ZEPHIR-02 is a multicentre, open-label phase II study that will enroll subjects with HER2-positive advanced/metastatic breast cancer (mBC) who have experienced disease progression under trastuzumab deruxtecan (T-DXd) in the metastatic setting.
All subjects will undergo baseline biopsy, blood collection, FDG-PET/CT and 89Zr-trastuzumab PET/CT (HER2-PET/CT) and will be classified as HER2-PET/CT positive or negative, as previously described in the ZEPHIR trial. Focusing on a central visual "patient-based" classification that captures the entire disease burden, a side-by-side display will be used, comparing baseline FDG-PET/CT (which identifies all FDG-positive metastases regardless of their HER2-imaging status) and HER2-PET/CT. Subjects will be categorized into two HER2-PET/CT patterns (positive vs. negative) based on proportion of FDG-avid tumor load with significant 89Zr-trastuzumab uptake.
Subjects classified as "positive" will receive T-DM1 as monotherapy, IV 3.6mg/kg every 3 weeks (21 days +- 3 days) until disease progression, unacceptable toxicity or request of the subject to withdraw from the study. FDG-PET/CT will be performed before cycle 2 of T-DM1 will serve as a research tool to correlate metabolic changes with clinical outcomes. Other FDG-PET/CT will be performed before cycle 4 of T-DM1 for assessment of response. Subjects who demonstrate a partial or complete response (responders) will continue treatment with T-DM1. Subjects who exhibit stable disease or disease progression (non-responders) will discontinue study treatment and enter the survival follow-up period. For responders, subsequent metabolic evaluations will be performed every 3 months, with FDG-PET/CT. Treatment response will be assessed according to metabolic response. For these subjects, mandatory blood samples will be obtained at all metabolic reassessments. Subjects with HER2-PET/CT classified as "negative" will receive treatment of physician's choice (TPC) as per the best local clinical practice and be out of the study.
All enrolled subjects will undergo a mandatory biopsy during the pre-treatment period.
The study also includes mandatory translational procedures (i.e. collection of tumour biopsy during pre-treatment period and blood samples at pre-specified time points) for exploratory molecular analyses.
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 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.
Significant symptoms (Grade ≥ 2) relating to LV dysfunction, cardiac arrhythmia, or cardiac ischemia while or since receiving preoperative therapy.
Sequential
Trastuzumab emtansine
DrugT-DM1 will be administered IV at a dose of 3.6 mg/kg every 3 weeks. (21 days +/- 3 days) until disease progression, unacceptable toxicity or request of the subject to withdraw from the study. The total dose will depend on the subject's weight on day 1 of each T-DM1 cycle.
Characterization of genomic alterations and HER2 expression.
To characterize the tumour landscape (molecular alterations on tissue and HER2 expression and its heterogeneity) in HER2-positive mBC after at least 1 line of systemic therapy for advanced disease in order to better inform the oncologist and the subject regarding next treatment options.
Time to treatment failure (TTF)
The time to treatment failure (TTF), defined as the time from T-DM1 start to discontinuation for any reason, including disease progression (clinical or image-based on 18FDG-PET/CT), treatment toxicity or death in participants classified as "positive" (per metabolic response). Time to Treatment Failure (TTF) of subjects classified as "positive" and its survival probability measures (median survival, survival rate at month 6) will be estimated using Kaplan-Meier method
Overall Survival under T-DM1
The Overall survival (OS) defined from the start of treatment to the date of death from any cause (subjects classified as "positive") Overall survival (OS) of subjects classified as "positive" will be analysed as time-to-event study and estimated using Kaplan-Meier method
Duration of Response under T-DM1
The Duration of response (DoR) defined as the time from the date of first documentation of response (CR or PR) to disease progression or death, in participants who achieve complete or partial response assessed by metabolic response (participants classified as "positive") DoR of subjects classified as "positive" will also be analysed as time-to-event study and estimated using Kaplan-Meier method
Disease Control Rate under T-DM1
The disease control rate (DCR) defined as absence of disease progression The DCR of subjects classified as "positive" will be described as proportion with two-sided 95% binomial proportion confidence intervals.
Safety of T-DM1
Incidence, nature, and severity of adverse events, including but not limited to drug induced liver injury The intensity of all AEs will be graded according to the NCI-CTCAE version 5.0 on a five-point scale (Grade 1 to 5)
Correlation between "HER2 positivity" assessments in tumour tissue, HER2-PET/CT and ctDNA
To characterize the correlation between different methods of HER2-expression assessment (i.e., tissue evaluation \[immunohistochemistry and in situ hybridization\], molecular imaging \[HER2-PET/CT\], and circulating tumour DNA \[ctDNA\])
Correlation between genomic and transcriptomic alterations with best overall response
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Jules Bordet Institute
Lead sponsor
Hoffmann-La Roche
Collaborator
