ENHERTU® Reduced the Risk of Disease Recurrence or Death by 53% Versus T-DM1 in Patients with High-Risk HER2 Positive Early Breast Cancer Following Neoadjuvant Therapy in DESTINY-Breast05 Phase 3 Trial

• More than 92% of patients treated with Daiichi Sankyo and AstraZeneca’s ENHERTU were free of invasive disease at three years
• DESTINY-Breast05 presented in ESMO Presidential Symposium I alongside DESTINY-Breast11 reinforces potential for 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-Breast05 phase 3 trial showed ENHERTU^® (trastuzumab deruxtecan) demonstrated a highly statistically significant and clinically meaningful improvement in invasive disease-free survival (IDFS) compared to trastuzumab emtansine (T-DM1) as a post-neoadjuvant treatment (after surgery) in patients with HER2 positive early breast cancer with residual invasive disease in the breast and/or axillary lymph nodes after neoadjuvant treatment and a high risk of disease recurrence. Results were presented today (LBA1) alongside the results of DESTINY-Breast11 (291O) in 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 primary endpoint analysis, ENHERTU significantly reduced the risk of invasive disease recurrence or death (invasive disease-free survival [IDFS]) by 53% (hazard ratio [HR]=0.47; 95% confidence interval [CI]: 0.34-0.66; p<0.0001) compared to T-DM1 as a post-neoadjuvant treatment. ENHERTU demonstrated a three-year IDFS rate of 92.4% (95% CI: 89.7-94.4) compared to 83.7% with T-DM1 (95% CI: 80.2-86.7). IDFS findings were consistent across all prespecified subgroups.

In the key secondary endpoint analysis of disease-free survival (DFS), ENHERTU also significantly reduced the risk of disease recurrence or death by 53% (HR=0.47; 95% CI: 0.34-0.66; p<0.0001) compared to T-DM1 as a post-neoadjuvant treatment. The three-year DFS rate for ENHERTU was 92.3% (95% CI: 89.5-94.3) compared to 83.5% with T-DM1 (95% CI: 79.9-86.4). Treatment with ENHERTU also reduced the risk of distant disease recurrence (distant recurrence-free interval [DRFI]) by 51% (HR=0.49; 95% CI: 0.34-0.71) and the risk of brain metastases (brain metastasis-free interval [BMFI]) by 36% (HR=0.64; 95% CI: 0.35-1.17) versus T-DM1. DRFI at three years was 93.9% with ENHERTU (95% CI: 91.4-95.7) compared to 86.1% with T-DM1 (95% CI: 82.5-89.1). BMFI at three years was 97.6% with ENHERTU (95% CI: 96.2-98.5) compared to 95.8% with T-DM1 (95% CI: 93.6-97.2).

Overall survival (OS) was not mature at the time of this planned interim analysis (2.9% maturity at data cut-off) and will be assessed in future analyses (HR=0.61; 95% CI: 0.34-1.10).

“For patients with residual disease after neoadjuvant treatment, the post-neoadjuvant setting represents a critical second opportunity to reduce recurrence risk, and in DESTINY-Breast05 ENHERTU reduced the risk of early recurrence or death by 53% compared to the current standard of T-DM1,” said Charles Geyer, MD, Chief Scientific Officer of the NSABP Foundation, Professor of Medicine at the UPMC Hillman Cancer Center in Pittsburgh, Pennsylvania and Principal Investigator for the trial. “These results, coupled with the safety data from the trial, are likely to transform clinical practice in the post-neoadjuvant setting for patients with high-risk disease, with the potential for ENHERTU to set a new standard of care.”

The safety profile of ENHERTU observed in DESTINY-Breast05 was consistent with its known profile with no new safety concerns identified. Grade 3 or higher treatment emergent adverse event (TEAE) rates were comparable between ENHERTU (50.6%) and T-DM1 (51.9%). The most common grade 3 or higher TEAEs occurring in 5% or more of patients treated with ENHERTU were decreased neutrophil count (15.5%), decreased white blood cell count (10.0%) and decreased platelet count (6.7%). Rates of interstitial lung disease (ILD) or pneumonitis were low in both arms with ILD events occurring in 9.6% of the ENHERTU arm and 1.6% of the T-DM1 arm. The majority of ILD or pneumonitis events were low grade (grade 1 [ENHERTU=16; 2.0%; T-DM1=8; 1.0%] or grade 2 [n=52; 6.5%; T-DM1=5; 0.6%]). There were no grade 3 or higher ILD or pneumonitis events for T-DM1. In the ENHERTU arm, there were seven grade 3 events (0.9%), zero grade 4 events and two grade 5 events (0.2%) as determined by an independent adjudication committee.

“The results of DESTINY-Breast05 demonstrate a clear benefit of ENHERTU over the current standard of care following surgery in patients with HER2 positive early breast cancer at high risk of recurrence after neoadjuvant treatment, improving their chance for sustained long-term outcomes,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “These results, coupled with the results of DESTINY-Breast11, illustrate the continued promise of ENHERTU to move earlier in the breast cancer treatment paradigm where it can have the greatest impact on the lives of patients.”

“Progress in treating HER2 positive early breast cancer has been significant, yet managing patients at a higher-risk of recurrence remains challenging,” said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology Hematology R&D, AstraZeneca. “These landmark data, alongside those from DESTINY-Breast11, underscore the potential of ENHERTU to become a foundational treatment in early-stage breast cancer, increasing the likelihood that more patients could be cured in this setting.”

All patients in the DESTINY-Breast05 trial had received prior neoadjuvant chemotherapy and HER2 targeted therapy and the majority of patients received either concurrent (ENHERTU=53.5%; T-DM1=58.8%) or sequential (ENHERTU=39.9%; T-DM1=34.1%) radiotherapy treatment. The majority of patients were pathologic node positive following neoadjuvant treatment (ENHERTU=80.7%; T-DM1=80.5%). As of the data cut-off date of July 2, 2025, the median study duration was 29.9 months in the ENHERTU arm (range: 0.3-53.4) and 29.7 months in the T-DM1 arm (range: 0.1-54.4).

Summary of DESTINY-Breast05 Interim Analysis Results

DESTINY-Breast05 was conducted in collaboration with the National Surgical Adjuvant Breast and Bowel Project Foundation (NSABP), the German Breast Group (GBG), Arbeitsgemeinschaft Gynäkologische Onkologie (AGO-B) and SOLTI Breast Cancer Research Group.

About DESTINY-Breast05

DESTINY-Breast05 is a global, multicenter, randomized, open-label, phase 3 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) versus T-DM1 in patients with HER2 positive primary breast cancer with residual invasive disease in breast or axillary lymph nodes following neoadjuvant therapy and a high risk of recurrence. High risk of recurrence was defined as presentation with inoperable cancer (prior to neoadjuvant therapy) or pathologically positive axillary lymph nodes following neoadjuvant therapy.

The primary endpoint of DESTINY-Breast05 is investigator-assessed IDFS. IDFS is defined as the time from randomization until first recurrence, distant recurrence or death from any cause. The key secondary endpoint is investigator-assessed DFS. Other secondary endpoints include OS, DRFI, BMFI and safety.

DESTINY-Breast05 enrolled 1,635 patients in Asia, Europe, North America, Oceania and South America. For more information about the trial, visit ClinicalTrials.gov.

About Post 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

For patients with HER2 positive early breast cancer, achieving pCR with neoadjuvant treatment is the earliest indicator of improved long-term survival.⁴ However, approximately half of patients who receive neoadjuvant treatment do not reach pCR and have poorer long-term outcomes, putting them at increased risk of disease recurrence.^4,5,6,7,8,9

Despite receiving additional treatment with T-DM1 for residual disease in the post-neoadjuvant setting, approximately 20% of patients still experience invasive disease or death, with no reduction in the risk of central nervous system (CNS) recurrence.^10,11 Once patients are diagnosed with metastatic disease, the five-year survival rate drops from nearly 90% to approximately 30%.¹²

Post-neoadjuvant therapy represents a key opportunity to minimize the risk of recurrence and prevent progression to metastatic disease for patients with residual disease. New treatment options are needed in the early breast cancer setting to help reduce the likelihood of disease progression and improve long-term outcomes for more patients.

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.

Contacts

Media Contacts:

Global/US:
Jennifer Brennan

Daiichi Sankyo

[email protected]
+1 908 900 3183 (mobile)

Japan:
Daiichi Sankyo Co., Ltd.

[email protected]

Investor Relations Contact:
[email protected]

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