T-DXd for HER2 Positive Breast Cancer

(DESTINY-B12 Trial)

Not currently recruiting at 93 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: Leptomeningeal disease, Hepatitis B/C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: Up to 2.5 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called Trastuzumab Deruxtecan (T-DXd) for individuals with advanced HER2-positive breast cancer, where cancer cells have an excess of HER2 protein. The trial aims to evaluate the treatment's effectiveness and safety, particularly for those whose cancer has returned or spread despite previous treatments. Individuals diagnosed with HER2-positive breast cancer, whose disease has progressed after specific treatments, might be suitable candidates for this trial. Participants may have brain metastasis if it is stable or does not require immediate treatment. The study involves receiving the drug through an IV every three weeks. As a Phase 3 trial, it represents the final step before FDA approval, offering participants access to a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does mention that any concurrent anticancer treatment is not allowed. There are also specific washout periods for certain treatments, such as 14 days for chloroquine/hydroxychloroquine and 3 weeks for some anticancer therapies.

Is there any evidence suggesting that Trastuzumab Deruxtecan is likely to be safe for humans?

Research has shown that trastuzumab deruxtecan (T-DXd) has been tested in individuals with breast cancer and other solid tumors. In 65% of patients, a drop in neutrophil count occurred, which may increase susceptibility to infections. However, studies indicate that T-DXd is effective and generally well-tolerated, even for those who have previously received treatments for HER2-positive metastatic breast cancer.

In everyday medical practice, the safety results for T-DXd align with previously published data, providing doctors with a clear understanding of potential side effects. While there are risks, evidence suggests that many patients can manage them. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for breast cancer?

Most treatments for HER2-positive breast cancer involve targeted therapies like trastuzumab and pertuzumab, which work by attaching to the HER2 protein on cancer cells to slow their growth. But Trastuzumab Deruxtecan (T-DXd) works differently—it's an antibody-drug conjugate that not only targets the HER2 protein but also delivers a powerful chemotherapy directly inside the cancer cells. This dual-action mechanism means T-DXd can potentially be more effective in killing cancer cells while sparing healthy ones. Researchers are excited about T-DXd because it shows promise in overcoming resistance seen with other HER2-targeted therapies, offering hope for improved outcomes for patients with this aggressive type of breast cancer.

What evidence suggests that Trastuzumab Deruxtecan might be an effective treatment for HER2-positive breast cancer?

Research has shown that Trastuzumab Deruxtecan (T-DXd), the treatment under study in this trial, is effective for treating HER2-positive breast cancer. In one study, more than 92% of patients who received T-DXd had no invasive cancer after three years. Another study found that T-DXd reduced the chance of cancer recurrence or death by 53% compared to T-DM1. Real-world studies also demonstrate that T-DXd is effective in treating both high and low levels of HER2 in advanced breast cancer. These results suggest that T-DXd can be a strong option for individuals with advanced HER2-positive breast cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Nadia Harbeck, MD, PhD

Principal Investigator

Head, Breast Center, Ludwig-Maximilians-University of Munich Department of Obstetrics and Gynecology Marchioninistr. 15, 81377 Munich, Germany

Nancy U. Lin, MD

Principal Investigator

Associate Chief, Division of Breast Oncology, Susan F. Smith Center for Women's Cancers Director, Metastatic Breast Cancer Program, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215

Are You a Good Fit for This Trial?

This trial is for people with advanced or metastatic HER2 positive breast cancer who have had disease progression after prior anti-HER2 therapies and no more than two treatments in the metastatic setting. It includes those with or without brain metastasis (BMs), provided BMs are stable, untreated but not needing immediate therapy, or previously treated. Participants must be physically capable (ECOG 0-1), have a heart ejection fraction ≥50%, and women of childbearing potential must test negative for pregnancy.

Inclusion Criteria

You have had breast cancer treatment that did not work, and you have tried no more than 2 different treatments for cancer that has spread.

You cannot have signs of brain metastases, or if you do, they must not need immediate treatment or must have been treated and are not getting worse.

You have at least one lesion that can be measured accurately and is at least 10 mm in diameter, or you have non-measurable bone disease that can be assessed by imaging. If you have only sclerotic/osteoblastic bone lesions without measurable disease, you are not eligible. If you have non-measurable central nervous system (CNS) disease, you may be eligible for a specific part of the study.

Exclusion Criteria

If you have hepatitis C, you can join the study only if a specific test shows that the virus is not active in your body.

You had a heart attack or have significant heart failure symptoms within the past 6 months.

You should not have untreated brain lesions larger than 2.0 cm, be using systemic corticosteroids for brain lesion symptoms, or have uncontrolled seizures or worsening neurological symptoms due to brain lesions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

Treatment

Participants receive intravenous Trastuzumab Deruxtecan (T-DXd) every 3 weeks until progression, unacceptable toxicity, or withdrawal

Up to 2.5 years

Every 3 weeks (21-day cycle)

End-of-Treatment

End-of-treatment visit conducted within 7 days of discontinuation of study intervention

1 week

Safety Follow-up

Participants are followed up for safety assessments 40 (+ up to 7) days after the discontinuation of all study intervention

6 weeks

Survival Follow-up

Participants are followed up for survival status and duration of treatment on subsequent therapies every 3 months until death, withdrawal of consent, or end of study

Up to 2.5 years

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Trastuzumab Deruxtecan

Trial Overview The study tests Trastuzumab Deruxtecan (T-DXd) on participants to evaluate its effectiveness and safety. The trial is open-label, meaning everyone knows which treatment they're getting, and it's conducted at multiple centers internationally. Patients included may have measurable lesions suitable for repeated assessments or non-measurable bone-only diseases assessable by scans.

How Is the Trial Designed?

Group I: Trastuzumab Deruxtecan Experimental Treatment 1 Intervention

Participants with or without BM at baseline will receive intravenous (IV) T-DXd, 5.4 mg/kg, every 3 weeks (21-day cycle) until Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) defined radiological progression outside central nervous system, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation is met.

Trastuzumab Deruxtecan is already approved in European Union, United States, Japan for the following indications:

Approved in European Union as Enhertu for:

• Unresectable or metastatic HER2-positive breast cancer
• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma

Approved in United States as Enhertu for:

• Unresectable or metastatic HER2-positive breast cancer
• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma
• HER2-low breast cancer

Approved in Japan as Enhertu for:

• Unresectable or metastatic HER2-positive breast cancer
• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Daiichi Sankyo, Inc.

Industry Sponsor

Trials

390

Recruited

442,000+

Yuki Abe

Daiichi Sankyo, Inc.

Chief Medical Officer since 2022

MD

Hiroyuki Okuzawa

Daiichi Sankyo, Inc.

Chief Executive Officer

Degree in Social Sciences from Hitotsubashi University

Daiichi Sankyo

Industry Sponsor

Trials

443

Recruited

493,000+

Hiroyuki Okuzawa

Daiichi Sankyo

Chief Executive Officer

Degree in Social Sciences from Hitotsubashi University

Yuki Abe

Daiichi Sankyo

Chief Medical Officer since 2023

MD

Published Research Related to This Trial

Trastuzumab deruxtecan (T-DXd) is a promising new antibody-drug conjugate that has been approved for treating HER2-positive metastatic breast cancer and gastric cancer, showing potential for use in other solid tumors as well.

T-DXd is expected to become the standard second-line treatment for HER2-positive metastatic breast cancer and may also benefit patients with hormone receptor-positive and triple-negative breast cancer that express low levels of HER2.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in HER2-positive metastatic breast cancer and beyond. Perez, J., Garrigós, L., Gion, M., et al.[2022]

Trastuzumab-deruxtecan (T-DXd) is a promising antibody-drug conjugate that shows clinically relevant activity in heavily pretreated patients with HER2-positive metastatic breast cancer, particularly those who have progressed on T-DM1.

While T-DXd demonstrates efficacy, it is important to monitor for interstitial lung disease, which occurred in about 13% of patients, highlighting the need for careful patient management during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab-deruxtecan: an investigational agent for the treatment of HER2-positive breast cancer. Bartsch, R.[2022]

Trastuzumab deruxtecan (T-DXd) is effective for breast cancer patients with low ERBB2 positivity (IHC scores of 1+ or 2+), but current standard assays show poor accuracy in distinguishing between low scores (0 and 1+), which could misassign patients for treatment.

In a study involving 18 pathologists assessing 170 breast cancer biopsies, there was only 26% concordance in scoring between 0 and 1+, indicating significant variability in ERBB2 IHC scoring that may impact patient eligibility for T-DXd.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Examination of Low ERBB2 Protein Expression in Breast Cancer Tissue. Fernandez, AI., Liu, M., Bellizzi, A., et al.[2023]

Trastuzumab deruxtecan (Enhertu®) has been shown to be significantly more effective than standard chemotherapy in improving overall survival and achieving objective responses in adults with advanced HER2-positive gastric or gastro-oesophageal junction adenocarcinoma, based on results from the phase II DESTINY-Gastric01 trial.

The treatment is generally well-tolerated, with common side effects including nausea and fatigue, but it does carry important safety warnings for interstitial lung disease and embryo-foetal toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Gastric or Gastro-Oesophageal Junction Adenocarcinoma. Kang, C.[2023]

In the DESTINY-Breast03 trial, trastuzumab deruxtecan (T-DXd) demonstrated superior progression-free survival and overall survival compared to trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer, while maintaining quality of life (QoL) throughout treatment.

Patients receiving T-DXd experienced a median time to first hospitalization that was three times longer than those on T-DM1, indicating better overall health management and fewer hospital visits during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes and hospitalization data in patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan or trastuzumab emtansine in the phase III DESTINY-Breast03 study. Curigliano, G., Dunton, K., Rosenlund, M., et al.[2023]

In a phase 1 trial involving 115 patients with HER2-positive breast cancer previously treated with trastuzumab emtansine, trastuzumab deruxtecan demonstrated a manageable safety profile, with 59.5% of patients achieving a confirmed objective response.

Despite some serious treatment-emergent adverse events, including cases of interstitial lung disease and pneumonitis, the preliminary efficacy results suggest that trastuzumab deruxtecan is a promising treatment option, warranting further investigation in larger clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. Tamura, K., Tsurutani, J., Takahashi, S., et al.[2020]

Trastuzumab deruxtecan (Enhertu®) has been shown to significantly improve progression-free survival in adults with unresectable or metastatic HER2-positive breast cancer compared to the previous standard treatment, trastuzumab emtansine, in a pivotal phase 3 trial.

The treatment has a generally manageable safety profile, although it is associated with common adverse events like hematological and gastrointestinal disorders, and requires careful monitoring for interstitial lung disease (ILD)/pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Unresectable or Metastatic HER2-Positive Breast Cancer. Nie, T., Blair, HA.[2023]

Trastuzumab deruxtecan (ENHERTU®) is an innovative treatment that combines an antibody targeting HER2 with a DNA topoisomerase I inhibitor, specifically designed for HER2-expressing solid tumors, including various types of cancer.

It received accelerated approval in the USA based on the promising results from the phase 2 DESTINY-Breast01 trial, which focused on patients with advanced HER2-positive breast cancer who had already undergone multiple treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: First Approval. Keam, SJ.[2020]

Fam-trastuzumab deruxtecan-nxki (ENHERTU) received accelerated FDA approval for treating HER2-positive breast cancer in patients who have already undergone two or more anti-HER2 therapies, based on a study involving 184 patients that showed a confirmed overall response rate of 60.3%.

While ENHERTU is effective, it carries significant risks, including severe interstitial lung disease and neutropenia, highlighting the importance of monitoring for serious side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Fam-Trastuzumab Deruxtecan-Nxki for the Treatment of Unresectable or Metastatic HER2-Positive Breast Cancer. Narayan, P., Osgood, CL., Singh, H., et al.[2022]

In the DESTINY-Breast01 trial with 184 patients, trastuzumab deruxtecan (T-DXd) showed a confirmed objective response rate of 62.0% and a median overall survival of 29.1 months, indicating its effectiveness in treating HER2-positive metastatic breast cancer after previous treatment with trastuzumab emtansine.

While T-DXd demonstrated sustained antitumor activity, it also had a notable safety profile, with 99.5% of patients experiencing drug-related adverse events, including a 15.8% incidence of interstitial lung disease/pneumonitis, highlighting the importance of monitoring for serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan in Previously Treated Patients With HER2-Positive Metastatic Breast Cancer: Updated Survival Results From a Phase 2 Trial (DESTINY-Breast01). Saura, C., Modi, S., Krop, I., et al.[2023]

In a phase II study involving 267 patients with HER2-expressing solid tumors, trastuzumab deruxtecan (T-DXd) showed an overall objective response rate (ORR) of 37.1%, with a median duration of response of 11.3 months, indicating its efficacy in treating these cancers.

Patients with central HER2 IHC 3+ expression had even better outcomes, with an ORR of 61.3% and a median overall survival of 21.1 months, highlighting T-DXd's potential as a targeted therapy for HER2-positive tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. Meric-Bernstam, F., Makker, V., Oaknin, A., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12479221/

Efficacy of Trastuzumab Deruxtecan in HER2-Positive and ... In this real-world analysis, T-DXd demonstrated robust clinical activity in both HER2-positive and HER2-low MBC, consistent with the findings ...

2. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2025/ENHERTU-fam-trastuzumab-deruxtecan-nxki-reduced-the-risk-of-disease-recurrence-or-death-by-53-percent-vs-T-DM1-in-patients-with-high-risk-HER2-positive-early-breast-cancer-following-neoadjuvant-therapy-in-DESTINY-Breast05-Phase-III-trial.html

ENHERTU® (fam-trastuzumab deruxtecan-nxki) reduced ... More than 92% of patients treated with AstraZeneca and Daiichi Sankyo's ENHERTU were free of invasive disease at three years.

3. enhertuhcp.com enhertuhcp.com/en/breast/efficacy/efficacy-data

Efficacy data | ENHERTU® (fam-trastuzumab deruxtecan-nxki) 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.

4. astrazeneca.com astrazeneca.com/content/astraz/media-centre/press-releases/2025/enhertu-reduced-the-risk-of-disease-recurrence-or-death-by-53-vs-t-dm1-in-patients-with-high-risk-her2-positive-early-breast-cancer.html

Enhertu reduced the risk of disease recurrence or death by ... Enhertu reduced the risk of disease recurrence or death by 53% vs. T-DM1 in patients with high-risk HER2-positive early breast cancer following ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40947843/

Real-world safety and efficacy of trastuzumab deruxtecan ... Earlier large studies showed that T-DXd works for patients with high levels of HER2 (HER2-positive) and for those with low levels of HER2 (HER2- ...

6. enhertuhcp.com enhertuhcp.com/en/breast/safety

Safety Data | ENHERTU® (fam-trastuzumab deruxtecan-nxki) In patients with metastatic breast cancer and other solid tumors treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11178646/

Safety profile of trastuzumab deruxtecan in advanced breast ... Patient-reported outcomes and hospitalization data in patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan or trastuzumab ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e13023

Efficacy and safety of trastuzumab deruxtecan in HER2+ ... Our study supports the efficacy and safety of T-DXd in India in a real-world clinical setting with results being consistent across published literature.

9. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2025/ENHERTU-fam-trastuzumab-deruxtecan-nxki-plus-pertuzumab-reduced-the-risk-of-disease-progression-or-death-by-44-percent-vs-THP-as-1st-line-therapy-in-patients-with-HER2-positive-metastatic-breast-cancer-in-DESTINY-Breast09-Phase-III-trial.html

ENHERTU® (fam-trastuzumab deruxtecan-nxki) plus ... ENHERTU® (fam-trastuzumab deruxtecan-nxki) plus pertuzumab reduced the risk of disease progression or death by 44% vs. THP as 1st-line therapy ...

10. nejm.org nejm.org/doi/full/10.1056/NEJMoa1914510

Trastuzumab Deruxtecan in Previously Treated HER2- ... Trastuzumab deruxtecan showed durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer.