Evaluation of [68Ga]Ga-ABY-025 PET Imaging for HER2 Expression and Predictive Value of Trastuzumab Deruxtecan in Metastatic Breast Cancer

Trial ID: 2024-512721-89-00
Protocol: HER2-Ex PET
Sponsor: Karolinska University Hospital

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Diseases & Conditions

Breast cancer female

Objectives

The primary objective of this study is to investigate the **therapy-predictive** role of HER2-PET imaging for assessing the clinical benefit of treatment with trastuzumab deruxtecan (T-DXd) in patients with HER2-expressing metastatic breast cancer. This is clinically relevant as it aims to enhance the precision of treatment strategies by identifying patients who are more likely to benefit from T-DXd therapy, potentially improving outcomes and optimizing resource allocation.

Secondary objectives include:

Assessing changes in HER2-status according to [68Ga]Ga-ABY-025 uptake before and after two cycles of T-DXd treatment.
Studying the correlation between the proportion of HER2-avid metastases and the total burden of disease on CT, and evaluating its prognostic and therapy-predictive value for T-DXd treatment.
Examining health-related quality of life at baseline, the first response evaluation, and at disease progression.

Participants

The clinical trial focuses on **breast cancer** and involves a study population exclusively composed of female participants aged 18 years and older. The trial targets individuals with metastatic or locally advanced breast cancer who have experienced disease progression following at least one line of chemotherapy in a palliative setting or disease relapse within six months after completing (neo-) adjuvant chemotherapy. Participants are required to have a WHO performance status of 2 or less and an expected survival of more than 12 weeks. The trial population was selected based on their ability and willingness to provide written consent, and the presence of at least one metastatic lesion of 10 mm or more available for biopsy. Additionally, participants must have at least one additional metastatic index lesion of 10 mm or more for treatment effect evaluation. The study does not include male subjects, and the sponsor has not provided the total number of participants. Lifestyle considerations include the requirement for females of child-bearing potential to use adequate contraception during the study and for six months after the last dose of [68Ga]Ga-ABY-025. The trial does not provide information on specific dietary or physical activity requirements.

Plans and Procedures

The clinical trial is designed as a **prospective, open-label study** to evaluate the therapy-predictive role of HER2-PET imaging in patients with metastatic **breast cancer**. The trial will utilize [68Ga]Ga-ABY-025 PET imaging to characterize HER2 expression and assess the clinical benefit of treatment with trastuzumab deruxtecan (T-DXd). The study is expected to commence recruitment on December 2, 2024, and conclude by December 2, 2032. Participants will be involved for a maximum treatment period of 12 months, with the primary endpoint being the mean SUVmax in up to five ABY-025 avid lesions at baseline, related to the response according to RECIST v1.1 after two treatment cycles with T-DXd.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease progression, and performance status. The trial will include follow-up visits to monitor treatment effects and safety, with imaging assessments conducted to evaluate changes in HER2 status and tumor volume. The end-of-study visit will assess the overall response and health-related quality of life changes. Participants are expected to remain in the study for the duration of the treatment phase, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent.

The trial will employ a **randomized** design, with participants receiving either the investigational product or standard care, ensuring a controlled comparison of outcomes. The study will not be blinded, allowing for open-label administration of the investigational product. The primary objective is to relate HER2 status on PET imaging to treatment response, while secondary endpoints include changes in HER2 status, correlation with overall survival, and quality of life assessments. Participants must adhere to contraceptive guidelines and meet all inclusion criteria to ensure the integrity and safety of the trial.

Treatment

The clinical trial involves the administration of **Enhertu**, a pharmaceutical product containing the active substance **trastuzumab deruxtecan**. This medication is provided in the form of a **powder for concentrate for solution for infusion**. The route of administration is via **infusion**, with a maximum daily dose of 5.4 mg/kg. The treatment period is set for a maximum of 12 months. **Enhertu** is classified as a HER2-inhibitor and is not formulated for pediatric use. The product is manufactured by Daiichi Sankyo Europe GmbH and is authorized under the marketing authorization number EU/1/20/1508/001.

Additionally, the trial utilizes **68Ga-ABY-025**, a solution for injection containing the active substance **gallium (68Ga) tezatabep matraxetan**. This compound is administered via **injection**, with a maximum daily dose of 100 MBq and a total dose limit of 250 MBq over a treatment period of up to 6 months. The product is developed by Affibody AB and serves as an auxiliary agent in the study. It is not intended for pediatric use and is classified under chemical substances.

Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The study aims to explore the therapy-predictive value of HER2-PET imaging in patients with metastatic breast cancer, assessing the clinical benefit of treatment with T-DXd.

Efficacy

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint involves evaluating the mean **SUVmax** (Standardized Uptake Value maximum) in up to five ABY-025 avid lesions at baseline. This measurement will be used to relate the **HER2-status** on PET imaging to the response according to RECIST v1.1 after two treatment cycles with T-DXd. Secondary endpoints include changes in **HER2-status** (deltaSUVmax) in up to five target lesions based on [68Ga]Ga-ABY-025 uptake before and after two cycles of treatment with T-DXd. Additionally, the correlation between **HER2-expressing** total tumor volume (HER2-TTV) at baseline and outcomes such as Overall Response Rate (ORR), Progression-Free Survival (PFS), and Overall Survival (OS) after treatment with T-DXd will be analyzed. Patient-reported outcomes will also be assessed, specifically changes in Health-Related Quality of Life (HR-QoL) as measured by the EQ-5D-5L questionnaire from baseline to the first treatment evaluation. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to determine the clinical benefit of the treatment in patients with metastatic breast cancer.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Female age ≥18 years
Metastatic or locally advanced breast cancer with disease progression after ≥ 1 line of chemotherapy in the palliative setting, or with disease relapse within six months after completion of (neo-) adjuvant chemotherapy
The patient must be able and willing to provide written consent to participate in the study
At least one metastatic lesion ≥ 10 mm is available for biopsy. o Exception can be made when a recent biopsy is available (no more than 12 months old and without exposition to HER2-targeted therapy or local radiotherapy to the specific lesion).
At least one additional metastatic index lesion ≥ 10 mm for evaluation of treatment effect (according to RECIST v1.1)
WHO performance status ≤ 2
Expected survival > 12 weeks
Contraceptives: Females of child-bearing potential must agree to use adequate contraception prior to study entry, , for the duration of the study treatment phase and for six months after the last dose of [68Ga]Ga-ABY-025. Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, established, proper use of hormonal contraceptives that inhibit ovulation, hormone- releasing intrauterine devices (IUDs), and copper IUDs. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Women must refrain from donating eggs during this same period. Should a female become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately. If a female participant is of child-bearing potential (females are considered not of childbearing potential if they are at least one year postmenopausal and/or surgically sterile), she must have a documented negative serum pregnancy test before [68Ga]Ga-ABY-025 administration. Pregnancy testing prior to each administration of the IMP is obligatory.

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Exclusion Criteria

Contra-indications for treatment for trastuzumab deruxtecan and inability to undergo this treatment as per local treatment routines
A previously documented metastatic tumor biopsy that was HER2-positive (IHC 3+ and/or HER2 gene amplification)
Other manifest malignancies except for basal cell carcinoma of the skin
Inadequate cardiac, renal, bone marrow or liver function
Patients with increased risk of complications from biopsies, i.e. increased risk of bleeding, defined as; prothrombin time test (INR value) >1.4, platelet count <70 (109/l), activated partial thromboplastin time (APTT) >30s, known bleeding disorders such as haemophilia, von Willebrand disease or platelet disorders or any anticoagulants or antiplatelet treatment that cannot be temporarily paused