• Groundbreaking phase 3 head-to-head DESTINY-Breast03 results featured at ESMO Presidential Symposium support ENHERTU as the potential new standard of care in previously treated patients
  • DESTINY-Breast01 phase 2 trial data also presented at ESMO showed impressive median overall survival of 29.1 months in HER2 positive patients following two or more HER2 based regimens

TOKYO, Japan & MUNICH, Germany & BASKING RIDGE, NJ, USA I September 18, 2021 I Detailed positive results from the head-to-head DESTINY-Breast03 phase 3 trial showed that ENHERTU® (trastuzumab deruxtecan), the Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) and AstraZeneca HER2 directed antibody drug conjugate (ADC), demonstrated superior progression-free survival (PFS) versus trastuzumab emtansine (T-DM1), a HER2 directed ADC currently approved to treat patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane. Results were presented as the first late-breaking presentation (#LBA1) in the ESMO Presidential Symposium at the European Society for Medical Oncology (#ESMO21) 2021 Virtual Congress.

At a pre-specified interim analysis of DESTINY-Breast03, ENHERTU demonstrated a 72% reduction in the risk of disease progression or death compared to T-DM1 (hazard ratio [HR] = 0.28; 95% CI: 0.22-0.37; p=7.8×10-22). After 15.5 and 13.9 months of follow-up in the ENHERTU and T-DM1 arms respectively, the median PFS for patients treated with ENHERTU was not reached (95% CI: 18.5-NE) compared to 6.8 months for T-DM1 (95% CI: 5.6-8.2) as assessed by blinded independent central review (BICR). In the key secondary endpoint analysis of PFS assessed by investigators, patients treated with ENHERTU experienced a three-fold improvement in PFS of 25.1 months (95% CI: 22.1-NE) compared to 7.2 months (95% CI: 6.8-8.3) for T-DM1 (HR=0.26; 95% CI: 0.20-0.35; p=6.5×10-24). A consistent PFS benefit was observed in key subgroups of patients treated with ENHERTU, including those with a history of stable brain metastases.

There was a strong trend towards improved overall survival (OS) with ENHERTU (HR=0.56; 95% CI: 0.36-0.86; p=0.007172), however, this analysis is not yet mature and is not statistically significant. Nearly all patients treated with ENHERTU were alive at one year (94.1%; 95% CI: 90.3-96.4) compared to 85.9% of patients treated with T-DM1 (95% CI: 80.9-89.7).

Confirmed objective response rate (ORR) was more than doubled in the ENHERTU arm versus the T-DM1 arm (79.7%; n=208; 95% CI: 74.3-84.4) versus 34.2% (n=90; 95% CI: 28.5-40.3; p<0.0001). Forty-two (16.1%) complete responses (CR) and 166 (63.6%) partial responses (PR) were observed in patients treated with ENHERTU compared to 23 (8.7%) CRs and 67 (25.5%) PRs in patients treated with T-DM1.

The safety profile of the most common adverse events with ENHERTU in DESTINY-Breast03 was consistent with previous clinical trials with no new safety concerns identified. The most common grade 3 or higher drug-related treatment emergent adverse events in the ENHERTU arm were neutropenia (19.1%), thrombocytopenia (7.0%), leukopenia (6.6%), nausea (6.6%), anemia (5.8%), fatigue (5.1%), vomiting (1.6%), increase in ALT (1.6%), decreased appetite (1.2%), increase in AST (0.8%), diarrhea (0.4%) and alopecia (0.4%). Overall, 10.5% of patients had confirmed interstitial lung disease (ILD) or pneumonitis related to treatment as determined by an independent adjudication committee. The majority of ILD events (9.7%) were primarily low grade (grade 1 (2.7%) or grade 2 (7.0%)) with two grade 3 (0.8%) events reported. No grade 4 or grade 5 ILD or pneumonitis events occurred.

“Patients with previously treated HER2 positive metastatic breast cancer will typically experience disease progression in less than a year with available HER2 directed treatments,” said Javier Cortés, MD, PhD, Head, International Breast Cancer Center (IBCC), Barcelona, Spain. “The high and consistent benefit seen across efficacy endpoints and key subgroups of patients receiving ENHERTU in DESTINY-Breast03 is remarkable and supports the potential of ENHERTU to become the new standard of care for those who have previously been treated for HER2 positive metastatic breast cancer.”

“The early survival data, which evaluated ENHERTU against another HER2 directed ADC, showed that nearly all patients treated with ENHERTU were alive after a year and is a positive indication of the potential of this medicine to transform the treatment of HER2 positive metastatic breast cancer,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “These landmark data will form the basis of our discussions with global health authorities to potentially bring ENHERTU to patients with previously treated HER2 positive metastatic breast cancer as a more effective treatment option as soon as possible.”

“Today’s results are groundbreaking; ENHERTU tripled progression-free survival as assessed by investigators and provided a disease control rate exceeding 95% compared to 77% for T-DM1 in DESTINY-Breast03,” said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology R&D, AstraZeneca. “In addition, the safety profile was encouraging with no grade 4 or 5 interstitial lung disease events in this trial. These unprecedented data represent a potential paradigm shift in the treatment of HER2 positive metastatic breast cancer and illustrate the potential for ENHERTU to transform more patient lives in earlier treatment settings.”

All patients in DESTINY-Breast03 received at least one prior cancer therapy, including trastuzumab (ENHERTU = 99.6%; T-DM1 = 99.6%), pertuzumab (ENHERTU = 62.1%; T-DM1 = 60.1%), an anti-HER2 TKI (ENHERTU = 16.1%; T-DM1 = 13.7%) or another anti-HER2 antibody or ADC (ENHERTU = 0.8%; T-DM1 = 1.1%). At the start of the trial, 23.8% of patients in the ENHERTU arm and 19.8% of patients in the T-DM1 arm had stable brain metastases. As of data cut-off on May 21, 2021, 132 patients remained on treatment with ENHERTU and 47 patients on T-DM1.

Summary of DESTINY-Breast03 Results

Efficacy Measure

ENHERTU (5.4 mg/kg)


T-DM1 (3.6 mg/kg)


Median PFS (months) (95% CI), per BICRi

HR=0.28, 95% CI: 0.22-0.37 p=7.8×10-22

NR (18.5-NE) 6.8 months (5.6-8.2)
Landmark 12-month PFS (%) (95% CI) ii 75.8% (69.8-80.7) 34.1% (27.7-40.5)

Median PFS (months) (95% CI), investigator assessedi

HR=0.26, 95% CI: 0.20-0.35 p=6.5×10-24

25.1 months (22.1-NE) 7.2 months (6.8-8.3)
Median OS (months) (95% CI) NE NE

Landmark 12-month OS (%) (95% CI)

HR=0.56, 95% CI: 0.36-0.86; p=0.007172iii

94.1% (90.3-96.4) 85.9% (80.9-89.7)
Confirmed ORR (%) (95% CI; p<0.0001)ii, iv 79.7% (74.3-84.4) 34.2% (28.5-40.3)
CR (%) 16.1% (n=42) 8.7% (n=23)
PR (%) 63.6% (n=166) 25.5% (n=67)
SD (%) 16.9% (n=44) 42.6% (n=112)
PD (%) (95% CI) 1.1% (n=3) 17.5% (n=46)
DCRv 96.6% (n=252) 76.8% (n=202)
CI, confidence interval; CR, complete response; DCR, disease control rate; NE, not estimable; NR, not reached; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease
i Median PFS follow-up for ENHERTU was 15.5 months (range, 15.1-16.6) and for T-DM1 was 13.9 months (range, 11.8-15.1)
ii As assessed by BICR
iii Not statistically significant
iv ORR is (CR + PR)
v DCR is (CR+PR+SD)

DESTINY-Breast01 Updated Results

Updated results from the pivotal DESTINY-Breast01phase 2 trial were also presented at ESMO and showed that ENHERTU (5.4 mg/kg) continued to demonstrate impressive efficacy and durable responses in patients with HER2 positive metastatic breast cancer following two or more prior HER2 based regimens. With a median duration of follow-up of 26.5 months, a continued increase in response was seen in patients treated with ENHERTU with an updated ORR of 62.0% (n=114; 95% CI: 54.4-69.0), including one additional CR (7.1%). A median duration of response (DoR) of 18.2 months (95% CI: 15.0-NE) was also observed. The median PFS was 19.4 months (95% CI: 14.1-25.0). In an exploratory analysis of OS with a median follow-up of 31.1 months (95% CI: 30.7-32.0), evaluated at a greater maturity (52%), the updated median OS was 29.1 months (95% CI: 24.6-36.1).

The overall safety profile seen with ENHERTU in DESTINY-Breast01 continues to be consistent with what has been previously observed. There has been one new case of treatment-related grade 1 ILD or pneumonitis, as determined by an independent adjudication committee as of data cut-off of March 26, 2021.

About DESTINY-Breast03

DESTINY-Breast03 is a global, head-to-head, randomized, open-label, pivotal phase 3 trial evaluating the safety and efficacy of ENHERTU (5.4 mg/kg) versus T-DM1 in patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane. The primary efficacy endpoint of DESTINY-Breast03 is PFS based on BICR. Secondary efficacy endpoints include OS, ORR, DoR, clinical benefit rate, PFS based on investigator assessment and safety.

DESTINY-Breast03 enrolled 524 patients at multiple sites in Asia, Europe, North America, Oceania and South America. For more information about the trial, visit ClinicalTrials.gov.

About DESTINY-Breast01

DESTINY-Breast01 is a global, single-arm, open-label, pivotal phase 2, two-part trial evaluating the safety and efficacy of ENHERTU in patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with T-DM1. The primary endpoint of the trial is ORR, as determined by independent central review. Secondary objectives include DoR, disease control rate, clinical benefit rate, PFS, OS and safety.

DESTINY-Breast01 enrolled 253 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

About HER2 Positive Breast Cancer

Breast cancer is the most common cancer and one of the leading causes of cancer-related deaths worldwide.1 More than two million cases of breast cancer were diagnosed in 2020, resulting in nearly 685,000 deaths globally.1 Approximately one in five cases of breast cancer are considered HER2 positive.2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast, gastric, lung and colorectal cancers.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.4

Despite initial treatment with trastuzumab and a taxane, patients with HER2 positive metastatic breast cancer will often experience disease progression.5 More effective options are needed to further delay progression and extend survival.3,6,7


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 topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

ENHERTU (5.4 mg/kg) is approved in Canada, EU, Israel, Japan, UK and U.S. for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting based on the results from the DESTINY-Breast01 trial.

ENHERTU (6.4 mg/kg) is also approved in Israel, Japan and U.S. for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.

ENHERTU is approved in the U.S. with Boxed WARNINGS for Interstitial Lung Disease and Embryo-Fetal Toxicity. For more information, please see the accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

About the ENHERTU Clinical Development Program

A comprehensive global development program is underway evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2 targetable cancers including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

ENHERTU was highlighted in the Clinical Cancer Advances 2021 report as one of two significant advancements in the “ASCO Clinical Advance of the Year: Molecular Profiling Driving Progress in GI Cancers,” based on data from both the DESTINY-Gastric01 and DESTINY-CRC01 trials, as well as one of the targeted therapy advances of the year in non-small cell lung cancer (NSCLC) based on the interim results of the HER2 mutated cohort of the DESTINY-Lung01 trial.

In May 2020, ENHERTU received Breakthrough Therapy Designation in the U.S. for the treatment of patients with metastatic NSCLC whose tumors have a HER2 mutation and with disease progression on or after platinum-based therapy.

About the Daiichi Sankyo and AstraZeneca Collaboration

Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019and datopotamab deruxtecan (Dato-DXd) 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 datopotamab deruxtecan.


ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:

  • Unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.

    This indication is approved under accelerated approval based on tumor 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 gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.

Please see accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

About Daiichi Sankyo in Oncology

The oncology portfolio of Daiichi Sankyo is powered by our team of world-class scientists that push beyond traditional thinking to create transformative medicines for people with cancer. Anchored by our DXd antibody drug conjugate (ADC) technology, our research engines include biologics, medicinal chemistry, modality and other research laboratories in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in the U.S. We also work alongside leading academic and business collaborators to further advance the understanding of cancer as Daiichi Sankyo builds towards our ambitious goal of becoming a global leader in oncology by 2025.

About Daiichi Sankyo

Daiichi Sankyo is dedicated to creating new modalities and innovative medicines by leveraging our world-class science and technology for our purpose “to contribute to the enrichment of quality of life around the world.” In addition to our current portfolio of medicines for cancer and cardiovascular disease, Daiichi Sankyo is primarily focused on developing novel therapies for people with cancer as well as other diseases with high unmet medical needs. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 16,000 employees around the world draw upon a rich legacy of innovation to realize our 2030 Vision to become an “Innovative Global Healthcare Company Contributing to the Sustainable Development of Society.” For more information, please visit: www.daiichisankyo.com.

1 Sung H, et al. CA Cancer J Clin. 2021;10.3322/caac.21660.
2 Ahn S, et al. J Pathol Transl Med. 2020;54(1): 34–44.
3 Iqbal N, et al. Mol Biol Int. 2014;852748.
4 Pillai R, et al. Cancer. 2017;1;123(21):4099-4105.
5 Barok M, et al. Breast Cancer Res. 2014;16(2):209.
6 Mounsey L, et al. Clin Breast Cancer. 2018;18(1):29-37
7 Martínez-Sáez O, Prat A. JCO Oncol Pract. 2021;10.1200/OP.21.00172.

SOURCE: Daiichi Sankyo