Trastuzumab Deruxtecan for Breast Cancer

Overseen By Laura Kane

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Yale University

Must not be taking: Strong CYP3A4 inhibitors

Disqualifiers: Cardiovascular disease, ILD, CNS metastases, 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: 3

Duration: 21 days per cycle, indefinite number of cycles

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effects of trastuzumab deruxtecan on patients with metastatic HER2-negative breast cancer. Researchers seek to determine the drug's effectiveness and identify who benefits most. Participants should have breast cancer that is either inoperable or has metastasized, and they must not have received any anti-HER2 therapies previously. This trial might be suitable for those who have experienced disease progression or cannot tolerate their current treatment. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) before starting the study drug. This means you may need to stop taking some of your current medications for a certain period before joining the trial. It's best to discuss your specific medications with the study team to understand what changes might be needed.

Is there any evidence suggesting that trastuzumab deruxtecan is likely to be safe for humans?

Research has shown that trastuzumab deruxtecan (T-DXd) is generally safe for patients. Studies indicate that while side effects can occur, they are usually mild to moderate and manageable. Common side effects include nausea, tiredness, and low blood cell counts, typical of cancer treatments. In some cases, more serious issues like lung problems have been reported, but these are less common. Overall, evidence suggests that T-DXd is effective and has a safety profile similar to other cancer drugs. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Trastuzumab Deruxtecan is unique because it combines two powerful elements: a HER2-targeting antibody and a potent chemotherapy drug. This design allows it to precisely attack HER2-positive breast cancer cells, minimizing damage to healthy cells. Researchers are excited because this targeted approach not only enhances effectiveness but also has the potential to reduce side effects compared to traditional chemotherapy treatments. Additionally, its delivery method, administered intravenously every three weeks, offers a convenient schedule for patients.

What evidence suggests that trastuzumab deruxtecan might be an effective treatment for metastatic HER2-negative breast cancer?

Research has shown that trastuzumab deruxtecan (T-DXd), which participants in this trial will receive, offers promising results for treating certain types of breast cancer. In earlier studies, patients treated with T-DXd lived for a median of about 14.9 months, with half of the patients living longer. The median time patients lived without their cancer worsening was about 5 months. These findings suggest that T-DXd can help control cancer and extend life for some patients. ^{3 6 7 8 9}

Who Is on the Research Team?

Adriana Kahn, M.D.

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

Adults with metastatic HER2-negative breast cancer, either hormone receptor-positive or negative, who have had 1-2 prior systemic treatments but no anti-HER2 therapy. Participants must have measurable disease and good heart, bone marrow, kidney, liver, and blood clotting function. They should not be pregnant or breastfeeding and must use contraception.

Inclusion Criteria

I can understand and sign the consent form.

Pathologically documented breast cancer that is unresectable or metastatic, has always been HER2-IHC 0 and never previously HER2-positive (IHC 3+ or ISH+) or HER2-low (1+, or 2+ ISH-) on prior pathology testing according to ASCO-CAP guidelines, is either HR-positive or HR-negative per ASCO-CAP guidelines, has or has not been treated with a CDK4/6 inhibitor, has been treated with 1 or 2 prior lines of systemic therapy in the metastatic setting, was never previously treated with anti-HER2 therapy, documented radiologic progression during or after most recent treatment, adequate archival tumor sample <3 years-old available for assessment of HER2 status, presence of at least 1 measurable lesion based on CT or MRI per mRECIST version 1.1, ECOG PS 0 or 1, LVEF ≥50% within 28 days prior to C1D1, adequate bone marrow function, renal function, hepatic function, blood clotting function, treatment washout period, evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential, and appropriate contraceptive measures for sexually active patients

Exclusion Criteria

Uncontrolled or significant cardiovascular disease including recent myocardial infarction or symptomatic congestive heart failure, history of ILD/pneumonitis, spinal cord compression or active CNS metastases, multiple primary malignancies within 3 years, severe hypersensitivity reactions, uncontrolled infections, substance abuse or medical conditions that may increase safety risk, social, familial, or geographical factors interfering with study participation, HIV infection or active hepatitis B or C infection, unresolved toxicities from previous anticancer therapy, recent therapeutic radiation therapy or major surgery, recent systemic treatment with anticancer therapy, current treatment with specific inhibitors, recent participation in other clinical studies, pregnancy, breastfeeding, or planning pregnancy, study site personnel or immediate family members, recent live attenuated vaccine receipt, lung-specific intercurrent illnesses, autoimmune disorders with pulmonary involvement, prior pneumonectomy, and other reasons deemed inappropriate by the Investigator

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Trastuzumab Deruxtecan intravenously every 3 weeks at a dose of 5.4 mg/kg until disease progression, limiting toxicity, withdrawal of consent, or death

21 days per cycle, indefinite number of cycles

1 visit every 3 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

40 days

1 visit (in-person)

Long-term follow-up

Overall survival and progression-free survival are monitored every 3 months

Up to 3 years

1 visit every 3 months (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Trastuzumab Deruxtecan

Trial Overview The trial is evaluating the effects of Trastuzumab Deruxtecan (T-DXd) on patients with advanced breast cancer that lacks a protein called HER2. The study aims to determine both positive outcomes and potential adverse reactions to T-DXd in this specific patient group.

How Is the Trial Designed?

Group I: Trastuzumab Deruxtecan Experimental Treatment 1 Intervention

T-DXd will be administered intravenously every 3 weeks at a dose of 5.4 mg per kilogram of body weight until disease progression, limiting toxicity, withdrawal of consent, or death. For T-DXd, each cycle of treatment will be 21 days. The number of treatment cycles with T-DXd is not fixed.

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

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

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) was evaluated for safety in 1457 patients across 8 clinical trials, revealing that gastrointestinal disorders and blood-related issues were the most common adverse events, with neutropenia being the most severe (21.4% incidence).

The study highlighted significant concerns regarding interstitial lung disease (10.9% incidence) and decreased left ventricular ejection fraction (1.2% incidence), suggesting that while T-DXd is generally well tolerated, these specific side effects require careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of trastuzumab deruxtecan: A meta-analysis and pharmacovigilance study. Guo, Z., Ding, Y., Wang, M., et al.[2023]

In the phase 3 DESTINY-Breast02 trial involving 608 patients with HER2-positive metastatic breast cancer, trastuzumab deruxtecan significantly improved median progression-free survival to 17.8 months compared to 6.9 months for treatment of physician's choice, demonstrating its efficacy in a population with limited treatment options.

While trastuzumab deruxtecan had a higher incidence of treatment-emergent adverse events, including nausea and interstitial lung disease, it still showed a favorable benefit-risk profile, indicating its potential as a viable treatment option for patients resistant to previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. André, F., Hee Park, Y., Kim, SB., et al.[2023]

In a meta-analysis of 1970 patients with metastatic breast cancer, trastuzumab deruxtecan (T-DXd) was associated with an 11.7% incidence of interstitial lung disease (ILD), with most cases being mild (grade 1 or 2).

The treatment also showed a low incidence of cardiotoxicity, with only 1.95% of patients experiencing decreased left ventricular ejection fraction (LVEF) and 7.77% experiencing QT interval prolongation, indicating that while T-DXd has some risks, serious heart-related side effects are relatively rare.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence of interstitial lung disease and cardiotoxicity with trastuzumab deruxtecan in breast cancer patients: a systematic review and single-arm meta-analysis. Soares, LR., Vilbert, M., Rosa, VDL., et al.[2023]

In a phase 1 trial involving 44 patients with HER2-positive gastric or gastro-oesophageal junction cancer, trastuzumab deruxtecan demonstrated a manageable safety profile, with the most common serious side effects being anemia and decreases in blood cell counts, but no drug-related deaths were reported.

The treatment showed promising preliminary activity, with 43.2% of patients achieving a confirmed objective response, indicating its potential effectiveness in patients who had previously been treated with trastuzumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. Shitara, K., Iwata, H., Takahashi, S., et al.[2020]

In a phase 2 study involving 184 patients with HER2-positive metastatic breast cancer who had previously been treated with trastuzumab emtansine, trastuzumab deruxtecan demonstrated a significant response rate of 60.9%, with a median response duration of 14.8 months.

While trastuzumab deruxtecan showed promising efficacy, it was associated with notable adverse effects, including interstitial lung disease in 13.6% of patients, highlighting the need for careful monitoring of pulmonary symptoms during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. Modi, S., Saura, C., Yamashita, T., et al.[2021]

In the TUXEDO-1 trial involving 15 patients with HER2-positive breast cancer and brain metastases, trastuzumab deruxtecan achieved a high overall intracranial response rate of 73.3%, indicating its efficacy in treating this challenging condition.

The treatment was well-tolerated, with no new safety concerns reported, and patients maintained their quality of life and cognitive functioning throughout the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in HER2-positive breast cancer with brain metastases: a single-arm, phase 2 trial. Bartsch, R., Berghoff, AS., Furtner, J., et al.[2022]

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]

Citations

1. nature.com nature.com/articles/s41523-025-00841-9

Real-world outcomes of trastuzumab deruxtecan in HR- ... Median real-world progression-free survival (rwPFS) and overall survival were 5.0 months and 14.9 months, respectively. Multivariate analysis ...

2. academic.oup.com academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djaf220/8234527

JNCI: Journal of the National Cancer Institute | Oxford Academic We identified 793 patients receiving a post-T-DXd treatment. Post-T-DXd treatment outcomes differed significantly by MBC subtype: median rwPFS ...

3. esmoopen.com esmoopen.com/article/S2059-7029(25)01380-8/fulltext

Effectiveness of post-trastuzumab deruxtecan treatments ... We found that median post-T-DXd rwPFS was 4.1 months and the median OS was 16.2 months, 73.2% of patients received a different anti-HER2 therapy ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40714515/

Effectiveness of post-trastuzumab deruxtecan treatments ... The median first post-T-DXd rwPFS was 4.1 months [95% confidence interval (CI) 3.9-4.5 months], and the median OS was 16.2 months (95% CI 13.8- ...

5. 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.

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

Safety profile of trastuzumab deruxtecan in advanced breast ... The article covers various aspects of T-DXd treatment, including its clinical efficacy, safety profile, and dosing considerations, and provides practical ...

7. esmoopen.com esmoopen.com/article/S2059-7029(25)01716-8/fulltext

Real-world safety and efficacy profiles of trastuzumab ... We conducted a retrospective, observational cohort study to evaluate safety and efficacy profiles of T-DXd in patients with ...

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. sciencedirect.com sciencedirect.com/science/article/pii/S2949820124000730

Real-world safety and effectiveness data of trastuzumab ... Real-world safety and effectiveness data of trastuzumab deruxtecan and sacituzumab govitecan in breast cancer: a Hellenic Cooperative Oncology Group study.