- Approved for use before surgery based on DESTINY-Breast11 phase 3 trial or following surgery based on DESTINY-Breast05 phase 3 trial
- Two new indications bring Daiichi Sankyo and AstraZeneca’s Enhertu into curative-intent setting, reinforcing its role across stages of HER2 positive breast cancer
- Enhertu now approved for nine indications with six across both early and metastatic HER2 positive breast cancer
TOKYO–(BUSINESS WIRE)–Enhertu® (fam-trastuzumab deruxtecan-nxki) has been approved by the U.S. Food and Drug Administration (FDA) for two new breast cancer indications in the neoadjuvant and adjuvant settings of patients with HER2 positive early breast cancer.
In the neoadjuvant setting, Enhertu followed by a taxane, trastuzumab and pertuzumab (THP) has been approved for the treatment of adult patients with HER2 positive stage 2 or stage 3 breast cancer. In the adjuvant setting, Enhertu has been approved for the treatment of adult patients with HER2 positive breast cancer who have residual invasive disease following neoadjuvant trastuzumab (with or without pertuzumab) and taxane-based treatment.
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/NYSE: AZN).
The neoadjuvant approval was based on results from the DESTINY-Breast11 phase 3 trial published in Annals of Oncology and the adjuvant approval was based on the results from the DESTINY-Breast05 phase 3 trial published in The New England Journal of Medicine. Data from both trials were presented at the 2025 European Society for Medical Oncology (ESMO) Congress.
In DESTINY-Breast11, Enhertu followed by THP demonstrated a statistically significant and clinically meaningful improvement in the pathologic complete response (pCR) rate compared to 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. The pCR rate with Enhertu followed by THP was 67.3% compared with 56.3% with ddAC-THP, representing a difference of 11.2% (95% confidence interval [CI]: 3.9-18.3; p=0.003).
In DESTINY-Breast05, Enhertu significantly reduced the risk of invasive disease recurrence or death (invasive disease-free survival [IDFS]) by 53% (hazard ratio [HR]=0.47; 95% CI: 0.34-0.66; p<0.0001) compared to trastuzumab emtansine (T-DM1) in patients with HER2 positive breast cancer with residual invasive disease following neoadjuvant therapy. Enhertu demonstrated a three-year IDFS rate of 92.4% (95% CI: 89.7-94.4) and 83.7% with T-DM1 (95% CI: 80.2-86.7). Data also showed that Enhertu significantly reduced the risk of disease recurrence or death (disease-free survival [DFS]) by 53% (HR=0.47; 95% CI: 0.34-0.66; p<0.0001) compared to T-DM1. Results showed a three-year DFS rate of 92.3% (95% CI: 89.5-94.3) in the Enhertu arm and 83.5% with T-DM1 (95% CI: 79.9-86.4).
Based on the results from DESTINY-Breast05, fam-trastuzumab deruxtecan-nxki (Enhertu) has been included in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) as a Category 1 recommended treatment in the adjuvant setting for patients with HER2 positive early breast cancer with residual disease following preoperative therapy and high risk of recurrence. See NCCN Guidelines® for detailed recommendations.
“HER2 positive breast cancer is an aggressive disease, and our goal is to reduce the risk of recurrence as early as possible to achieve the best long‑term outcomes. The neoadjuvant setting offers the earliest opportunity to improve outcomes, while the adjuvant setting provides another important chance to prevent recurrence for patients with residual disease after surgery,” said Shanu Modi, MD, medical oncologist, Memorial Sloan Kettering Cancer Center and principal investigator for the DESTINY-Breast11 trial. “These two new indications in HER2 positive early breast cancer will evolve how we treat patients in these settings and support trastuzumab deruxtecan as a potential new standard of care in early-stage disease.”
“Providing patients with early breast cancer more options to help prevent progression to metastatic disease can lead to improved outcomes,” said Victoria Smart, Senior Vice President, Mission, Susan G. Komen. “Progression and recurrence remain among the most significant unmet needs for those diagnosed with early breast cancer, and continued advances in treatment bring new hope to patients and families facing this disease.”
Enhertu is approved with Boxed WARNINGS for interstitial lung disease (ILD)/pneumonitis and Embryo-Fetal toxicity. The safety of Enhertu followed by THP was evaluated in 320 patients with HER2 positive (IHC 3+ or ISH+) early breast cancer who received at least one dose of Enhertu followed by THP in DESTINY-Breast11. The safety of Enhertu was evaluated in 806 patients with HER2 positive breast cancer with residual invasive disease following neoadjuvant therapy who received at least one dose of Enhertu in DESTINY-Breast05.
In DESTINY-Breast11, the most common adverse reactions (≥20%), including laboratory abnormalities, were decreased hemoglobin, increased alanine aminotransferase, increased aspartate aminotransferase, decreased white blood cell count, nausea, peripheral neuropathy, diarrhea, decreased neutrophil count, alopecia, fatigue, decreased lymphocyte count, rash, musculoskeletal pain, decreased blood potassium, constipation, vomiting, stomatitis and decreased appetite. Serious adverse reactions occurred in 11% of patients receiving Enhertu followed by THP, including COVID-19 (0.9%) and ILD/pneumonitis (0.6%). Fatal adverse reactions occurred in 0.6% of patients, including ILD or pneumonitis and death not otherwise specified (one patient each).
In DESTINY-Breast05, the most common adverse reactions (≥20%), including laboratory abnormalities, were decreased white blood cell count, decreased lymphocyte count, decreased neutrophil count, nausea, decreased hemoglobin, increased aspartate aminotransferase, fatigue, increased alanine aminotransferase, decreased platelet count, increased blood alkaline phosphatase, constipation, vomiting, decreased blood potassium, diarrhea, musculoskeletal pain and decreased appetite. Serious adverse reactions occurred in 17% of patients receiving Enhertu. Serious adverse reactions in ≥1% of patients who received Enhertu were ILD/pneumonitis, radiation pneumonitis and decreased platelet count. Fatal adverse reactions occurred in 0.4% of patients, including ILD/pneumonitis (two patients) and respiratory tract infection (one patient).
“Enhertu has redefined the treatment of HER2 expressing breast cancer with practice-changing data across six breast cancer indications in seven years,” said Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi Sankyo, Inc. “Enhertu is now approved in the U.S. across both early and metastatic HER2 positive breast cancer, accomplishing what we set out to achieve a little over a decade ago for patients at the start of our comprehensive clinical development program.”
“HER2 positive early disease is considered highly curable, however, up to one in four patients still experience disease recurrence, underscoring the need for new options in this setting,” said Dave Fredrickson, Executive Vice President, Oncology Hematology Business Unit, AstraZeneca. “These approvals mark an important step forward, expanding the possibility of cure to more patients for the first time in many years and positioning Enhertu as a foundational treatment in early breast cancer.”
These applications in the U.S. were reviewed under Project Orbis, which provides a framework for concurrent submission and review of oncology medicines among participating international partners. As part of Project Orbis, reviews for both DESTINY-Breast11 and DESTINY-Breast05 are ongoing in Australia, Brazil, Canada, Israel, Singapore and the UK. Additional regulatory submissions for Enhertu based on DESTINY-Breast05 are under review in Japan, the EU and Switzerland.
Daiichi Sankyo and AstraZeneca are committed to ensuring that patients in the U.S. who are prescribed Enhertu can access the medication and receive necessary financial support. Provider and patient support, reimbursement and distribution for Enhertu in the U.S. will be accessible by visiting www.Enhertu4U.com or calling 1-833-Enhertu (1-833-364-3788).
Please visit www.Enhertu.com for full Prescribing Information, including Boxed WARNINGS, and Medication Guide.
Financial Considerations
Following these approvals in the U.S., an amount of $155 million ($30 million for the neoadjuvant approval and $125 million for the adjuvant approval) is due from AstraZeneca to Daiichi Sankyo as milestone payments for these HER2 positive early-stage breast cancer indications. Sales of Enhertu in the U.S. are recognized by Daiichi Sankyo. For further details on the financial arrangements, please consult the collaboration agreement from March 2019.
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 compared to ddAC-THP in patients with high-risk 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 event-free survival, IDFS, overall survival (OS) 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 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 early 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, which is defined as the time from randomization until first invasive local, axillary or distant recurrence or death from any cause. The key secondary endpoint is investigator-assessed DFS. Other secondary endpoints include OS, distant recurrence-free interval, brain metastases-free interval 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 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 In the U.S., approximately 320,000 cases of breast cancer are diagnosed annually with more than 42,000 deaths.2
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including breast cancer.3 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.3 An estimated one in five cases of breast cancer is considered HER2 positive.4 Approximately one in three patients with HER2 positive early-stage breast cancer is considered high-risk, meaning they are more likely to experience disease recurrence and have a poor prognosis.5
There are two treatment settings for HER2 positive early breast cancer: neoadjuvant (before surgery) and adjuvant (after surgery). In the neoadjuvant setting, the current standard of care varies across regions but generally consists of combination chemotherapy regimens. In the U.S., the current standard of care consists of a combination regimen of carboplatin, trastuzumab, pertuzumab and a taxane.6 For patients with HER2 positive early breast cancer, reaching pCR with neoadjuvant treatment is an early indicator of improved long-term survival.7 However, 39% to 66% of patients who receive neoadjuvant treatment do not reach pCR, putting them at increased risk of disease recurrence.8,9,10,11,12
In the adjuvant setting, despite receiving additional treatment with current standard of care for residual disease, some patients still experience invasive disease or death.13 Once patients are diagnosed with metastatic disease, the five-year survival rate drops from nearly 90% to approximately 30%.14 Adjuvant therapy represents a key opportunity to minimize the risk of recurrence and prevent progression to metastatic disease for patients with residual disease.15,16
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 the U.S. for the treatment of adult patients with HER2 positive breast cancer who have residual invasive disease following neoadjuvant trastuzumab (with or without pertuzumab) and taxane-based treatment based on the DESTINY-Breast05 trial.
Enhertu (5.4 mg/kg) followed by THP is approved in China and the U.S. as a neoadjuvant treatment for adult patients with HER2 positive (IHC 3+ or ISH+) stage 2 or stage 3 breast cancer based on the results from the DESTINY-Breast11 trial. 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) in combination with pertuzumab is approved in Israel, Saudi Arabia, Switzerland, the United Arab Emirates and the U.S. as a first-line treatment for adult patients with unresectable or metastatic HER2 positive (IHC 3+ or ISH+) breast cancer, as determined by an FDA-approved test, based on the results from the DESTINY-Breast09 trial.
Enhertu (5.4 mg/kg) is approved in more than 95 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+ or 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 95 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 70 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 75 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 90 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-Gastric04 trials.
Enhertu (5.4 mg/kg) is approved in more than 15 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, DESTINY-CRC02 and/or HERALD trials. Continued approval in the U.S. 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.
Enhertu U.S. Indications and Important Safety Information
Indications
ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for:
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HER2-Positive Early Breast Cancer
- As neoadjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) Stage II or III breast cancer, as determined by an FDA-authorized test followed by a taxane, trastuzumab, and pertuzumab (THP)
- As adjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) breast cancer who have residual invasive disease following neoadjuvant trastuzumab (with or without pertuzumab) and taxane-based treatment
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HER2-Positive Metastatic Breast Cancer
- In combination with pertuzumab as first-line treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer, as determined by an FDA-authorized test
- As monotherapy for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or 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
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HER2-Low and HER2-Ultralow Metastatic Breast Cancer
- As monotherapy 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 an FDA-authorized test, that has progressed on one or more endocrine therapies in the metastatic setting
- As monotherapy for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-authorized test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy
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HER2-Mutant Unresectable or Metastatic Non-Small Cell Lung Cancer (NSCLC)
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As monotherapy for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-authorized 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.
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As monotherapy for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-authorized test, and who have received a prior systemic therapy
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HER2-Positive Locally Advanced or Metastatic Gastric Cancer
- As monotherapy for the treatment of adult patients with 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
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HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors
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As monotherapy 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
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.
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As monotherapy 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
Important Safety Information
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WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY |
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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).
Contacts
MEDIA CONTACTS:
Global:
Jennifer Brennan
jennifer.brennan@daiichisankyo.com
+1 908 900 3183 (mobile)
Japan:
DS-PR_jp@daiichisankyo.com
INVESTOR RELATIONS CONTACT:
DaiichiSankyoIR_jp@daiichisankyo.com
