T-DXd vs T-DM1 for HER2-Positive Breast Cancer

Not currently recruiting at 205 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Daiichi Sankyo

Must not be taking: Corticosteroids, Anticonvulsants

Disqualifiers: Cardiovascular disease, ILD, CNS metastases, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 3

Duration: Up to 33 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine which treatment is more effective and safe for individuals with HER2-positive breast cancer that cannot be surgically removed or has metastasized. Researchers are comparing two treatments: T-DXd (trastuzumab deruxtecan) and T-DM1 (ado-trastuzumab emtansine). They seek to identify which treatment better shrinks tumors and has fewer side effects. Individuals with this type of breast cancer who have previously received trastuzumab and taxane may be suitable candidates for this study. As a Phase 3 trial, this study represents the final step before FDA approval, providing participants access to potentially effective treatments.

Do I need to stop my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have shown that trastuzumab deruxtecan (T-DXd) is generally well-tolerated by patients with HER2-positive metastatic breast cancer. However, some side effects require attention. For instance, 65% of patients experienced a drop in neutrophil count, a type of white blood cell that helps fight infections, increasing the risk of infections.

Ado-trastuzumab emtansine (T-DM1) is already approved for certain breast cancer treatments, providing extensive safety information. This approval indicates that its safety is well understood and considered acceptable for use.

Both treatments have proven effective in treating breast cancer, but each has its own possible side effects. Anyone considering joining a clinical trial should discuss these options thoroughly with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Trastuzumab deruxtecan (T-DXd) because it represents a novel approach for treating HER2-positive breast cancer. Unlike traditional treatments like Ado-trastuzumab emtansine (T-DM1), T-DXd is an antibody-drug conjugate that delivers a chemotherapy payload directly to cancer cells while minimizing damage to healthy cells. This targeted delivery is due to its unique mechanism of action, which combines an anti-HER2 antibody with a potent topoisomerase I inhibitor. This feature not only promises enhanced effectiveness but also potentially reduces side effects, giving patients a more manageable treatment experience.

What evidence suggests that this trial's treatments could be effective for HER2-positive breast cancer?

This trial will compare Trastuzumab deruxtecan (T-DXd) with Ado-trastuzumab emtansine (T-DM1) for treating HER2-positive breast cancer. Research has shown that T-DXd is highly effective for this condition. Specifically, studies found that T-DXd reduces the risk of cancer recurrence or death by 53% compared to T-DM1. It also extends patient survival and delays cancer progression. T-DXd has proven effective in treating both HER2-positive and HER2-low breast cancer. While T-DM1 is a well-established treatment for HER2-positive breast cancer, recent studies indicate that T-DXd offers superior results. ^{3 6 7 8 9}

Who Is on the Research Team?

Global Team Leader

Principal Investigator

Daiichi Sankyo

Are You a Good Fit for This Trial?

This trial is for adults with HER2-positive, unresectable or metastatic breast cancer who have previously been treated with trastuzumab and taxane. They must have adequate organ function and agree to use effective contraception. Those with symptomatic brain metastases, a history of certain lung conditions, uncontrolled heart disease, or previous anti-HER2 ADC treatment in the metastatic setting are excluded.

Inclusion Criteria

My kidney and liver are functioning well.

I am legally considered an adult in my country.

My cancer is confirmed HER2-positive by specific guidelines.

Exclusion Criteria

I have or had lung inflammation that needed steroids, or it might be seen in my recent lung scans.

I have untreated, symptomatic brain or spinal cord metastases requiring medication.

I have been treated with an anti-HER2 drug for cancer that has spread.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either DS-8201a or T-DM1 for HER2-positive, unresectable and/or metastatic breast cancer

Up to 33 months

Every 3 weeks (Q3W) for T-DXd

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ado-trastuzumab emtansine (T-DM1)
• Trastuzumab deruxtecan (DS-8201a)
• Trastuzumab deruxtecan (T-DXd)

Trial Overview The study compares DS-8201a (Trastuzumab deruxtecan) against T-DM1 (Ado-trastuzumab emtansine) in terms of tumor control and overall safety for patients with advanced HER2-positive breast cancer that has not responded to initial treatments.

How Is the Trial Designed?

Group I: Trastuzumab deruxtecan (T-DXd) Experimental Treatment 1 Intervention

Participants with HER2-positive, unresectable and/or metastatic breast cancer participants previously treated with trastuzumab and taxane who received T-DXd as a sterile intravenous (IV) solution at a dose of 5.4 mg/kg every 3 weeks (Q3W).

Group II: Ado-trastuzumab emtansine (T-DM1) Active Control 1 Intervention

Participants with HER2-positive, unresectable and/or metastatic breast cancer participants previously treated with trastuzumab and taxane who received T-DM1 in accordance with the approved label.

Ado-trastuzumab emtansine (T-DM1) is already approved in United States, European Union for the following indications:

Approved in United States as Kadcyla for:

• HER2-positive, metastatic breast cancer

Approved in European Union as Kadcyla for:

• HER2-positive, metastatic breast cancer

Who Is Running the Clinical Trial?

Daiichi Sankyo

Lead 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

Daiichi Sankyo, Inc.

Lead 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 Co., Ltd.

Industry Sponsor

Trials

116

Recruited

49,200+

AstraZeneca

Industry 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

Published Research Related to This Trial

Trastuzumab deruxtecan (T-DXd) has shown superior efficacy compared to capecitabine-based chemotherapy and T-DM1 in patients with metastatic HER2-positive breast cancer, based on the latest phase III data from the DESTINY-Breast02 and DESTINY-Breast03 trials.

T-DXd may also be effective as a neoadjuvant treatment for HER2-low breast cancer, suggesting its potential for broader applications in HER2-targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-DXd Keeps Shining in Breast Cancer. [2023]

Ado-trastuzumab emtansine (T-DM1) was approved in the U.S. for treating HER2 positive metastatic breast cancer based on the EMILIA phase III trial, which showed it was more effective than the standard treatment of lapatinib plus capecitabine.

Ongoing and planned trials are exploring T-DM1's use in various stages of breast cancer, and the review discusses its toxicity management and potential resistance mechanisms, highlighting its importance in current cancer treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ado-trastuzumab emtansine (T-DM1) in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer: latest evidence and clinical potential. Peddi, PF., Hurvitz, SA.[2022]

In a comparison of the safety profiles of trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) using data from 3723 and 2045 adverse event reports respectively, T-DXd was associated with higher rates of fatal outcomes in the hematologic and respiratory systems, while T-DM1 had more severe outcomes in the hepatobiliary system.

Both drugs showed distinct adverse event patterns, with T-DM1 linked to nervous and musculoskeletal issues, and T-DXd associated with respiratory and gastrointestinal problems, highlighting the need for careful monitoring of specific risks in patients, especially those over 65 or on certain drug combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Event Profile Differences between Trastuzumab Emtansine and Trastuzumab Deruxtecan: A Real-world, Pharmacovigilance Study. Liu, F., Yin, G., Xue, S., et al.[2023]

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]

In a study of 128 patients with advanced HER2+ breast cancer treated with ado-trastuzumab emtansine (T-DM1), the median progression-free survival was 8.7 months and overall survival was 20.4 months, indicating its efficacy in a real-world setting.

The safety profile of T-DM1 was consistent with existing literature, but the study noted higher rates of peripheral neuropathy (21.9%) and liver toxicity (19.5%), which are important considerations for its use in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of T-DM1 in patients with advanced HER2-positive breast cancer The Royal Marsden experience. Battisti, NML., Rogerson, F., Lee, K., et al.[2021]

In a study of 22 patients with HER2-positive metastatic breast cancer, trastuzumab deruxtecan (T-DXd) showed a median progression-free survival of 9.7 months and an objective response rate of 61.9%, indicating its efficacy as a treatment option.

T-DXd was particularly effective in patients with heterogeneous or reduced HER2 expression, achieving partial responses in patients who did not respond to the previous treatment with ado-trastuzumab emtansine (T-DM1), highlighting its potential to overcome resistance in these cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impacts of clinicopathological factors on efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer. Nakajima, H., Harano, K., Nakai, T., et al.[2022]

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]

Fam-trastuzumab deruxtecan (T-DXd) is an effective treatment for HER2-positive breast cancer, showing significant clinical activity in advanced cases and in patients with HER2-low disease, based on recent studies.

The toxicity of T-DXd is manageable, with fewer side effects reported when used as an earlier line of therapy, suggesting it may be safer and more beneficial for patients compared to later treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploring DESTINY: the Past, Present, and Future of Trastuzumab Deruxtecan. Ali, A., Graff, SL.[2023]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/41036093/

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 ...

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 ... ENHERTU® (fam-trastuzumab deruxtecan-nxki) reduced the risk of disease recurrence or death by 53% vs. T-DM1 in patients with high-risk HER2- ...

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

Efficacy data | ENHERTU® (fam-trastuzumab deruxtecan-nxki) Learn about median progression-free survival, overall survival, confirmed objective response rate, tumor response, and NCCN recommendation for patients on ...

4. nature.com nature.com/articles/s41591-025-03981-4

Trastuzumab deruxtecan in HER2-low metastatic breast ... In DESTINY-Breast04 (NCT03734029), trastuzumab deruxtecan (T-DXd) significantly improved overall survival (OS) and progression-free survival ...

5. daiichisankyo.com daiichisankyo.com/files/news/pressrelease/pdf/202510/20251018_E1.pdf

"ENHERTU® (Trastuzumab Deruxtecan) DESTINY- ... “The results from DESTINY-Breast11 show that treatment with ENHERTU followed by THP prior to surgery resulted in no evidence of residual ...

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

Safety Data | ENHERTU® (fam-trastuzumab deruxtecan- ... 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. 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.

9. oncologynewscentral.com oncologynewscentral.com/breast-cancer/t-dxd-shows-superiority-in-high-risk-her2-positive-residual-breast-cancer

T-DXd Shows Superiority in High-Risk, HER2-Positive ... Patients treated with adjuvant T-DXd had a 53% reduction in the risk for invasive disease recurrence or death compared with patients treated ...