A Randomized Phase II Study to Evaluate the Safety and Efficacy of Trastuzumab Deruxtecan Versus CDK4/6 Inhibitor-based Endocrine Therapy as First-line Therapy of HR-positive and HER2-low/Ultralow Advanced Breast Cancer Patients Classified as Non-luminal Subtype According to Gene Expression Profiling.

Plain English Summary

Safety and Efficacy of T-DXd vs. CDK4/6i-based ET as First-line Therapy of HR-positive and HER2-low/Ultralow Advanced Breast Cancer Patients Classified as Non-luminal Subtype is a Phase 2 clinical trial sponsored by MedSIR studying Advanced Breast Cancer, Advanced Breast Carcinoma, Hormone Receptor Positive Breast Carcinoma. This trial tests a new drug combination (T-DXd) against a standard treatment for advanced breast cancer. It is for patients with hormone-receptor positive, HER2-low/ultralow advanced breast cancer that is not a 'luminal' subtype. Participation involves receiving either T-DXd or a doctor-chosen CDK4/6 inhibitor with endocrine therapy. Alternative treatments include standard chemotherapy or other targeted therapies depending on the patient's specific cancer. The trial aims to enroll 200 participants.

Official Summary

This trial studies a type of advanced breast cancer defined as hormone receptor HR-positive/HER2-negative and classified as non-luminal by gene expression profiling (PAM50). Patients will be treated with trastuzumab deruxtecan (T-DXd) or with physician's choice of CDK4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET). The main purpose of the study is to analyze the efficacy of T-DXd in patients who have HR-positive and HER2-low/ultralow advanced breast cancer classified as non-luminal subtype.

Who Can Participate

Here is what you need to know about eligibility for this trial. Patients must be 18 or older and have advanced breast cancer that is HR-positive and HER2-low/ultralow. The cancer must also be classified as 'non-luminal' by gene testing and have progressed on or after endocrine therapy. Patients cannot have received prior treatment for advanced disease, except for certain adjuvant CDK4/6 inhibitor therapies. Good general health, including adequate organ function (bone marrow, liver, kidney), is required. This trial is studying Advanced Breast Cancer, Advanced Breast Carcinoma, Hormone Receptor Positive Breast Carcinoma, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

Progression-free survival (PFS) means how long patients live without their cancer getting worse, which is a key measure of how well the treatment is working. The specific primary outcome measures are: Progression-free survival (PFS) (Up to 25 months); Progression-free survival (PFS) (Up to 25 months). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 2, which tests whether the treatment actually works against the target condition. Phase 2 trials involve 100-300 patients and continue to monitor safety while evaluating effectiveness. This phase often tests different dosages to find the optimal amount. About 33% of Phase 2 drugs advance to Phase 3. If successful, the treatment will move to large-scale Phase 3 trials needed for FDA approval.

Why This Trial Matters

This trial addresses a gap in treatment for a specific subtype of advanced breast cancer (HR+, HER2-low/ultralow, non-luminal) by evaluating a novel therapy. Phase 2 success would typically lead to larger Phase 3 trials needed for regulatory approval. This research targets Advanced Breast Cancer, Advanced Breast Carcinoma, Hormone Receptor Positive Breast Carcinoma, where improved treatment options are needed.

Investor Insight

This trial targets a growing segment of the breast cancer market (HER2-low) and could position T-DXd as a first-line option, potentially leading to significant market share if successful. Phase 2 trials have approximately a 15-20% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor if your specific breast cancer subtype (HR+, HER2-low/ultralow, non-luminal) makes you eligible for this trial. Participation involves regular clinic visits for treatment infusions, monitoring, and tests. Be prepared for potential side effects and discuss any concerns openly with your healthcare team. This trial is currently recruiting participants. The trial is being conducted at 20 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 200 participants

Interventions

• DRUG: Trastuzumab deruxtecan (T-DXd, DS-8201a) — Patients will receive T-DXd 5.4 mg/kg body weight administered as an intravenous (IV) infusion on Day 1 (D1) of each 21-day cycle. The initial dose will be administered as a 90-minute IV infusion.
• DRUG: CDK4/6i plus ET — Patients will receive physician's choice of CDK4/6 inhibitor (CDK4/6i) including palbociclib, ribociclib, and abemaciclib; physician's choice of endocrine therapy (ET) including fulvestrant, letrozole, anastrozole, and exemestane.

Primary Outcomes

• Progression-free survival (PFS) (Up to 25 months)
• Progression-free survival (PFS) (Up to 25 months)

Secondary Outcomes

• Overall survival (OS) (Up to 25 months)
• Objective response rate (ORR) (Up to 25 months)
• Clinical benefit rate (CBR) (Up to 25 months)
• Duration of response (DoR) (Up to 25 months)
• Time to response (TTR) (Up to 25 months)

Full Eligibility Criteria

Inclusion Criteria:

1. Patients must be capable to understand the purpose of the study and have signed written informed consent form (ICF) prior to beginning specific protocol procedures.
2. Female or male patients ≥ 18 years of age at the time of signing ICF.
3. ECOG performance status of 0-1.
4. Minimum life expectancy of ≥ 12 weeks at screening.
5. Evidence of HER2-low expression (1+ by immunohistochemistry (IHC) or 2+ and negative by an in situ hybridization \[ISH\] test) or HER2-ultralow (IHC 0 with faint membrane staining and in ≤ 10% of tumor cells) breast cancer according to the most recent American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines determined by a MEDSIR's designated central laboratory, using Ventana 4B5 antibody. This assessment has to be done on the most recently available (archived or newly collected) formalin-fixed, paraffin-embedded (FFPE) tumor tissue blocks (≤ 6 weeks or FFPE of a tumor sample obtained after last prior systemic therapy) from core or excisional biopsy from a locally recurrent (breast or locoregional lymph nodes) or metastatic tumor lesion, excluding bone metastases.
6. Non-luminal breast cancer subtype as per central PAM50 analysis determined in the most recently available (archived or newly collected) FFPE tumor tissue blocks (≤ 6 weeks or FFPE of a tumor sample obtained after last prior systemic therapy) from core or excisional biopsy from a locally recurrent (breast or locoregional lymph nodes) or metastatic tumor lesion with the exception of bone metastases.
7. Patients must have HR-positive (estrogen receptor \[ER\] and/or progesterone receptor \[PgR\]-positive defined as ≥ 1% positive stained cells) status according to the most recent ASCO/CAP guidelines locally determined prior to study entry.
8. Unresectable locally recurrent or metastatic breast cancer documented by computerized tomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable to resection with curative intent.
9. Evaluable disease according to RECIST v.1.1. Patients with bone-only disease are not allowed. Patients with bone metastases with soft tissue masses measuring \> 10 mm are eligible.
10. Patients must have endocrine resistance criteria:

    • disease progression during adjuvant ET or within the first year of completing adjuvant ET;

    or endocrine sensitivity criteria:

    • de novo metastatic disease or disease progression ≥ 12 months after completing adjuvant ET with at least one of the following requirements:
    * Estrogen receptor ≤ 50% positive stained cells;
    * and/or high histological grade or Ki67 \> 50% on primary tumor;
    * and/or liver metastases;
    * and/or known non-luminal subtype as per local PAM50 analysis.
11. No prior treatment with any systemic therapy for advanced disease.
12. Patients treated with a CDK4/6i in the adjuvant setting with a treatment-free interval (TFI) ≥ 12 months following CDK4/6i treatment completion are eligible.
13. Patients have adequate bone marrow, liver, and renal function:

    * Hematological (without platelet, red blood cell transfusion, and/or granulocyte colony-stimulating factor support within 14 days before first study treatment dose): White blood cell (WBC) count \> 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x 109/L, and hemoglobin ≥ 9.0 g/dL (≥ 5.6mmol/L).
    * Hepatic: Serum albumin ≥ 2.5 g/dL; total bilirubin ≤ 1.5 times upper limit of normal (x ULN) (≤ 3 x ULN in patients with liver metastases or know history of Gilbert's disease); alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5 x ULN in patients with liver/or bone metastases); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN (≤ 5 x ULN in patients with liver metastases).
    * Renal: Creatinine clearance ≥ 30 mL/min as determined by Cockcroft Gault (using actual body weight).
    * Coagulation: International normalized ratio or prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN.
14. Resolution of all acute toxic effects of prior anti-cancer therapy to Grade ≤ 1 as determined by the US National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (v.5.0) (except for alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).
15. Women of childbearing potential who are sexually active with a non-sterilized male partner must have a negative serum pregnancy test within 14 days before study treatment initiation. In addition, they must agree to use one highly effective method of birth control from the time of screening until 7 months after the last dose of T-DXd, or within the time period specified per local prescribing guidelines after the final dose of physician's choice of CDK4/6i plus ET. Female patients must refrain from egg cell donation and breastfeeding during this same period.
16. Male participants who are sexually act

Trial Locations

• Algemeen Ziekenhuis Klina, Brasschaat, Belgium
• CHU Helora - Hopital de Mons, Mons, Belgium
• Cliniques universitaires Saint-Luc, Woluwe-Saint-Lambert, Belgium
• CHU Lyon Sud, Lyon, France
• Institut Curie, Paris, France
• CHU Saint Etienne, Saint-Priest-en-Jarez, France
• Klinikum Worms - Frauenklinik, Worms, Germany
• A.O.U. Ospedali Riuniti di Ancona, Ancona, Italy
• Centro di Riferimento Oncologico di Aviano, Aviano, Italy
• AOU Careggi, Florence, Italy
• ...and 10 more locations

Frequently Asked Questions

Related Conditions

• Advanced Breast Cancer
• Hormone Receptor-Positive Breast Cancer
• HER2-Low Breast Cancer
• HER2-Ultralow Breast Cancer
• Metastatic Breast Cancer
• Non-Luminal Breast Cancer Subtype
• Endocrine-Resistant Breast Cancer
• Targeted Cancer Therapy
• Oncology
• Breast Carcinoma

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