Advanced Breast Cancer, HER2 Positive, HR Positive, Metastatic Breast Cancer
Conditions
Keywords
Advanced Breast Cancer, Metastatic Breast Cancer, T-DXd, HER2 positive, HR positive
Brief summary
This study will evaluate a structured sequential treatment strategy starting with T-DXd + pertuzumab upfront therapy, followed by an optimized maintenance therapy with dual HER2+blockade + CDK4/6i + ET and the opportunity to retreat with T-DXd once patients progress under maintenance aimed to maximizing disease control, optimizing tolerability, and preserving T-DXd as a future therapeutic option, while ensuring participant safety and regulatory compliance in participants with HER2+/HR+ advanced/metastatic breast cancer.
Detailed description
This global, interventional, open-label, phase 3b trial will evaluate the efficacy and safety of a sequential treatment approach for first-line HER2+/HR+ advanced/metastatic breast cancer, initiating with upfront T-DXd + pertuzumab administered for 18 to 24 cycles, followed by a transition to trastuzumab + pertuzumab + ET + palbociclib. Participants who experience disease progression while receiving trastuzumab + pertuzumab + ET + palbociclib will receive T-DXd as 2L therapy. The study objectives will assess efficacy, safety, and quality-of-life in patients with advanced/metastatic breast cancer.
Interventions
DRUGTrastuzumab deruxtecan
Upfront treatment: One IV infusion Q3W 5.4 mg/kg (starting dose) on Day 1 of each 21-day cycle T-DXd Retreatment: One IV infusion Q3W 5.4 mg/kg (starting dose) on Day 1 of each 21-day cycle \*Dose reductions implemented during Upfront treatment phase will be maintained.
DRUGTrastuzumab
Maintenance treatment: One IV infusion Q3W 6 mg/kg on Day 1 of each 21-day cycle
DRUGPertuzumab
Upfront treatment: One IV infusion Q3W loading dose of 840 mg, then 420 mg Q3W thereafter on Day 1 of each 21-day cycle Maintenance treatment: One IV infusion Q3W 420 mg on Day 1 of each 21-day cycle
DRUGEndocrine Therapy
Aromatase inhibitors or fulvestrant administered as approved product label
DRUGPalbociclib
Maintenance treatment: Daily (3 out of 4 weeks, Q4W) oral 125 mg
Sponsors
Daiichi Sankyo
AstraZeneca
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria for Upfront Treatment Phase 1. Sign and date the Main Trial informed consent form (ICF), prior to the start of any trial-specific procedures. 2. Participant must be ≥18 years of age at the time the ICF is signed. 3. Have pathologically documented breast cancer that: * Is locally advanced and unresectable or metastatic (participants who can be treated with curative intent are not eligible). * Participant must have histologically confirmed HER2+ and HR+ (ER+ and/or PR+), mBC. ER, PR, and HER2 measurements should be locally performed according to institutional guidelines. * Is documented by local testing as HR-positive (either ER and/or PgR positive \[ER or PgR ≥1%\]) per ASCO/CAP guidelines in the metastatic setting or from the primary tumor with the latest sample available. 4. Has not received prior chemotherapy or HER2-targeted therapy for mBC. Participant who has received chemotherapy or HER2-targeted therapy or radiotherapy or surgery in the neoadjuvant or adjuvant setting are eligible, with a DFI of \>6 months (\>183 days) from completion of systemic chemotherapy or any HER2-targeted therapy (antibody, TKI or T-DM1) to diagnosis of advanced or metastatic disease. 5. ECOG PS of 0 or 1 assessed no more than 3 days prior to initiation of trial intervention. 6. Has at least 1 lesion, not previously irradiated, that can be measured accurately at baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have short axis ≥15 mm) with CT or MRI, which is suitable for accurate repeated measurements, or nonmeasurable, bone-only disease that can be assessed by CT, MRI, or X-ray. 7. Participant with brain metastases are allowed if participant is asymptomatic and does not require immediate local intervention. Additional Key Criteria to Transition into the Maintenance Treatment Phase 1\. Participant transitioning into the Maintenance Treatment Phase must meet the following inclusion criteria for Maintenance Treatment: * Participant is without evidence of disease progression under T-DXd + pertuzumab treatment by local assessment according to RECIST v1.1 (ie, CR, PR, or SD), and * Participant is willing to switch therapy, and * Participant completed at least 8 cycles of T-DXd + pertuzumab and achieved cCR (confirmation of CR should be obtained during the next protocol defined scheduled tumor assessment.), or * Participant completed 18 cycles (in total) of T-DXd and achieved a SD or PR, and the last 2 scans showed no further tumor shrinkage (defined as 2 subsequent scans at least 6 weeks apart) or has an unconfirmed CR. Additional Key Criteria for T-DXd Retreatment Phase 1. Has received at least 1 dose of Maintenance Treatment. 2. Has documented disease progression per RECIST v1.1 per investigator assessment during Maintenance Treatment. 3. Participant who experienced ILD Grade 1 during the Maintenance Treatment Phase, must have fully resolved before starting T-DXd during the Retreatment Phase. Key
Exclusion criteria
for Upfront Treatment Phase 1. Has prior therapy with any CDK inhibitor. 2. Previous T-DXd therapy for early BC with an EFS or disease-free interval of \< 12 months from completion of T-DXd therapy in the neoadjuvant or post-neoadjuvant setting. Key
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Rate at 24 Months | From start of Upfront Treatment phase until disease progression (PD) or death, whichever occurs first, up to approximately 24 months | PFS is defined as the time from initiation of T-DXd + pertuzumab until PD or death, whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Rate at 12 Months | From start of Upfront Treatment phase until disease progression (PD) or death, whichever occurs first, up to approximately 12 months | PFS is defined as the time from initiation of T-DXd + pertuzumab until PD or death, whichever occurs first. |
| Objective Response Rate | From start of Upfront Treatment phase until disease progression (PD) or death, whichever occurs first, up to approximately 24 months | ORR is defined as the proportion of participants with measurable disease at baseline who have a CR or PR during the Upfront Treatment Phase. |
| Progression-free Survival (PFS) Rate From Start of Maintenance Treatment at 12 Months | From start of Maintenance Treatment until disease progression (PD) or death, whichever occurs first, up to approximately 12 months | PFS from start of Maintenance Treatment is defined as the time from initiation of Maintenance Treatment until PD or death, whichever occurs first. |
| Overall Survival at 24 Months | From start of Upfront Treatment phase until the date of death, up to approximately 24 months | OS is defined as the time from initiation of T-DXd + pertuzumab until the date of death due to any cause. |
| Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), and Death | From start of T-DXd Retreatment phase up to approximately 24 months | — |
| Time to First AESI and TEAE | From start of T-DXd Retreatment phase up to approximately 24 months | — |
| Change From Maintenance Treatment Baseline in EORTC-QLQC30 Global Health Score, Functional, and Symptom Scales. | From start of Maintenance Treatment phase until approximately 24 months | The EORTC-QLQ-C30 includes both multi-item scales and single-item measures. These include 5 functional scales, 3 symptom scales, a global health status/QoL scale, and 6 single items. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning, a high score for the global health status/QoL represents a high QoL, but a high score for a symptom scale/item represents a high-level of symptomatology/problems. |
| Change From Maintenance Treatment Baseline in EQ-5D-5L Overall Score | From start of Maintenance Treatment phase until approximately 24 months | The EQ-5D-5L questionnaire comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For each dimension, participants select the statement that best describes their health on that day from 5 levels of increasing severity: "No problems", "Slight problems", "Moderate problems", "Severe problems", and "Unable to / Extreme problems", with higher levels indicating worse severity. A unique health state (EQ-5D-5L profile) is defined by the combination of responses across the 5 dimensions and is represented as a five-digit code. The EQ-5D-5L profile will be converted into a health state utility index value reported here. |
| Change From Maintenance Treatment Baseline in EQ-5D-5L Dimension-specific Scores | From start of Maintenance Treatment phase until approximately 24 months | The EQ-5D-5L questionnaire comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For each dimension, participants select the statement that best describes their health on that day from 5 levels of increasing severity: "No problems", "Slight problems", "Moderate problems", "Severe problems", and "Unable to / Extreme problems", with higher levels indicating worse severity. |
| Change From Maintenance Treatment Baseline in EQ-VAS | From start of Maintenance Treatment phase until approximately 24 months | The EQ-VAS records the participant's self-rated health on a vertical visual analogue scale ranging from 0 to 100, where: 0 represents "the worst imaginable health", and 100 represents "the best imaginable health". Higher scores indicate worse clinical outcome. |
| Time to Deterioration/Improvement After the Transition to Maintenance Treatment Phase | From start of Maintenance Treatment phase until approximately 24 months | — |
| Change From Upfront Treatment Baseline in EORTC-QLQC30 Global Health Score, Functional, Symptom Scales. | From start of Upfront Treatment phase to end of Maintenance Treatment phase, up to approximately 24 months | The EORTC-QLQ-C30 includes both multi-item scales and single-item measures. These include 5 functional scales, 3 symptom scales, a global health status/QoL scale, and 6 single items. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning, a high score for the global health status/QoL represents a high QoL, but a high score for a symptom scale/item represents a high-level of symptomatology/problems. |
| Change From Upfront Treatment Baseline in EQ-5D-5L Overall Score | From start of Upfront Treatment phase through end of Maintenance Treatment phase, up to approximately 24 months | The EQ-5D-5L questionnaire comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For each dimension, participants select the statement that best describes their health on that day from 5 levels of increasing severity: "No problems", "Slight problems", "Moderate problems", "Severe problems", and "Unable to / Extreme problems", with higher levels indicating worse severity. A unique health state (EQ-5D-5L profile) is defined by the combination of responses across the 5 dimensions and is represented as a five-digit code. The EQ-5D-5L profile will be converted into a health state utility index value reported here. |
| Change From Upfront Treatment Baseline in EQ-5D-5L Dimension-specific Scores | From start of Upfront Treatment phase through end of Maintenance Treatment phase, up to approximately 24 months | The EQ-5D-5L questionnaire comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For each dimension, participants select the statement that best describes their health on that day from 5 levels of increasing severity: "No problems", "Slight problems", "Moderate problems", "Severe problems", and "Unable to / Extreme problems", with higher levels indicating worse severity. |
| Change From Upfront Treatment Baseline in EQ-VAS | From start of Upfront Treatment phase through end of Maintenance Treatment phase, up to approximately 24 months | The EQ-VAS records the participant's self-rated health on a vertical visual analogue scale ranging from 0 to 100, where: 0 represents "the worst imaginable health", and 100 represents "the best imaginable health". Higher scores indicate worse clinical outcome. |
Contacts
CONTACTContact for Clinical Trial Information
Outcome results
None listed