Dato-DXd + T-DXd for Breast Cancer

(TRADE DXd Trial)

Recruiting at 11 trial locations

Overseen By Ana Garrido-Castro, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Ana C Garrido-Castro, MD

Must not be taking: Topoisomerase inhibitors

Disqualifiers: Corneal disease, Pneumonitis, Uncontrolled infection, others

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

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

Compensation: Varies

Number of Visits: 16

Duration: Up to 36 months

357 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of two investigational drugs, trastuzumab deruxtecan and datopotamab deruxtecan, for treating HER2-negative metastatic breast cancer. Researchers aim to determine how these drugs perform when administered in different sequences. Suitable candidates include those with HER2-low or HER2-0 breast cancer that has metastasized and who have not responded to other treatments. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

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

The trial protocol does not specify if you need to stop all current medications. However, you must stop any prior chemotherapy, biologic, or targeted therapy at least 14 days before starting the study treatment. You can continue taking bisphosphonates or RANK ligand inhibitors if needed.

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

Research shows that both datopotamab deruxtecan and trastuzumab deruxtecan are generally safe for patients. Studies on datopotamab deruxtecan in people with advanced breast cancer have shown promising results, with usually manageable side effects. While some side effects might occur, they typically do not outweigh the potential benefits.

Similarly, trastuzumab deruxtecan has been studied in various contexts and has proven safe. It is already approved for certain types of breast cancer, indicating confidence in its safety. However, a small risk of serious lung problems occurred in less than 1% of patients, which is important to discuss with a doctor.

Overall, both treatments are being tested for effectiveness and safety in this trial, and past research suggests they are generally well-tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Datopotamab Deruxtecan and Trastuzumab Deruxtecan for breast cancer because they represent a new class of targeted therapies known as antibody-drug conjugates (ADCs). Unlike traditional chemotherapy, which affects both healthy and cancerous cells, these treatments use a targeted approach to deliver chemotherapy directly to cancer cells, minimizing harm to healthy tissues. Datopotamab Deruxtecan targets the TROP2 protein, while Trastuzumab Deruxtecan targets HER2-positive cancer cells, both common in aggressive forms of breast cancer. This precision targeting is what makes these treatments stand out from current options, potentially offering improved efficacy and reduced side effects.

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

Research has shown that datopotamab deruxtecan, one of the treatments studied in this trial, yields promising results for metastatic breast cancer. Specifically, it helped patients live about five months longer than those receiving standard chemotherapy in some cases and delayed cancer progression. Meanwhile, trastuzumab deruxtecan, another treatment option in this trial, lowered the risk of death by 31% in patients with HER2-low metastatic breast cancer. It also significantly reduced the chance of cancer returning or progressing. Both treatments are antibody-drug conjugates, designed to target and kill cancer cells more effectively. ^{1 4 5 6 7}

Who Is on the Research Team?

Ana C. Garrido-Castro

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for individuals with HER2-low metastatic breast cancer. Participants should be those whose cancer has not responded to previous treatments (ADC-refractory). Specific eligibility criteria are not provided, but typically include factors like age, health status, and prior therapies.

Inclusion Criteria

I am eligible even with new or worsening brain metastases under certain conditions.

I stopped any experimental cancer treatments 21 days before starting this study.

Women of childbearing potential and the female partners of male participants must agree to use contraception.

Exclusion Criteria

Concurrent use of any other investigational or study agents that are being used to treat the underlying malignancy.

Corrected QT interval prolongation.

My HIV infection is not well controlled.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Datopotamab deruxtecan or Trastuzumab deruxtecan in 21-day cycles, with imaging every 9 weeks

Up to 36 months

Cycle 1 through end of treatment: Day 1 of 21-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment with imaging every 9 weeks

Up to 36 months

Imaging every 9 weeks

Long-term Follow-up

Participants are followed approximately every six months after the study treatment ends

Up to 5 years

Visits every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Datopotamab Deruxtecan
• Trastuzumab Deruxtecan

Trial Overview The study tests the safety and effectiveness of two drugs: Datopotamab Deruxtecan and Trastuzumab Deruxtecan. It explores whether using these drugs in sequence can treat this type of breast cancer effectively.

How Is the Trial Designed?

Group I: Arn B (ADC1 T-DXd HR-) Experimental Treatment 1 Intervention

Enrolled participants will complete: * Baseline visit with tumor biopsy, imaging, electrocardiogram and echocardiogram. * Tumor biopsy between Cycle 2 Day 1 and Day 8. * Imaging every 9 weeks. * Cycle 1 through end of treatment: --Day 1 of 21 day cycle: Predetermined dose of Trastuzumab deruxtecan 1x daily. * Cycle 4 through end of treatment: * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab deruxtecan 1x daily. * Imaging on Day 1. * End of Treatment visit with imaging, tumor biopsy, echocardiogram * Follow up: imaging every 9 weeks. * Long-term Follow Up: visits every 6 months.

Group II: Arm H (ADC2 T-DXd HR-) Experimental Treatment 1 Intervention

Participants will complete: * Baseline visit with imaging, tumor biopsy, electrocardiogram, echocardiogram. * Imaging every 9 weeks. * Cycle 1 through Cycle 3: --Day 1 of 21 day cycle: Predetermined dose of Trastuzumab deruxtecan 1x daily. * Cycle 1 through end of treatment: * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab deruxtecan 1x daily. * Imaging on Day 1. * End of Treatment visit with imaging, tumor biopsy, echocardiogram * Follow up: imaging every 9 weeks. * Long-term Follow Up: visits every 6 months.

Group III: Arm G (ADC2 T-DXd HR+) Experimental Treatment 1 Intervention

Participants will complete: * Baseline visit with imaging, tumor biopsy, electrocardiogram, echocardiogram. * Imaging every 9 weeks. * Cycle 1 through Cycle 3: --Day 1 of 21 day cycle: Predetermined dose of Trastuzumab deruxtecan 1x daily. * Cycle 1 through end of treatment: * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab deruxtecan 1x daily. * Imaging on Day 1. * End of Treatment visit with imaging, tumor biopsy, echocardiogram * Follow up: imaging every 9 weeks. * Long-term Follow Up: visits every 6 months.

Group IV: Arm F (ADC2 Dato-DXd HR-) Experimental Treatment 1 Intervention

Participants will complete: * Baseline visit with imaging, tumor biopsy, electrocardiogram, eye exam. * Imaging every 9 weeks. * Cycle 1 through Cycle 3: --Day 1 of 21 day cycle: Predetermined dose of Datopotamab deruxtecan 1x daily. * Cycle 1 through end of treatment: * Day 1 of 21 day cycle: Predetermined dose of Datopotamab deruxtecan 1x daily. * Imaging on Day 1. * End of Treatment visit with imaging, tumor biopsy, eye exam. * Follow up: imaging every 9 weeks. * Long-term Follow Up: visits every 6 months.

Group V: Arm E (ADC2 Dato-DXd HR+) Experimental Treatment 1 Intervention

Participants will complete: * Baseline visit with imaging, tumor biopsy, electrocardiogram, eye exam. * Imaging every 9 weeks. * Cycle 1 through Cycle 3: --Day 1 of 21 day cycle: Predetermined dose of Datopotamab deruxtecan 1x daily. * Cycle 4 through end of treatment: * Day 1 of 21 day cycle: Predetermined dose of Datopotamab deruxtecan 1x daily. * Imaging on Day 1. * End of Treatment visit with imaging, tumor biopsy, eye exam. * Follow up: imaging every 9 weeks. * Long-term Follow Up: visits every 6 months.

Group VI: Arm D (ADC1 Dato-DXd HR-) Experimental Treatment 1 Intervention

Enrolled participants will complete: * Baseline visit with tumor biopsy, imaging, electrocardiogram and eye exam. * Tumor biopsy between Cycle 2 Day 1 and Day 8. * Imaging every 9 weeks. * Cycle 1 through Cycle 3: --Day 1 of 21 day cycle: Predetermined dose of Datopotamab deruxtecan 1x daily. * Cycle 4 through end of treatment: * Day 1 of 21 day cycle: Predetermined dose of Datopotamab deruxtecan 1x daily. * Imaging on Day 1. * End of Treatment visit with imaging, tumor biopsy, eye exam. * Follow up: imaging every 9 weeks. * Long-term Follow Up: visits every 6 months.

Group VII: Arm C (ADC1 Dato-DXd HR+) Experimental Treatment 1 Intervention

Enrolled participants will complete: * Baseline visit with tumor biopsy, imaging, electrocardiogram and eye exam. * Tumor biopsy between Cycle 2 Day 1 and Day 8. * Imaging every 9 weeks. * Cycle 1 through end of treatment: --Day 1 of 21 day cycle: Predetermined dose of Datopotamab deruxtecan 1x daily. * Cycle 4 through end of treatment: * Day 1 of 21 day cycle: Predetermined dose of Datopotamab deruxtecan 1x daily. * Imaging on Day 1. * End of Treatment visit with imaging, tumor biopsy, eye exam. * Follow up: imaging every 9 weeks. * Long-term Follow Up: visits every 6 months.

Group VIII: Arm A (ADC1 T-DXd HR+) Experimental Treatment 1 Intervention

Enrolled participants will complete: * Baseline visit with tumor biopsy, imaging, electrocardiogram and echocardiogram. * Tumor biopsy between Cycle 2 Day 1 and Day 8. * Imaging every 9 weeks. * Cycle 1 through Cycle 3: --Day 1 of 21 day cycle: Predetermined dose of Trastuzumab deruxtecan 1x daily. * Cycle 4 through end of treatment: * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab deruxtecan 1x daily. * Imaging on Day 1. * End of Treatment visit with imaging, tumor biopsy, echocardiogram * Follow up: imaging every 9 weeks. * Long-term Follow Up: visits every 6 months.

Who Is Running the Clinical Trial?

Ana C Garrido-Castro, MD

Lead Sponsor

Trials

2

Recruited

470+

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

Translational Breast Cancer Research Consortium

Collaborator

Trials

27

Recruited

3,100+

Published Research Related to This Trial

Trastuzumab deruxtecan (T-DXd) showed promising antitumor activity in patients with advanced HER2-low breast cancer, achieving a 37% objective response rate in a study of 54 patients who had undergone a median of 7.5 prior therapies.

While T-DXd demonstrated efficacy, it also presented significant safety concerns, with 98% of patients experiencing treatment-emergent adverse events, including severe cases of interstitial lung disease (ILD) that led to fatalities, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low-Expressing Advanced Breast Cancer: Results From a Phase Ib Study. Modi, S., Park, H., Murthy, RK., et al.[2021]

In an expanded-access study involving 64 patients with HER2-positive gastric or gastroesophageal junction adenocarcinomas, trastuzumab deruxtecan (T-DXd) was administered safely, with no new safety concerns identified prior to its marketing approval in Japan.

Serious adverse events (SAEs) were reported in 26.6% of patients, with febrile neutropenia being the most common; however, drug-related SAEs led to death in only one patient, indicating a manageable safety profile for T-DXd.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in patients with locally advanced or metastatic HER2-positive gastric cancer: a multicenter, open-label, expanded-access study. Shitara, K., Yamaguchi, K., Muro, K., et al.[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]

The phase III DESTINY-Breast04 trial demonstrated that trastuzumab deruxtecan (T-DXd) is effective for patients with inoperable or metastatic HER2-low breast cancer, providing a new treatment option for this group.

Given the limited treatment options available for patients with HER2-low breast cancer, T-DXd is recommended as a new standard of care, highlighting its significance in improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-DXd: New Standard for HER2-Low Breast Cancer. [2022]

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 a real-world study of 143 patients with HER2+ metastatic breast cancer, trastuzumab deruxtecan (T-DXd) demonstrated a high overall response rate of 68% and a median progression-free survival of 16 months, confirming its efficacy in routine clinical practice.

The safety profile of T-DXd was consistent with previous studies, with 59% of patients experiencing any-grade toxicity, primarily nausea and neutropenia, but no new safety concerns were identified, indicating it is a well-tolerated treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Outcomes of Trastuzumab Deruxtecan in Patients With HER2+ Metastatic Breast Cancer: The DE-REAL Study. Botticelli, A., Caputo, R., Scagnoli, S., et al.[2023]

In a phase II study involving 152 patients with HER2-mutant metastatic non-small-cell lung cancer, trastuzumab deruxtecan (T-DXd) showed a confirmed objective response rate of 49% at 5.4 mg/kg and 56% at 6.4 mg/kg, indicating robust antitumor activity.

The safety profile of T-DXd was generally manageable, with fewer severe adverse events reported in the 5.4 mg/kg group compared to the 6.4 mg/kg group, suggesting that the lower dose may be preferable for patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic Non-Small-Cell Lung Cancer: Primary Results From the Randomized, Phase II DESTINY-Lung02 Trial. Goto, K., Goto, Y., Kubo, T., et al.[2023]

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]

Datopotamab deruxtecan (Dato-DXd) is a promising new treatment for patients with metastatic HR+/HER2- breast cancer, particularly for those who have limited options after endocrine therapy and chemotherapy.

The ongoing phase III TROPION-Breast01 study is comparing the efficacy and safety of Dato-DXd against standard chemotherapy in patients who have already received one or two lines of systemic treatment, aiming to improve outcomes in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TROPION-Breast01: Datopotamab deruxtecan vs chemotherapy in pre-treated inoperable or metastatic HR+/HER2- breast cancer. Bardia, A., Jhaveri, K., Kalinsky, K., et al.[2023]

In a phase I trial, the TROP2-directed antibody-drug conjugate datopotamab deruxtecan showed promising activity in patients with advanced or metastatic non-small cell lung cancer, with nearly 25% of participants responding to the treatment.

The treatment was associated with manageable side effects, suggesting it could be a safe option for patients with this type of lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TROP2 ADC Intrigues in NSCLC. [2021]

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]

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that effectively targets HER2-positive unresectable/metastatic breast cancer, showing a generally manageable safety profile with common low-grade side effects like nausea and neutropenia, but also carries risks of severe interstitial lung disease (ILD)/pneumonitis.

Effective management strategies for T-DXd-related adverse events, particularly proactive measures for nausea and ILD/pneumonitis, are crucial for maximizing treatment benefits and minimizing the risk of treatment discontinuation or dose reductions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing treatment management of trastuzumab deruxtecan in clinical practice of breast cancer. Rugo, HS., Bianchini, G., Cortes, J., et al.[2022]

Citations

1. astrazeneca.com astrazeneca.com/content/astraz/media-centre/press-releases/2024/datopotamab-deruxtecan-final-overall-survival-results-reported-in-patients-with-metastatic-hr-positive-her2-low-or-negative-breast-cancer-in-tropion-breast01-phase-iii-trial.html

Datopotamab deruxtecan final overall survival results ... Datopotamab deruxtecan has previously shown a statistically significant progression-free survival benefit in TROPION-Breast01, a result supported by multiple ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.23.01909

Datopotamab Deruxtecan in Advanced or Metastatic HR+/ ... In patients with heavily pretreated advanced HR+/HER2– BC and TNBC, Dato-DXd demonstrated promising clinical activity and a manageable safety profile.

3. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2025/DATROWAY-datopotamab-deruxtecan-dlnk-demonstrated-an-unprecedented-median-overall-survival-improvement-of-five-months-vs-chemotherapy-as-1st-line-treatment-for-patients-with-metastatic-triple-negative-breast-cancer-for-whom-immunotherapy-was-not-an-option-in-TROPION-Breast02.html

DATROWAY® (datopotamab deruxtecan-dlnk) ... DATROWAY® (datopotamab deruxtecan-dlnk) demonstrated an unprecedented median overall survival improvement of five months vs. chemotherapy as 1st ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9398094/

Datopotamab Deruxtecan, a Novel TROP2-directed ... These results indicate that Dato-DXd is effective in the inhibition of cancer cell growth from multiple tumor types and that it requires TROP2 expression on ...

5. annalsofoncology.org annalsofoncology.org/article/S0923-7534(21)01141-8/fulltext

LBA4 Datopotamab deruxtecan (Dato-DXd), a TROP2 ... Results from the ongoing phase I TROPION-PanTumor01 (NCT03401385) study showed encouraging antitumor activity of Dato-DXd in heavily pretreated patients (pts) ...

6. daiichisankyo.com daiichisankyo.com/files/news/pressrelease/pdf/202409/20240923_E.pdf

Datopotamab Deruxtecan Final Overall Survival Results ... “Datopotamab deruxtecan has previously shown a statistically significant progression-free survival benefit in. TROPION-Breast01, a result ...

7. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2025/DATROWAY-datopotamab-deruxtecan-dlnk-demonstrated-statistically-significant-and-clinically-meaningful-improvement-in-overall-survival-as-1st-line-therapy-for-patients-with-metastatic-triple-negative-breast-cancer-for-whom-immunotherapy-was-not-an-option-in-TROPION-Breast02.html

DATROWAY® (datopotamab deruxtecan-dlnk) ... The safety profile of DATROWAY was consistent with previous clinical trials of DATROWAY in breast cancer. These data will be presented at an ...