• Submission based on DESTINY-Breast06 phase 3 trial results that showed ENHERTU demonstrated astatistically significant and clinically meaningful improvement in progression-free survival compared tostandard of care chemotherapy
• ENHERTU has the potential to become the first HER2 directed therapy and antibody drug conjugateapproved in Japan in this setting
Tokyo – (October 4, 2024) – Daiichi Sankyo (TSE: 4568) today announced that it has submitted asupplemental New Drug Application (sNDA) to Japan’s Ministry of Health, Labour and Welfare (MHLW)for ENHERTU®(trastuzumab deruxtecan) for the treatment of adult patients with HER2 low (IHC 1+ or IHC2+/ISH-) or ultralow (IHC 0 with membrane staining) unresectable or recurrent breast cancer.
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deathsworldwide, with more than 665,000 deaths globally.1In Japan, breast cancer is the most common cancer inwomen, with approximately 92,000 cases of breast cancer diagnosed in 2022.2 Hormone receptor (HR)positive, HER2 negative is the most common breast cancer subtype, accounting for approximately 70% of allbreast cancers.3It is estimated that approximately 60% to 65% of HR positive, HER2 negative breast cancersare HER2 low and potentially an additional 25% may be HER2 ultralow.4,5
The sNDA is based on data from the DESTINY-Breast06 phase 3 trial presented as a late-breaking oralpresentation at the 2024 American Society of Clinical Oncology (#ASCO24) Annual Meeting and recentlypublished in The New England Journal of Medicine.
“This submission builds on the current HER2 low indication and if approved will provide the opportunity forthe earlier use of ENHERTU for patients with HER2 low expression as well as expanding into the HER2ultralow patient population,” said Toshinori Agatsuma, PhD, Executive Officer, Head of R&D Division inJapan, Daiichi Sankyo. “The DESTINY-Breast06 results represent the first time a HER2 directed therapy hasshown a clinically meaningful benefit in these patient populations and we look forward to working withregulatory authorities in Japan to bring ENHERTU to these patients.”
Additional regulatory submissions for ENHERTU based on data from DESTINY-Breast06 are under reviewin the EU and U.S.
About DESTINY-Breast06
DESTINY-Breast06 is a global, randomized, open-label, phase 3 trial evaluating the efficacy and safety ofENHERTU (5.4 mg/kg) versus investigator’s choice of chemotherapy (capecitabine, paclitaxel or nabpaclitaxel) in patients with HR positive, HER2 low (IHC 1+ or IHC 2+/ISH-) or HER2 ultralow (IHC 0 withmembrane staining) advanced or metastatic breast cancer. Patients in the trial had no prior chemotherapy foradvanced or metastatic disease and received at least two lines of prior endocrine therapy in the metastaticsetting. Patients also were eligible if they had received one prior line of endocrine therapy combined with aCDK4/6 inhibitor in the metastatic setting and experienced disease progression within six months of startingfirst-line treatment or received endocrine therapy as an adjuvant treatment and experienced disease recurrence within 24 months.
DESTINY-Breast06 enrolled 866 patients (n=713 for HER2 low and n=153 for HER2 ultralow) at multiplesites in Asia, Europe, North America, Oceania and South America. For more information about the trial, visitClinicalTrials.gov.
About Breast Cancer and HER2 Expression
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deathsworldwide.1 More than two million breast cancer cases were diagnosed in 2022 with more than 665,000deaths globally.1In Japan, breast cancer is the most common cancer in women, with approximately 92,000cases of breast cancer diagnosed in 2022.2 While survival rates are high for those diagnosed with early breastcancer, only about 30% of patients diagnosed with or who progress to metastatic disease are expected to livefive years following diagnosis.3
The primary endpoint is progression-free survival (PFS) in the HR positive, HER2 low patient population asmeasured by blinded independent central review (BICR). Key secondary endpoints include PFS by BICR inthe overall trial population (HER2 low and HER2 ultralow), overall survival (OS) in patients in the HER2low patient population and OS in the overall trial population. Other secondary endpoints include objectiveresponse rate, duration of response, time to first subsequent treatment or death, time to second subsequenttreatment or death and safety. Analysis of the HER2 ultralow subgroup was not powered to demonstratestatistical significance.
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types oftumors, including breast cancer.6 Patients with high levels of HER2 expression (IHC 3+ or IHC2+/ISH+) areclassified as HER2 positive and treated with HER2 targeted therapies, representing approximately 15 to 20% of all breast cancers.7 Historically, tumors that were not classified as HER2 positive were classified as HER2negative, despite the fact that many of these tumors still carry some level of HER2 expression.8It isestimated that approximately 60% to 65% of HR positive, HER2 negative breast cancers are HER2 low andpotentially an additional 25% may be HER2 ultralow.4,5
Endocrine therapies are widely given consecutively in the early lines of treatment for HR positive metastaticbreast cancer. However, following two lines of endocrine therapy, further efficacy with additional endocrinetreatment is often limited. 9 The current standard of care following endocrine therapy is chemotherapy, whichis associated with poor response rates and outcomes.9,10,11,12
Prior to the approval of ENHERTU following chemotherapy in HER2 low metastatic breast cancer based onthe DESTINY-Breast04 trial, there were no targeted therapies approved specifically for patients with HER2low expression.13 There are no targeted therapies specifically approved for patients with HER2 ultralowexpression.14
About ENHERTU
ENHERTU (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) is a HER2 directedantibody drug conjugate (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 inAstraZeneca’s ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to anumber of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavablelinkers.
ENHERTU (5.4 mg/kg) is approved in more than 65 countries worldwide for the treatment of adult patientswith 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 orin the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months ofcompleting therapy based on the results from the DESTINY-Breast03 trial.
ENHERTU (5.4 mg/kg) is approved in more than 65 countries worldwide for the treatment of adult patientswith unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a priorsystemic therapy in the metastatic setting or developed disease recurrence during or within six months ofcompleting adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial.
ENHERTU (5.4 mg/kg) is approved in more than 45 countries worldwide for the treatment of adult patientswith unresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations, as detectedby a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial. Continued approval in the U.S. for this indication may be contingent uponverification 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 patientswith locally advanced or metastatic HER2 positive (IHC 3+ or IHC 2+/ISH+) gastric or gastroesophagealjunction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the resultsfrom the DESTINY-Gastric01, DESTINY-Gastric02 and/or DESTINY-Gastric06 trials. Full approval inChina for this indication will depend on whether a randomized controlled confirmatory clinical trial candemonstrate clinical benefit in this population.
ENHERTU (5.4 mg/kg) is approved in the U.S. for the treatment of adult patients with unresectable ormetastatic HER2 positive (IHC 3+) solid tumors who have received prior systemic treatment and have nosatisfactory alternative treatment options based on efficacy results from the DESTINY-PanTumor02,DESTINY-Lung01 and DESTINY-CRC02 trials. Continued approval for this indication in the U.S. may becontingent 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 ofENHERTU monotherapy across multiple HER2 targetable cancers. Trials in combination with otheranticancer 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 commercializeENHERTU in March 2019 and datopotamab deruxtecan in July 2020, except in Japan where Daiichi Sankyomaintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply ofENHERTU and datopotamab deruxtecan.
About the ADC Portfolio of Daiichi Sankyo
The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinctADC technology platforms discovered in-house by Daiichi Sankyo.
The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where eachADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (anexatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADC portfolio currentlyconsists of ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directedADC, which 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 andcommercialized globally with Merck. DS-3939, a TA-MUC1 directed ADC, is being developed by DaiichiSankyo.
The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modifiedpyrrolobenzodiazepine (PBD) payload. DS-9606, a CLDN6 directed PBD ADC, is the first of severalplanned ADCs in clinical development utilizing this platform.
Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939and DS-9606 are investigational medicines that have not been approved for any indication in any country.Safety and efficacy have not been established.
About Daiichi Sankyo
Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development ofsociety that discovers, develops and delivers new standards of care to enrich the quality of life around theworld. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science andtechnology to create new modalities and innovative medicines for people with cancer, cardiovascular andother diseases with high unmet medical need. For more information, please visit www.daiichisankyo.com.
References
1 Bray F, et al. CA Cancer J Clin. 2024; 10.3322/caac.21834.
2 GLOBOCAN. Cancer Fact Sheets, Japan. Accessed September 2024.
3 National Cancer Institute. SEER Cancer Stat Facts: Female Breast Cancer Subtypes. Accessed September 2024.
4 Denkert C, et al. Lancet Oncol. 2021 Aug;22(8):1151-1161.
5 Chen Z, et al. Breast Cancer Res Treat. 2023 Nov;202(2):313-323.
6Iqbal N, et al. Mol Biol Int. 2014;852748.
7 Ahn S, et al. J Pathol Transl Med. 2020;54(1):34-44.
8 Sajjadi E, et al. Cancer Drug Resist. 2022;5(4):882-888.
9 Manohar P, et al. Cancer Biol Med. 2022 Feb 15; 19(2):202–212.
10 Cortes J, et al. Lancet. 2011;377:914-923.
11 Yuan P, et al. Eur J Cancer. 2019;112:57-65.
12 Jerusalem G, et al. JAMA Oncol. 2018;4(10):1367–1374.
13 Modi S, et al. N Engl J Med. 2022;387:9-20.
14 Eiger D, et al. Cancers. 2021 Mar; 13(5): 1015.