ENHERTU® Followed by THP Before Surgery Resulted in a Pathologic Complete Response in 67% of Patients with High-Risk HER2 Positive Early-Stage Breast Cancer in DESTINY-Breast11 Phase 3 Trial

• Highest reported pathologic complete response rate seen in a phase 3 registrational trial for HER2 positive early breast cancer with favorable safety profile versus standard treatment
• DESTINY-Breast11 presented in ESMO Presidential Symposium I alongside DESTINY-Breast05 reinforces potential for Daiichi Sankyo and AstraZeneca’s ENHERTU to become a foundational treatment in curative-intent early breast cancer setting

TOKYO & BASKING RIDGE, N.J.--(BUSINESS WIRE)--Positive results from the DESTINY-Breast11 phase 3 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 when compared 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. Results were presented today (291O) alongside the results from the DESTINY-Breast05 (LBA1) phase 3 trial during Presidential Symposium I at the 2025 European Society for Medical Oncology (#ESMO25) Congress.

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).

In the trial, ENHERTU followed by THP resulted in a pCR rate of 67.3% compared to 56.3% with ddAC-THP, representing a pCR rate improvement of 11.2% (95% confidence interval [CI]: 4.0-18.3; p=0.003). Improvements in pCR rates were observed across both HR positive and HR negative subgroups. After surgery, 81.3% of patients who received neoadjuvant therapy 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 cut-off); however, an early analysis showed a trend favoring ENHERTU followed by THP versus ddAC-THP (HR=0.56; 95% CI: 0.26-1.17).

“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, optimize safety and improve the potential for cure,” said Nadia Harbeck, Director of Breast Center, Cancer Department of OB&GYN and CCC Munich, LMU University Hospital, Germany and Principal Investigator for the trial. “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.”

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 favorable safety profile compared to ddAC-THP with reduced rates of grade 3 or higher treatment emergent adverse events (TEAEs) (ENHERTU followed by THP=37.5%; ddAC-THP=55.8%), serious adverse events (AEs) (ENHERTU followed by THP=10.6%; ddAC-THP=20.2%), treatment interruptions (ENHERTU followed by THP=37.8%; ddAC-THP=54.5%) and left ventricular dysfunction (ENHERTU followed by THP=1.3%; ddAC-THP=6.1%). The most common grade 3 or higher TEAEs occurring in 5% or more of patients treated with ENHERTU followed by THP were neutropenia (13.8%), diarrhea (5.9%) and increased transaminases (5.0%). Rates of interstitial lung disease (ILD) or pneumonitis were low and similar between arms with ILD events occurring in 4.4% (n=14/320) of patients treated with ENHERTU followed by THP compared to 5.1% (n=16/312) in those treated with ddAC-THP. The majority of ILD or pneumonitis events were low grade (grade 1 or grade 2 [ENHERTU followed by THP=12; ddAC-THP=10]), with one grade 3 or grade 4 events in the ENHERTU followed by THP arm and five grade 3 or 4 events in the ddAC-THP arm. There was one grade 5 ILD event in each arm as determined by an independent adjudication committee.

“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,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “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.”

“The goal of treatment in the early breast cancer setting is to provide patients with the best possible chance for cure while optimizing the tolerability of the treatment regimen,” said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology Hematology R&D, AstraZeneca. “The impressive pathologic response rates and favorable 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.”

Approximately half of patients in DESTINY-Breast11 had a primary clinical tumor stage of 0-2 (cT0-2; ENHERTU followed by THP=54.8%; ddAC-THP=58.8%) and nearly half had a primary clinical tumor stage of 3-4 (cT3-4; ENHERTU followed by THP=45.2%; ddAC-THP=41.3%). The majority of patients were node positive (ENHERTU followed by THP=89.4%; ddAC-THP=87.8%) and had an ECOG PS (Eastern Cooperative Oncology Group performance status) of 0 (ENHERTU followed by THP=86.6%; ddAC-THP=87.5%). Nearly all patients underwent surgery following neoadjuvant treatment (ENHERTU followed by THP=97.2%; ddAC-THP=93.8%). As of the data cut-off date of March 12, 2025, the median duration of follow-up was 24.3 months in the ENHERTU followed by THP arm and 23.6 months in the ddAC-THP arm.

Summary of DESTINY-Breast11 Primary Results

The ENHERTU monotherapy arm (n=286) 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 the timing of surgery. The recommendation was not related to safety.

A supplemental Biologics License Application for ENHERTU followed by THP based on data from DESTINY-Breast11 is currently under review by the U.S. Food and Drug Administration (FDA).

About DESTINY-Breast11
DESTINY-Breast11 is a global, multicenter, randomized, open-label, phase 3 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 tumor stage T3-4), locally advanced or inflammatory HER2 positive early-stage breast cancer.

Patients were randomized 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 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.

About Neoadjuvant 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 tumors, 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-stage 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, putting them at increased risk of disease recurrence.^5,6,7,8,9,10

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.^11,12,13

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 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 hormone receptor (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 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 the DESTINY-Lung02 and/or DESTINY-Lung05 trials. Continued approval in China and 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 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 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 as a monotherapy or in combination or sequentially with other cancer medicines across multiple HER2 targetable cancers.

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 DATROWAY^® 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.

About the ADC Portfolio of Daiichi Sankyo
The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by Daiichi Sankyo.

The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where 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. The DXd ADC portfolio currently consists 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), 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, 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 modified pyrrolobenzodiazepine (PBD) payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform.

Ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 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:
  • Hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-approved test, that has progressed on one or more endocrine therapies in the metastatic setting
  • 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 (IHC 3+) 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.

Contraindications
None.

Warnings and Precautions
Interstitial Lung Disease / Pneumonitis
Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose 1 level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)
In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Median time to first onset was 5.5 months (range: 0.9 to 31.5). Fatal outcomes due to ILD and/or pneumonitis occurred in 0.9% of patients treated with ENHERTU.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21).

Neutropenia
Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 10⁹/L), interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 10⁹/L), interrupt ENHERTU until resolved to Grade 2 or less, then reduce dose by 1 level. For febrile neutropenia (ANC <1.0 x 10⁹/L and temperature >38.3º C or a sustained temperature of ≥38º C for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by 1 level.

HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)
In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients. Nineteen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 939). Febrile neutropenia was reported in 1.2% of patients.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients.

Left Ventricular Dysfunction
Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU.

Media Contacts:

Global/US:
Jennifer Brennan
Daiichi Sankyo
Jennifer.brennan@daiichisankyo.com
+1 908 900 3183 (mobile)

Japan:
Daiichi Sankyo Co., Ltd.
DS-PR_jp@daiichisankyo.com

Investor Relations Contact:
DaiichiSankyoIR_jp@daiichisankyo.com