- Daiichi Sankyo and AstraZeneca’s ENHERTU also demonstrated a clinically meaningful progression-free survival improvement in patients with HER2 ultralow expression
- Plans for global regulatory submissions are underway
TOKYO, Japan & BASKING RIDGE, NJ, USA I April 29, 2024 I Positive topline results from the DESTINY-Breast06 phase 3 trial showed that ENHERTU® (trastuzumab deruxtecan) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to standard of care chemotherapy in the primary trial population of patients with HR positive, HER2 low (IHC 1+ or IHC 2+/ISH-) metastatic breast cancer following one or more lines of endocrine therapy.
A statistically significant and clinically meaningful improvement in PFS also was observed in the overall trial population (patients with HER2 low and HER2 ultralow [defined as IHC 0 with membrane staining; IHC >0 <1+] metastatic breast cancer). A pre-specified subgroup analysis showed that the clinically meaningful improvement was consistent between patients with HER2 low and HER2 ultralow expression.
Overall survival (OS) data were not mature at the time of the analysis. However, ENHERTU showed an early trend towards an OS improvement versus standard of care 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.
ENHERTU is a specifically engineered HER2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN).
It is estimated that approximately 60% to 65% of HR positive, HER2 negative breast cancers are HER2 low and potentially an additional 25% may be HER2 ultralow.1,2 Endocrine therapies are widely used in the early lines of treatment for HR positive metastatic breast cancer. However, after two lines of treatment, further efficacy from endocrine therapy is often limited.3 The current standard of care following endocrine therapy is chemotherapy, which is associated with poor response rates and outcomes.3,4,5,6
“The topline results from DESTINY-Breast06 highlight the importance of continuing to challenge current treatment paradigms and established breast cancer classifications to evolve how we treat patients with HR positive, HER2 expressing metastatic breast cancer,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “Building on the practice-changing data seen in DESTINY-Breast04, these results reinforce the potential for use of ENHERTU earlier in the treatment landscape and in an even broader patient population.”
“DESTINY-Breast06 shows that ENHERTU could become a new standard of care for patients with HER2 low and HER2 ultralow metastatic breast cancer following one or more lines of endocrine therapy,” said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology R&D, AstraZeneca. “These data underscore the potential for treatment with ENHERTU across the spectrum of HR positive breast cancer, further redefining the treatment of metastatic breast cancer.”
The safety profile of ENHERTU was consistent with previous breast cancer clinical trials with no new safety signals identified.
Data from DESTINY-Breast06 will be presented at an upcoming medical meeting and shared with global regulatory authorities.
About DESTINY-Breast06
DESTINY-Breast06 is a global, randomized, open-label, phase 3 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) versus investigator’s choice of chemotherapy (capecitabine, paclitaxel or nab-paclitaxel) in patients with HR positive, HER2 low (IHC 1+ or IHC 2+/ISH-) or HER2 ultralow (defined as IHC 0 with membrane staining [IHC >0 <1+]) advanced or metastatic breast cancer. Patients in the trial had no prior chemotherapy for advanced or metastatic disease and either experienced disease progression within six months of starting first-line treatment with an endocrine therapy combined with a CDK4/6 inhibitor or received at least two previous lines of endocrine therapy in the metastatic setting.
The primary endpoint is PFS in the HR positive, HER2 low patient population as measured by blinded independent central review (BICR). Key secondary endpoints include OS in patients with HER2 low expression and PFS by BICR and OS in the overall trial population (HER2 low and HER2 ultralow). Other secondary endpoints include objective response rate, duration of response, time to first subsequent treatment or death, time to second subsequent treatment or death and safety. Analysis of the HER2 ultralow subgroup was not powered to demonstrate statistical significance.
DESTINY-Breast06 enrolled 866 patients (n=713 for HER2 low and n=153 for HER2 ultralow) at multiple sites in Asia, Europe, North America and South America. For more information about the trial, visit ClinicalTrials.gov.
About Breast Cancer and HER2 Expression
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide.7 More than two million breast cancer cases were diagnosed in 2022 with more than 665,000 deaths globally.7 While survival rates are high for those diagnosed with early breast cancer, only approximately 30% of patients who are diagnosed with or progress to metastatic disease are expected to live five years after their diagnosis.8
HR positive, HER2 negative is the most common breast cancer subtype, accounting for approximately 70% of all breast cancers.8 HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including breast cancer.9 Patients with high levels of HER2 expression (IHC 3+ or IHC2+/ISH+) are classified as HER2 positive and treated with HER2 targeted therapies, representing approximately 15 to 20% percent of all breast cancers.10 Historically, tumors that were not classified as HER2 positive were classified as HER2 negative; however, many of these tumors still carry some level of HER2 expression.11 It is estimated that approximately 60% to 65% of HR positive, HER2 negative breast cancers are HER2 low and potentially an additional 25% may be HER2 ultralow.1,2
Prior to the approval of ENHERTU in HER2 low metastatic breast cancer post chemotherapy based on the DESTINY-Breast04 trial, there were no targeted therapies approved specifically for patients with HER2 low expression.12 There are no targeted therapies specifically approved for patients with HER2 ultralow expression.13
About ENHERTU
ENHERTU (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) 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 program 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 60 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+ or IHC 2+/ 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 55 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 (5.4 mg/kg) is approved in more than 35 countries worldwide for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors 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 theDESTINY-Lung02 trial. Continued approval in the U.S. 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 45 countries 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 and/or DESTINY-Gastric02 trials.
ENHERTU (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 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.
About the ENHERTU Clinical Development Program
A comprehensive global clinical development program is underway evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2 targetable cancers. Trials in combination with other anticancer treatments, such as immunotherapy, also are underway.
About the Daiichi Sankyo and AstraZeneca Collaboration
Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and 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 datopotamab deruxtecan.
About the DXd ADC Portfolio of Daiichi Sankyo
The DXd ADC portfolio of Daiichi Sankyo currently consists of six ADCs in clinical development across multiple types of cancer. ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck & Co., Inc., Rahway, N.J. USA. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo.
Designed using Daiichi Sankyo’s proprietary DXd ADC Technology to target and deliver 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, raludotatug deruxtecan and DS-3939 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.
ENHERTU U.S. Important Safety Information
Indications
ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:
- Unresectable or metastatic HER2-positive (IHC 3+ or ISH positive) 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
- Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy
- Unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy
This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. - Locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen
- Unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options
This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Please see accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.
About Daiichi Sankyo
Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical need. For more information, please visit www.daiichisankyo.com.
References
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4 Cortes J, et al. Lancet. 2011;377:914-923.
5 Yuan P, et al. Eur J Cancer. 2019;112:57-65.
6 Jerusalem G, et al. JAMA Oncol. 2018;4(10):1367–1374.
7 Bray F, et al. CA Cancer J Clin. 2024; 10.3322/caac.21834.
8 National Cancer Institute. SEER Cancer Stat Facts: Female Breast Cancer Subtypes. Accessed April 2024.
9 Iqbal N, et al. Mol Biol Int. 2014;852748.
10 Ahn S, et al. J Pathol Transl Med. 2020;54(1):34-44.
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13 Eiger D, et al. Cancers. 2021 Mar; 13(5): 1015.
SOURCE: Daiichi Sankyo
