• Daiichi Sankyo and AstraZeneca’s ENHERTU followed by THP showed an improved safety profileversus standard of care
• First phase 3 trial to demonstrate benefit of ENHERTU in early breast cancer
• Results will be shared with regulatory authorities
Tokyo and Basking Ridge, NJ – (May 7, 2025) – Positive topline results from the DESTINY-Breast11phase 3 trial showed ENHERTU®(trastuzumab deruxtecan) followed by paclitaxel, trastuzumab andpertuzumab (THP) demonstrated a statistically significant and clinically meaningful improvement inpathologic complete response (pCR) rate versus standard of care (dose-dense doxorubicin andcyclophosphamide followed by THP [ddAC-THP]) when used in the neoadjuvant setting (before surgery) inpatients with high-risk, locally advanced HER2 positive early-stage breast cancer. Pathologic completeresponse is defined as no evidence of invasive cancer cells in the removed breast tissue and lymph nodesfollowing treatment.
The secondary endpoint of event-free survival (EFS) was not mature at the time of this analysis; however,EFS data showed an early positive trend favoring ENHERTU followed by THP compared to standard ofcare. The trial will continue to follow EFS.
ENHERTU is a specifically engineered HER2 directed DXd antibody drug conjugate (ADC) discovered byDaiichi Sankyo (TSE: 4568) and being jointly developed and commercialized by Daiichi Sankyo andAstraZeneca (LSE/STO/Nasdaq: AZN).
Approximately one in three patients with early-stage breast cancer are considered high-risk, as they are morelikely to experience disease recurrence and have a poor prognosis.1,2 Achieving pCR in early-stage HER2positive breast cancer is associated with improved long-term outcomes.3,4 The current standard of care inmany regions of the world in this neoadjuvant setting consists of combination chemotherapy regimens. Theseregimens often include anthracyclines, which can be challenging for patients to tolerate and may result inlong-term cardiovascular side effects. Further, nearly half of patients who receive neoadjuvant treatment donot achieve pCR, reinforcing the need for new treatment options.2,5
“There are still many patients with early-stage breast cancer who do not achieve a pathologic completeresponse with treatment in the neoadjuvant setting, increasing the risk of disease recurrence,” said KenTakeshita, MD, Global Head, R&D, Daiichi Sankyo. “These topline results from DESTINY-Breast11demonstrate that ENHERTU followed by THP could offer patients with HER2 positive breast cancer apromising new treatment approach prior to surgery, setting more patients on a path towards a potential cure.”
“The clinically meaningful improvement in pathologic complete response and the safety data seen inDESTINY-Breast11 highlight the potential of ENHERTU to challenge the current standard of care in earlystage HER2 positive breast cancer,” said Susan Galbraith, MBBChir, PhD, Executive Vice President,Oncology Hematology R&D, AstraZeneca. “ENHERTU is already an important treatment option in themetastatic setting, and these data have the potential to allow this medicine to move into early stages ofdisease where cure is possible.”
ENHERTU followed by THP showed an improved safety profile compared to ddAC-THP. The safetyprofiles of ENHERTU and THP were consistent with the known profiles of each individual medicine with nonew safety concerns identified. Rates of interstitial lung disease were similar across the ENHERTU followedby THP and the ddAC-THP arms as determined by an independent adjudication committee.
Following a recommendation by the Independent Data Monitoring Committee, patient enrollment in a thirdarm of the study evaluating ENHERTU alone was closed based on a previous interim efficacy assessment ofthe study arms.
Data from DESTINY-Breast11 will be presented at an upcoming medical meeting and shared with regulatoryauthorities.
ENHERTU has demonstrated improved outcomes in six phase 3 breast cancer trials across different subtypesand stages of disease, including the recently announced DESTINY-Breast09 trial in the first-line HER2positive metastatic setting. ENHERTU is also being studied in several ongoing breast cancer trials, includingthe DESTINY-Breast05 phase 3 trial, which is evaluating ENHERTU in the high-risk adjuvant early HER2positive setting.
About DESTINY-Breast11
DESTINY-Breast11 is a global, multicenter, randomized, open-label, phase 3 trial evaluating the efficacyand safety of neoadjuvant ENHERTU (5.4 mg/kg) monotherapy or ENHERTU followed by THP (paclitaxel,trastuzumab and pertuzumab) versus the standard of care regimen in patients with high-risk (lymph node positive [N1-3] or primary tumor stage T3-4), locally advanced or inflammatory HER2 positive early-stagebreast cancer.
Patients were randomized 1:1:1 to receive either eight cycles of ENHERTU monotherapy; four cycles ofENHERTU followed by four cycles of THP; or four cycles of ddAC (dose-dense doxorubicin andcyclophosphamide) followed by four cycles of THP.
The primary endpoint of DESTINY-Breast11 is rate of pCR (absence of invasive disease in the breast andlymph 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 SouthAmerica. For more information about the trial, visit ClinicalTrials.gov.
About HER2 Positive Early Breast Cancer
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deathsworldwide.6 More than two million breast cancer cases were diagnosed in 2022, with more than 665,000deaths globally.6HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types oftumors including breast, gastric, lung and colorectal cancers.7
HER2 protein overexpression may occur as aresult of HER2 gene amplification and is often associated with aggressive disease and poor prognosis inbreast cancer.8
Approximately one in five cases of breast cancer are considered HER2 positive.9Approximately one in three patients with early-stage breast cancer are considered high-risk, as they are morelikely to experience disease recurrence and have a poor prognosis.1,2 Achieving pCR in early-stage HER2positive breast cancer is associated with improved long-term outcomes.3,4 The current standard of care inmany regions of the world in this neoadjuvant setting consists of combination chemotherapy regimens. Theseregimens often include anthracyclines, which can be challenging for patients to tolerate and may result inlong-term cardiovascular side effects. Further, nearly half of patients who receive neoadjuvant treatment donot achieve pCR, reinforcing the need for new treatment options.2,5
About ENHERTU
ENHERTU (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) is a HER2 directedADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, ENHERTU is the lead ADC inthe oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientificplatform. ENHERTU consists of a HER2 monoclonal antibody attached to a number of topoisomerase Iinhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.
ENHERTU (5.4 mg/kg) is approved in more than 75 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 75 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 30 countries for the treatment of adult patients withunresectable or metastatic hormone receptor (HR) positive, HER2 low (IHC 1+ or IHC 2+/ISH-) or HER2ultralow (IHC 0 with membrane staining) breast cancer, as determined by a locally or regionally approvedtest, that has progressed on one or more endocrine therapies in the metastatic setting based on the resultsfrom the DESTINY-Breast06 trial.
ENHERTU (5.4 mg/kg) is approved in more than 50 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 resultsfrom the DESTINY-Lung02 and/or DESTINY-Lung05 trials. Continued approval in China and the U.S. forthis 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 65 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. Continued approvalin China for this indication may be contingent upon verification and description of clinical benefit in aconfirmatory trial.
ENHERTU (5.4 mg/kg) is approved in Brazil, Israel, Russia, Saudi Arabia, Taiwan, U.K. and the U.S. forthe treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+) solid tumors whohave received prior systemic treatment and have no satisfactory alternative treatment options based onefficacy 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 benefitin a confirmatory trial.
About the ENHERTU Clinical Development Program
A comprehensive global clinical development program is underway evaluating the efficacy and safety ofENHERTU as a monotherapy or in combination or sequentially with other anti-cancer therapies acrossmultiple HER2 targetable cancers.
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 DATROWAY®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 DATROWAY.
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 DATROWAY, a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), aHER3 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, NJ, USA. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo.
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.
Ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 areinvestigational medicines that have not been approved for any indication in any country. Safety and efficacyhave not been established.