Trastuzumab Deruxtecan for Breast Cancer

Overseen By Julie Holub, MBA

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

50 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug Trastuzumab Deruxtecan for breast cancer?

Trastuzumab Deruxtecan has shown effectiveness in treating HER2-positive breast cancer, especially in patients who have already tried other treatments. In studies, it helped patients live longer without the cancer getting worse compared to previous treatments, and it was generally safe to use with manageable side effects. ^{1 2 3 4 5}

Is Trastuzumab Deruxtecan safe for humans?

Trastuzumab Deruxtecan has a generally manageable safety profile, but it can cause some side effects like nausea, vomiting, and blood and stomach issues. Serious concerns include lung problems (interstitial lung disease) and heart issues, which require careful monitoring. ^{2 5 6 7 8}

How is the drug Trastuzumab Deruxtecan unique for treating HER2-positive breast cancer?

Trastuzumab Deruxtecan is unique because it is an antibody-drug conjugate that combines a targeted anti-HER2 antibody with a powerful chemotherapy agent, allowing it to deliver the drug directly to cancer cells. This approach can be more effective and have a longer response duration compared to previous treatments like trastuzumab emtansine, especially in patients who have already received other anti-HER2 therapies. ^{1 2 3 5 9}

What is the purpose of this trial?

The purpose of this study is to test the good and bad effects of a drug called trastuzumab deruxtecan (T-DXd) in adult patients with metastatic HER2-negative breast cancer and which patients might benefit the most from T-DXd.

Research Team

Maryam Lustberg, M.D.

Principal Investigator

Yale University

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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 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 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 (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 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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in HER2-positive breast cancer with brain metastases: a single-arm, phase 2 trial. [2022]

2. France pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Unresectable or Metastatic HER2-Positive Breast Cancer. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. [2021]

4. England 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. [2023]

5. England 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. [2020]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Management of Chemotherapy-Induced Nausea and Vomiting with Trastuzumab Deruxtecan: A Case Series. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Safety of trastuzumab deruxtecan: A meta-analysis and pharmacovigilance study. [2023]

8. England 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. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. [2020]