T-DXd Based Therapy Followed by Endocrine Therapy Plus Dual HER2 Blockade in First-line HER2+/ HR+ Metastatic Breast Cancer and Retreatment With T-DXd (DB-Guide)

A Global, Interventional, Open-label Trial of T-DXd-based Therapy Followed by Palbociclib, Endocrine Therapy and Dual HER2 Blockade in First-line HER2+/ HR+ Advanced or Metastatic Breast Cancer and Retreatment With T-DXd (DB-Guide)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Advanced Breast Cancer; Metastatic Breast Cancer; HR Positive; HER2 Positive
• Intervention / Treatment: Drug: Trastuzumab deruxtecan; Drug: Trastuzumab; Drug: Pertuzumab; Drug: Endocrine Therapy; Drug: Palbociclib

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.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Contact for Clinical Trial Information; Phone Number: 908-992-6400; Email: CTRinfo_us@daiichisankyo.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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. Participant who has received one prior line of endocrine therapy in the metastatic setting.
6. ECOG PS of 0 or 1 assessed no more than 3 days prior to initiation of trial intervention.
7. 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.
8. 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 Exclusion Criteria for Maintenance Treatment Phase

1. Is receiving concurrent therapy with other trial interventions (except pertuzumab which is part of Upfront Treatment and Maintenance Treatment).
2. Has prior therapy with any CDK inhibitor.
3. Has any unresolved SAE related to prior T-DXd + pertuzumab treatment from the Upfront Treatment Phase, defined as an event that has not resolved to baseline by the time of the eligibility assessment for the Maintenance Treatment Phase.
4. Has experienced Grade 3 or 4 ILD/pneumonitis during the Upfront Treatment Phase.
5. Has spinal cord compression or clinically active CNS metastases, defined as untreated or symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.

Key Exclusion Criteria for T-DXd Retreatment Phase

1. Participant who developed ILD/pneumonitis Grade ≥2 during the Upfront Treatment Phase or Maintenance Treatment Phase.
2. Participant has any unresolved SAE related to prior Maintenance Treatment Phase therapies defined as an event that has not resolved to baseline by the time of the eligibility assessment for the T-DXd Retreatment Phase.
3. Participant who developed non-ILD toxicities related to T-DXd in the Upfront Treatment Phase that required T-DXd discontinuation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: T-DXd; Adult participants with previously untreated advanced or metastatic HER2+/HR+ breast cancer who will receive T-DXd intravenously every 3 weeks (IV Q3W) in 3 treatment phases: Upfront treatment phase: T-DXd + pertuzumab IV Q3W Maintenance treatment phase: Trastuzumab + palbociclib + endocrine therapy + pertuzumab IV Q3W T-DXD retreatment phase: T-DXd monotherapy IV Q3W

Drug: Trastuzumab 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.; Other Names: T-DXd; ENHERTU®; Drug: Trastuzumab; Maintenance treatment: One IV infusion Q3W 6 mg/kg on Day 1 of each 21-day cycle; Other Names: Herceptin®; Drug: Pertuzumab; 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; Other Names: Perjeta®; Drug: Endocrine Therapy; Aromatase inhibitors or fulvestrant administered as approved product label; Drug: Palbociclib; Maintenance treatment: Daily (3 out of 4 weeks, Q4W) oral 125 mg; Other Names: Ibrance®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS) Rate at 24 Months	PFS is defined as the time from initiation of T-DXd + pertuzumab until PD or death, whichever occurs first.	From start of Upfront Treatment phase until disease progression (PD) or death, whichever occurs first, up to approximately 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS) Rate at 12 Months	PFS is defined as the time from initiation of T-DXd + pertuzumab until PD or death, whichever occurs first.	From start of Upfront Treatment phase until disease progression (PD) or death, whichever occurs first, up to approximately 12 months
Objective Response Rate	ORR is defined as the proportion of participants with measurable disease at baseline who have a CR or PR during the Upfront Treatment Phase.	From start of Upfront Treatment phase until disease progression (PD) or death, whichever occurs first, up to approximately 24 months
Progression-free Survival (PFS) Rate From Start of Maintenance Treatment at 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.	From start of Maintenance Treatment until disease progression (PD) or death, whichever occurs first, up to approximately 12 months
Overall Survival at 24 Months	OS is defined as the time from initiation of T-DXd + pertuzumab until the date of death due to any cause.	From start of Upfront Treatment phase until the date of death, up to approximately 24 months
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
Objective Response Rate		From start of T-DXd Retreatment phase until disease progression (PD) or death, whichever occurs first, up to approximately 24 months
Change From Maintenance Treatment Baseline in EORTC-QLQC30 Global Health Score, Functional, and Symptom Scales.	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.	From start of Maintenance Treatment phase until approximately 24 months
Change From Maintenance Treatment Baseline in EQ-5D-5L Overall Score	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.	From start of Maintenance Treatment phase until approximately 24 months
Change From Maintenance Treatment Baseline in EQ-5D-5L Dimension-specific Scores	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.	From start of Maintenance Treatment phase until approximately 24 months
Change From Maintenance Treatment Baseline in EQ-VAS	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.	From start of Maintenance Treatment phase until approximately 24 months
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.	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.	From start of Upfront Treatment phase to end of Maintenance Treatment phase, up to approximately 24 months
Change From Upfront Treatment Baseline in EQ-5D-5L Overall Score	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.	From start of Upfront Treatment phase through end of Maintenance Treatment phase, up to approximately 24 months
Change From Upfront Treatment Baseline in EQ-5D-5L Dimension-specific Scores	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.	From start of Upfront Treatment phase through end of Maintenance Treatment phase, up to approximately 24 months
Change From Upfront Treatment Baseline in EQ-VAS	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.	From start of Upfront Treatment phase through end of Maintenance Treatment phase, up to approximately 24 months
Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), and Death		From start of Upfront Treatment phase up to approximately 24 months
Time to First AESI and TEAE		From start of Upfront Treatment phase up to approximately 24 months

Collaborators and Investigators

• Sponsor: Daiichi Sankyo
• Collaborators: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Estimated): September 4, 2026
• Primary Completion (Estimated): July 4, 2030
• Study Completion (Estimated): August 28, 2030

Study Registration Dates

• First Submitted: June 25, 2026
• First Submitted That Met QC Criteria: July 1, 2026
• First Posted (Actual): July 6, 2026

Study Record Updates

• Last Update Posted (Actual): July 6, 2026
• Last Update Submitted That Met QC Criteria: July 1, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Advanced Breast Cancer; Metastatic Breast Cancer; HER2 positive; T-DXd; HR positive
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Trastuzumab; pertuzumab; trastuzumab deruxtecan; palbociclib
• Other Study ID Numbers: DS8201-0004-CIS-MA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) on completed studies and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• IPD Sharing Time Frame: Completed studies that has reached a global end or completion with all data set collected and analyzed, and for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• IPD Sharing Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents on completed clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No