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

NCT07683754 | Not Yet Recruiting Phase 3 FDA Drug

• 1 other identifier: DS8201-0004-CIS-MA
• Study Type: interventional
• Target: 200
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Advanced Breast Cancer; HER2 Positive; HR Positive; Metastatic Breast Cancer

Keywords

Advanced Breast Cancer; Metastatic Breast Cancer; T-DXd; HER2 positive; HR positive

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (18)

• 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

• Objective Response Rate

  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

  From start of Maintenance Treatment until disease progression (PD) or death, whichever occurs first, up to approximately 12 months

• Overall Survival at 24 Months

  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

Study Arms (1)

T-DXd

EXPERIMENTAL

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; Drug: Trastuzumab; Drug: Pertuzumab; Drug: Endocrine Therapy; Drug: Palbociclib

Interventions

Trastuzumab deruxtecan DRUG

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.

Also known as: T-DXd, ENHERTU®

T-DXd

Trastuzumab DRUG

Maintenance treatment: One IV infusion Q3W 6 mg/kg on Day 1 of each 21-day cycle

Also known as: Herceptin®

T-DXd

Pertuzumab DRUG

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

Also known as: Perjeta®

T-DXd

Endocrine Therapy DRUG

Aromatase inhibitors or fulvestrant administered as approved product label

T-DXd

Palbociclib DRUG

Maintenance treatment: Daily (3 out of 4 weeks, Q4W) oral 125 mg

Also known as: Ibrance®

T-DXd

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Sign and date the Main Trial informed consent form (ICF), prior to the start of any trial-specific procedures.
• Participant must be ≥18 years of age at the time the ICF is signed.
• 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.
• 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.
• ECOG PS of 0 or 1 assessed no more than 3 days prior to initiation of trial intervention.
• 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.
• 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
• 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.

You may not qualify if:

• Has prior therapy with any CDK inhibitor.
• 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.
• Is receiving concurrent therapy with other trial interventions (except pertuzumab which is part of Upfront Treatment and Maintenance Treatment).
• Has prior therapy with any CDK inhibitor.
• 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.
• Has experienced Grade 3 or 4 ILD/pneumonitis during the Upfront Treatment Phase.
• 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.
• Participant who developed ILD/pneumonitis Grade ≥2 during the Upfront Treatment Phase or Maintenance Treatment Phase.
• 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.
• Participant who developed non-ILD toxicities related to T-DXd in the Upfront Treatment Phase that required T-DXd discontinuation.

Sponsors & Collaborators

• Daiichi Sankyo: lead
• AstraZeneca: collaborator

MeSH Terms

Conditions

Breast Neoplasms

Interventions

trastuzumab deruxtecan; Trastuzumab; pertuzumab; palbociclib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Central Study Contacts

Contact for Clinical Trial Information

CONTACT

908-992-6400; CTRinfo_us@daiichisankyo.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 25, 2026
• First Posted: July 6, 2026
• Study Start (Estimated): September 4, 2026
• Primary Completion (Estimated): July 4, 2030
• Study Completion (Estimated): August 28, 2030
• Last Updated: July 23, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• 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.
• 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.