Using 89Zr‑trastuzumab PET/CT to guide antibody‑drug sequencing for advanced HER2‑positive breast cancer

HER2 Molecular Imaging With 89Zr-trastuzumab PET/CT as a Predictive Biomarker for Antibody-drug Conjugate Sequencing in Patients With Advanced HER2-positive Breast Cancer

This will see if a special HER2 PET scan (89Zr‑trastuzumab) can identify which patients with advanced HER2‑positive breast cancer who progressed on trastuzumab deruxtecan are likely to benefit from treatment with T‑DM1.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 87 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Jules Bordet Institute (Academic / other)
• Drugs / interventions: trastuzumab, pertuzumab, tucatinib
• Locations: 1 site (Anderlecht, Brussels Capital)
• Trial ID: NCT06595563 on ClinicalTrials.gov

What this trial studies

ZEPHIR‑02 is an open‑label phase II multicenter protocol enrolling patients with advanced or metastatic HER2‑positive breast cancer who progressed on trastuzumab deruxtecan. All participants undergo baseline biopsy, blood tests, FDG‑PET/CT and 89Zr‑trastuzumab PET/CT, with a central visual, patient‑based comparison of FDG and HER2 imaging to classify overall disease as HER2‑PET positive or negative. Patients with a HER2‑PET positive pattern receive T‑DM1 (3.6 mg/kg IV every 3 weeks) until progression, unacceptable toxicity, or withdrawal, and FDG‑PET/CT is repeated before cycle 2. The trial tests whether the proportion of FDG‑avid disease showing significant 89Zr‑trastuzumab uptake predicts benefit from T‑DM1.

Who should consider this trial

Good fit: Adults with histologically confirmed HER2‑positive advanced or metastatic breast cancer who progressed on trastuzumab deruxtecan as their last metastatic systemic therapy, with ECOG performance status 0–1 and ability to undergo PET/CT and biopsy, are ideal candidates.

Not a fit: Patients whose tumors show a HER2‑PET negative pattern, who cannot tolerate T‑DM1, or who did not receive T‑DXd as their immediate prior metastatic therapy are unlikely to benefit from the T‑DM1 sequencing tested here.

Why it matters

Potential benefit: If successful, this approach could help doctors choose the next antibody‑drug conjugate more accurately by matching treatment to HER2 expression across all metastases.

How similar studies have performed: A prior ZEPHIR trial using 89Zr‑trastuzumab PET/CT showed promising results for predicting response to HER2‑targeted therapy, but further validation in this specific post‑T‑DXd setting is needed.

Eligibility criteria

Inclusion Criteria:

* ECOG performance status ≤ 1
* Must have histologically or cytologically confirmed progressive advanced/metastatic HER2-positive breast carcinoma as per the updated American Society of Clinical Oncology (ASCO) - College of American Pathologists (CAP) guidelines according to local testing. HER2 status may be determined in the primary breast cancer tumour or, when not available, in a metastatic lesion.
* Multifocal unilateral or bilateral breast adenocarcinoma tumours are allowed if all tested HER2-positive, according to local testing
* Prior treatment with taxane, trastuzumab and pertuzumab (early or advanced setting) and T-DXd (metastatic setting). In order to be eligible, patients subjects must have received T-DXd as the last systemic metastatic treatment line before inclusion, and presented disease progression on this drug.

Prior therapy with tucatinib, trastuzumab, and capecitabine, in advanced setting, is permissible, provided that T-DXd serves as the last systemic metastatic treatment line before inclusion, and patient subject presented disease progression on this drug.

* Life expectancy ≥ 6 months.
* At screening FDG-PET at least two "target" lesions are required to fulfil the following criteria: (1) anatomically transaxial diameter ≥ 1.5 cm and (2) metabolically assessable with a maximum standard uptake value corrected for lean body mass (SUVmax) ≥ 1.5 x SUVmean + 2 standard deviations (SD) of the liver measured in a 3-cm-diameter spherical volume of interest (VOI) in normal liver parenchyma.

In case of suspected liver metastasis, a lesion should have a SUVmax ≥ 2 x SUVmean + 3 SD of the blood pool measured in a 1 cm-diameter VOI within descending thoracic aorta. Lesions pre-treated with irradiation are not eligible for consideration as "target" lesions.

* Adequate Bone Marrow Function including:

  * Absolute Neutrophil Count (ANC) ≥1000/μL or ≥1x109/L.
  * Platelets ≥100,000/μL or ≥ 100 x 109/L.
  * Haemoglobin ≥ 9 g/dL.
* Adequate Renal Function including serum creatinine ≤ 1.5 x upper limit of normal (ULN) or estimated creatinine clearance ≥ 60 ml/min as calculated using the method standard for the institution.
* Adequate Liver Function, including all the following parameters:

  * Total serum bilirubin ≤ 1.5 x ULN unless the patient subject has documented Gilbert syndrome.
  * Aspartate and Alanine Aminotransferase (AST and ALT) ≤ 2.5x ULN.
* Current left ventricular ejection fraction (LVEF) ≥ 50% on echocardiography or multiple-gated acquisition scanning and no history of a LVEF \< 40% or symptomatic heart failure or a recent myocardial infarction.
* Willingness to provide tumour tissue (mandatory biopsy) and blood samples (mandatory) for translational research activities.
* Willingness to comply with the protocol for the duration of the study including treatment and scheduled visits and examinations.
* Signed Informed Consent form (ICF) obtained prior to any study related procedure.

Inclusion criterion applicable to FRANCE only:

* Affiliated to the French Social Security System

Exclusion Criteria:

* Prior exposure to T-DM1 for the treatment of metastatic BC. For subjects exposed to T-DM1 for the treatment of early BC, subjects must not have relapsed while on or within 12 months of finishing treatment with T-DM1.
* Brain metastasis as sole metastasis and/or symptomatic or requiring therapy to control symptoms.
* History of interstitial lung disease / pneumonitis (grade 3 or 4) during the prior treatment with T-DXd.
* Cardiopulmonary dysfunction as defined by any of the following:

  * Significant symptoms (Grade ≥ 2) relating to LV dysfunction, cardiac arrhythmia, or cardiac ischemia while or since receiving preoperative therapy.
  * Uncontrolled hypertension (systolic blood pressure \> 180 mmHg and/or diastolic blood pressure \> 100 mmHg)
  * Inadequately controlled angina, serious cardiac arrhythmia not controlled by adequate medication, severe conduction abnormality, or clinically significant valvular disease
  * Screening LVEF \< 50% by either ECHO or MUGA
  * History of NCI CTCAE (Version 4.0) Grade ≥ 3 symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA) criteria Class ≥ II
  * History of a decrease in LVEF to \< 40% or symptomatic CHF with prior trastuzumab treatment (e.g., during preoperative therapy)
  * Myocardial infarction within 12 months prior to randomization
  * Requirement for continuous oxygen therapy
* Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to trastuzumab or excipients.
* Contra-indication for treatment with T-DM1.
* The number of subjects included in this trial, considered as "rapid progressors" (Rapid progressors defined as progressive disease within the first 6 months of T-DXd therapy) will be capped at 10% at enrolment (no more than 7 subjects out the 78 subjects planned to be recruited). After the first 7 "rapid progressors" included, progression within the first 6 months of T-DXd therapy will be considered as an exclusion criterion.
* Any known liver disease, including known carriers of hepatitis B virus, hepatitis C, autoimmune hepatic disorders and sclerosing cholangitis.
* Concurrent, serious, uncontrolled infections or known infection with HIV. Prior history of other invasive cancer in the past 5 years except basal or squamous cell carcinoma of skin that has been definitively treated.
* Pregnant and/or lactating women, or intending to become pregnant during the study. Serum pregnancy test (for subjects of childbearing potential) positive within 15 days prior to enrolment.
* Women of childbearing potential refusing to use one highly effective method of contraception from ICF signature, during the course of the study and at least 7 months after the last administration of T-DM1.
* Men with childbearing potential partner refusing to use condom during the course of this study and for at least 7 months after the last administration of T-DM1.
* Subject with a significant medical, neuro-psychiatric, or surgical condition, currently uncontrolled by treatment, which, in the principal investigator's opinion, may interfere with completion of the study.

Exclusion criterion applicable to FRANCE only:

* Vulnerable persons according to the article L.1121-6 of the Public Health Code, adults who are the subject of a measure of legal protection or unable to express their consent according to article L.1121-8 of the Public Health Code.

Where this trial is running

Anderlecht, Brussels Capital

• Institut Jules Bordet — Anderlecht, Brussels Capital, Belgium (Recruiting)

Study contacts

• Study coordinator: Margot Morelle

Conditions HER2-positive Metastatic Breast Cancer; HER2-positive Advanced Breast Cancer