinical practice-changing data seen in the DESTINY-Breast04 study, these results enhance the likelihood of trastuzumab's use in this therapeutic area and in the broader patient population, as well as earlier. ”
Trastuzumab is a uniquely designed HER2-targeting antibody drug conjugate (ADC) jointly developed and commercialized by AstraZeneca and Daiichi Sankyo.
It is estimated that approximately 60 to 65 percent of HR-positive, HER2-negative breast cancers are HER2 low, and another 25 percent may have HER2 ultralow [1,2]. Endocrine therapy is widely used for the early treatment of HR-positive metastatic breast cancer, however, the further efficacy of endocrine therapy is often limited after both treatments [3]. The current standard of care after endocrine therapy is chemotherapy, but it has poor response rates and efficacy [3-6].
The safety profile of Enhertu is consistent with previous breast cancer clinical trials, with no new safety signals identified.
The data will be presented at an upcoming medical conference and shared with regulators worldwide.
关于DESTINY-Breast06研究
DESTINY-Breast06 is a global, randomized, open-label, Phase III trial to evaluate the effects of trastuzumab (5.4 mg/kg) versus investigator's choice of chemotherapy (capecitabine, paclitaxel, or nab-paclitaxel) in HR-positive, HER2-low expression (IHC 1+ or 2+/ISH-), or HER2 ultralow (defined as IHC 0 with membrane staining; i.e., IHC >0). <1+) efficacy and safety in patients with advanced or metastatic breast cancer. Patients in the trial had not received chemotherapy for advanced or metastatic disease and had progressed within six months of initiation of first-line therapy with endocrine therapy in combination with a CDK4/6 inhibitor, or had received at least two lines of endocrine therapy in the metastatic setting.
The primary endpoint was PFS in the HR-positive, HER2-low expression patient population, as measured by blinded independent central review (BICR). Key secondary endpoints included OS in HER2-low patients and PFS calculated by BICR in the entire trial population (HER2-low and HER2 ultralow) and OS in the entire trial population (HER2-low and HER2 ultra-low). Other secondary endpoints include objective response rate, duration of response, time to first follow-up treatment or death, time to second follow-up treatment or death, and safety. Analyses of the HER2 ultralow subgroup were insufficient to demonstrate statistical significance.
DESTINY-Breast06 enrolled 866 patients (713 in the HER2 low expression group and 153 in the HER2 ultralow expression group) at multiple sites in Asia, Europe, North America, and South America. For more information about the trial, please visit ClinicalTrials.gov.
Regarding breast cancer and low HER2 expression levels
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide [7]. Globally, there were more than 2 million breast cancer patients and more than 665,000 deaths in 2020 [7]. Although survival rates for patients with early-stage breast cancer are high, only about 30 percent of patients diagnosed with or progressed metastatic disease are expected to survive for five years after diagnosis [8].
HR-positive and HER2-negative are the most common subtypes of breast cancer, accounting for approximately 70 percent of all breast cancers [8]. HER2 is a tyrosine kinase receptor growth promoter protein that is expressed on the surface of many types of tumors, including breast cancer [9]. Patients with high levels of HER2 expression (IHC 3+ or 2+/ISH+) are classified as HER2-positive and can be treated with HER2-targeted therapies, accounting for approximately 15 to 20 percent of all breast cancers [10]. Historically, tumors that are not classified as HER2-positive have been classified as HER2-negative, however, many of these tumors still carry some degree of HER2 expression [11]. It is estimated that approximately 60 to 65 percent of HR-positive, HER2-negative breast cancers are hypoHER2, and another 25 percent may be ultra-low [1,2].
Prior to the approval of trastuzumab for HER2-expressing metastatic breast cancer following chemotherapy under the DESTINY-Breast04 study, no targeted therapies were approved specifically for patients with low HER2 expression [12]. There are currently no approved targeted therapies specifically for patients with ultra-low HER2 expression.
About trastuzumab
Detrastuzumab is a HER2-targeted ADC. Designed using Daiichi Sankyo's proprietary DXd ADC technology, trastuzumab is the leading ADC in Daiichi Sankyo's oncology portfolio and the most advanced program in AstraZeneca's ADC science platform. Trastuzumab consists of a HER2 monoclonal antibody linked to a topoisomerase-I inhibitor (camptothecin derivative DXd) via a stable, cleavable tetrapeptide linker.
Based on the results of the DESTINY-Breast03 trial, trastuzumab (5.4 mg/kg) has been approved in more than 60 countries for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH+) breast cancer who have received one (or more) prior anti-HER2 regimens in the metastatic phase or who have experienced disease recurrence during and within six months of completion of neoadjuvant or adjuvant therapy.
Based on the results of the DESTINY-Breast04 trial, trastuzumab (5.4 mg/kg) has been approved in more than 60 countries for the treatment of adult patients with unresectable or metastatic HER2-low expression (IHC 1+ or IHC 2+/ISH-) breast cancer, who have received a prior systemic therapy in the metastatic phase, or who have had disease recurrence during or within six months of completion of adjuvant chemotherapy.
Based on the results of the DESTINY-Lung02 trial, trastuzumab (5.4 mg/kg) has been approved in more than 35 countries worldwide for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer whose tumors have been detected with an activating HER2 (ERBB2) mutation by a locally or regionally approved assay and who have been systematically treated. Continued approval of this indication in the U.S. may depend on the validation and description of the clinical benefit in a confirmatory trial.
Based on the results of the DESTINY-Gastric01 and/or DESTINY-Gastric02 trials, trastuzumab (6.4 mg/kg) has been approved in more than 40 countries for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH+) gastric adenocarcinoma or gastroesophageal junction (GEJ) adenocarcinoma who have received trastuzumab-based regimens.
Based on the results of the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02 trials, trastuzumab (5.4 mg/kg) is approved in the U.S. for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic therapy and for whom no other effective treatment options have been available.
About the trastuzumab clinical development program
A comprehensive R&D program to evaluate the efficacy and safety of trastuzumab monotherapy in multiple HER2-targeted cancers is underway worldwide. Trials of other anti-tumor therapies such as combination immunotherapy are also underway.
About cooperation with Daiichi Sankyo
In March 2019 and July 2020, Daiichi Sankyo and AstraZeneca entered into a global partnership to jointly develop and commercialize trastuzumab and datopotamab deruxtecan in markets other than Japan (where Daiichi Sankyo has exclusive rights to distribute in Japan). Daiichi Sankyo is responsible for the production and supply of trastuzumab and datopotamab deruxtecan.
About AstraZeneca's research in the field of breast cancer
Driven by a deeper understanding of breast cancer biology, AstraZeneca is challenging and redefining the current clinical treatment model for breast cancer classification and treatment to provide patients with the more precise and effective treatment options they need. AstraZeneca has ambitions to one day eliminate breast cancer, the common cause of death.
AstraZeneca has developed a range of approved or expected approved drugs that address the biodiversity of the breast cancer tumor microenvironment through multiple mechanisms.
With trastuzumab, an antibody-drug conjugate targeting HER2, AstraZeneca and Daiichi Sankyo aim to improve outcomes in previously treated HER2-positive and HER2-low metastatic breast cancers and are exploring their therapeutic potential in earlier and newer breast cancers.
In HR+ breast cancer, AstraZeneca continues to improve outcomes with its cornerstone drugs fulvestrant and goserelin, and aims to remodel HR-positive breast cancer treatment with the first-in-class AKT kinase inhibitor capivasertib and a new generation of potential new drugs, SERD camizestrant. At the same time, AstraZeneca has partnered with Daiichi Sankyo to explore the potential effects of TROP2-targeted ADC datopotamab deruxtecan.
The PARP inhibitor olaparib is a targeted therapy option that has been studied in patients with early and metastatic breast cancer with hereditary BRCA mutations. AstraZeneca and Merck continue to explore the potential of olaparib in early-stage breast cancer.
To meet the urgent need for more treatment options in patients with triple-negative breast cancer, AstraZeneca is evaluating the potential effects of datopotamab deruxtecan alone and in combination with immunology drugs durvalumab, capivasertib in combination with chemotherapy and durvalumab in combination with other oncology drugs, including olaparib and trastuzumab.
About AstraZeneca's research in the field of oncology
AstraZeneca is leading a revolution in oncology by providing a diverse range of oncology treatment options to scientifically explore the complexities of oncology and discover, develop and deliver life-changing medicines to patients.
With a focus on the most challenging oncology diseases, AstraZeneca has built an industry-leading diversified portfolio and pipeline through continuous innovation to transform healthcare practices and transform the patient experience.
AstraZeneca aims to redefine cancer treatment and conquer cancer in the future.
About AstraZeneca:
AstraZeneca (LSE/STO/Nasdaq:AZN) is a global, science-first biopharmaceutical company focused on developing, manufacturing and marketing prescription medicines, with a focus on oncology, rare diseases and biopharmaceuticals, including cardiovascular, renal and metabolic, respiratory and immunology. Headquartered in Cambridge, UK, AstraZeneca operates in more than 100 countries around the world, benefiting millions of patients with innovative medicines.
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statement
The use of the drug under study in this article has not yet been approved for an indication in China, and AstraZeneca does not recommend the use of any drug/indication that is not approved.
* This article is only for the purpose of providing scientific information to medical professionals and does not represent the views of this platform
