Trastuzumab Deruxtecan for Early Stage Breast Cancer

Recruiting at 129 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must not be taking: Anthracyclines, Cyclophosphamide, Taxanes

Disqualifiers: Invasive breast cancer, Stage IV, ILD/pneumonitis, others

Stay on Your Current Meds You can continue your current medications while participating

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

Compensation: Varies

Number of Visits: Unknown

Duration: Varies by treatment arm

927 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will look at the efficacy and safety of trastuzumab deruxtecan (T-DXd) in a neoadjuvant setting, in high-risk, HER2-positive early non-metastatic breast cancer.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it does exclude those who have had prior systemic therapy for breast cancer, which might imply some restrictions. It's best to discuss your specific medications with the study team.

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

The combination of trastuzumab and pertuzumab with chemotherapy has shown improved survival rates in HER2-positive breast cancer, as seen in trials like CLEOPATRA and Neosphere. These studies suggest that using trastuzumab and pertuzumab together can be effective in treating HER2-positive breast cancer, which may support the potential effectiveness of Trastuzumab Deruxtecan, a similar drug, in early-stage cases. ^{1 2 3 4 5}

Is Trastuzumab Deruxtecan safe for humans?

Trastuzumab and doxorubicin, which are components of Trastuzumab Deruxtecan, have been associated with heart-related side effects, known as cardiotoxicity (damage to the heart). However, in some studies, combinations including these drugs showed low rates of serious heart issues, suggesting they can be safe with careful monitoring. ^{6 7 8 9 10}

What makes the drug Trastuzumab Deruxtecan unique for early-stage breast cancer treatment?

Trastuzumab Deruxtecan is unique because it is a novel HER2-targeted antibody-drug conjugate that combines a humanized anti-HER2 antibody with a potent topoisomerase I inhibitor, offering a new mechanism of action compared to traditional treatments. It has shown effectiveness in advanced HER2-positive breast cancer and is now being explored for early-stage cases, potentially providing a new option for patients who have previously received other HER2-targeted therapies. ^{11 12 13 14 15}

Eligibility Criteria

This trial is for adults with high-risk, HER2-positive early breast cancer that hasn't spread (non-metastatic). Participants should have a certain level of tumor size and lymph node involvement, be in good physical condition (ECOG 0 or 1), have normal organ and bone marrow function, heart efficiency (LVEF ≥ 50%), and available tissue samples. Those with prior breast cancer treatment, stage IV cancer, other recent cancers except some skin cancers or in situ diseases, past anthracycline/cyclophosphamide/taxane use for any cancer are excluded.

Inclusion Criteria

I am fully active or restricted in physically strenuous activity but can do light work.

My breast cancer is HER2-positive and falls within specific stages as per the AJCC 8th edition.

LVEF ≥ 50% within 28 days before randomization

Exclusion Criteria

I haven't had cancer, except for non-melanoma skin cancer or in situ disease, in the last 3 years.

I have a history of or currently have lung inflammation.

I have received systemic therapy for breast cancer before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive neoadjuvant therapy with T-DXd monotherapy, T-DXd followed by THP, or ddAC-THP

Varies by treatment arm

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 39 months

Treatment Details

Interventions

• Cyclophosphamide
• Doxorubicin
• Pertuzumab
• Trastuzumab
• Trastuzumab Deruxtecan

Trial Overview The study tests the effectiveness and safety of Trastuzumab Deruxtecan (T-DXd) alone or followed by THP compared to standard treatment ddAC-THP in treating HER2-positive early-stage breast cancer before surgery. It aims to see if T-DXd can improve outcomes when used at an earlier stage of treatment.

Participant Groups

Group I: Arm B Experimental Treatment 4 Interventions

T-DXd, followed by THP

Group II: Arm A Experimental Treatment 1 Intervention

Trastuzumab deruxtecan

Group III: Arm C Active Control 5 Interventions

doxorubicin and cyclophosphamide, followed by THP

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

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

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

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

Findings from Research

In a study of 55 patients with early-stage, HER2-positive breast cancer, the neoadjuvant chemotherapy regimen combining epirubicin, cyclophosphamide, docetaxel, trastuzumab, and pertuzumab resulted in a high complete pathologic response rate of 64.8%.

The regimen demonstrated good cardiac safety, with only one case of significant left ventricular ejection fraction (LVEF) decline and no instances of symptomatic heart dysfunction, indicating that the treatment can be administered without major cardiac risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiac safety of neoadjuvant chemotherapy with epirubicin and cyclophosphamide followed by docetaxel/pertuzumab/trastuzumab for HER2-positive breast cancer patients. Douganiotis, G., Grigoriadis, S., Kontovinis, L., et al.[2021]

The ongoing PERUSE study, involving 1436 patients with HER2-positive advanced breast cancer, shows that the combination of pertuzumab, trastuzumab, and taxanes (docetaxel, paclitaxel, or nab-paclitaxel) is safe and effective, with a median progression-free survival (PFS) of 20.6 months and an overall response rate (ORR) of 80%.

Paclitaxel is a viable alternative to docetaxel, providing similar efficacy in terms of PFS and ORR, while presenting a more favorable safety profile with less febrile neutropenia and mucositis, despite a higher incidence of peripheral neuropathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE). Bachelot, T., Ciruelos, E., Schneeweiss, A., et al.[2023]

In a study of 152 patients with HER2-positive metastatic breast cancer, the combination of taxanes with trastuzumab and pertuzumab showed a significant progression-free survival (PFS) advantage over vinorelbine in patients with newly diagnosed metastatic disease, indicating a potential benefit for this specific group.

Overall, there was no significant difference in overall survival (OS) between the two treatment groups, suggesting that both taxanes and vinorelbine are viable options when combined with trastuzumab and pertuzumab for first-line treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Taxane versus vinorelbine in combination with trastuzumab and pertuzumab for first-line treatment of metastatic HER2-positive breast cancer: a retrospective two-center study. Reinhorn, D., Kuchuk, I., Shochat, T., et al.[2021]

A study involving 808 patients with HER-2 positive breast cancer showed that adding pertuzumab to trastuzumab and docetaxel significantly improved overall survival, with a 3-year survival rate increase of 10% to 15%.

While pertuzumab did not worsen cardiac toxicity in patients with low cardiovascular risk, it was associated with increased side effects such as severe diarrhea and skin disorders, indicating the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab. Promising for some women with metastatic breast cancer, but more assessment needed. [2016]

Paeonol (Pae) has been shown to protect against doxorubicin (Dox)-induced cardiotoxicity in both rat models and primary cardiomyocytes by enhancing mitochondrial fusion and restoring cardiac function.

The protective mechanism involves the PKCε-Stat3-Mfn2 signaling pathway, where Pae activates Stat3 to promote Mfn2-mediated mitochondrial fusion, without compromising the anticancer efficacy of Dox.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway. Ding, M., Shi, R., Fu, F., et al.[2023]

The combination of docetaxel, doxorubicin, and cyclophosphamide (TAC) shows high efficacy in treating metastatic breast cancer, with response rates reaching up to 80% in preliminary phase II trials.

The TAC regimen is well tolerated, with low rates of cardiac toxicity (only 2% experienced reversible congestive heart failure) despite the high incidence of grade 4 neutropenia in 68% of treatment cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel/doxorubicin/cyclophosphamide in the treatment of metastatic breast cancer. Nabholtz, JM., Smylie, M., Mackey, JR., et al.[2018]

The doxorubicin-docetaxel combination is an effective first-line chemotherapy for metastatic breast cancer, achieving an overall response rate of 67% among 40 assessable patients, with 16% achieving complete remission and 51% partial remission.

The treatment was well-tolerated, with no severe cardiac or neurological toxicity reported, although 58% of patients experienced significant neutropenia, which was managed with G-CSF or GM-CSF support.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-survival in responding patients with metastatic breast cancer treated with doxorubicin-docetaxel combination. A multicentre phase II trial. Mattioli, R., Lippe, P., Massacesi, C., et al.[2018]

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]

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]

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]

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]

References

1. Cyprus pubmed.ncbi.nlm.nih.gov

Cardiac safety of neoadjuvant chemotherapy with epirubicin and cyclophosphamide followed by docetaxel/pertuzumab/trastuzumab for HER2-positive breast cancer patients. [2021]

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

Efficacy and Safety of Gemcitabine With Trastuzumab and Pertuzumab After Prior Pertuzumab-Based Therapy Among Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer: A Phase 2 Clinical Trial. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE). [2023]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Taxane versus vinorelbine in combination with trastuzumab and pertuzumab for first-line treatment of metastatic HER2-positive breast cancer: a retrospective two-center study. [2021]

5. France pubmed.ncbi.nlm.nih.gov

Pertuzumab. Promising for some women with metastatic breast cancer, but more assessment needed. [2016]

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

The Cardioprotective Role of Flaxseed in the Prevention of Doxorubicin- and Trastuzumab-Mediated Cardiotoxicity in C57BL/6 Mice. [2023]

7. Egypt pubmed.ncbi.nlm.nih.gov

Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Docetaxel induced pericardial effusion. [2018]

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

Docetaxel/doxorubicin/cyclophosphamide in the treatment of metastatic breast cancer. [2018]

10. Greece pubmed.ncbi.nlm.nih.gov

Long-survival in responding patients with metastatic breast cancer treated with doxorubicin-docetaxel combination. A multicentre phase II trial. [2018]

11. 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]

12. 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]

13. France pubmed.ncbi.nlm.nih.gov

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

14. New Zealand pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: First Approval. [2020]

15. Japan 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. [2023]