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.
⁃ 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
• 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
⁃ Has received at least 1 dose of Maintenance Treatment.
⁃ Has documented disease progression per RECIST v1.1 per investigator assessment during Maintenance Treatment.
⁃ Participant who experienced ILD Grade 1 during the Maintenance Treatment Phase, must have fully resolved before starting T-DXd during the Retreatment Phase.