Phase II trial of HER2-PET/CT using 68Ga-anti-HER2 VHH1 for characterization of HER2 presence in brain metastases of breast cancer patients

Background: Brain metastases form a challenge in breast cancer patients, especially in HER2+ patients whose peripheral metastases can often be controlled using standard-of-care HER2 regimens, but with relapse or progression in the brain. This determines survival for such patients. Penetration in brain lesions as well as the therapeutic outcome can be hampered due to the particular tumour microenvironment. The here used anti-HER2 agent is a single-domain antibody or nanobody that targets HER2 with nanomolar affinity but with a size that is ten-fold smaller than conventional antibodies. This could be an important factor in diagnostic and even therapeutic efficacy for nanobody radiopharmaceuticals. The 68Ga-anti-HER2 VHH1 has been successfully tested in phase I trial in 20 breast cancer patients, confirming safety and tolerability, low irradiation burden for PET/CT procedures and high uptake in HER2-positive lesions. The aim of the current study is to test its application potential for PET/CT imaging of breast cancer brain metastases. If favourable, this would support the development therapeutic analogues for targeted radionuclide therapy. Trial design: This is an open label non-randomized monocenter phase II trial in breast cancer patients with brain metastasis, investigating the uptake of the radiopharmaceutical 68Ga-anti-HER2 VHH1 in brain metastasis using PET/CT imaging. To evaluate the specificity of uptake, both HER2-positive and HER2-negative patients are eligible. The tumor targeting potential in brain metastases and other known lesions will be visually scored and quantified by an experienced nuclear medicine physician, unaware of the HER2-status. HER2 amplification will be reassessed on blood-derived cell-free DNA. A total of 30 patients (10 HER2-neg, 20 HER2-pos) will be included. The most important inclusion criteria are (i) presence of at least 1 brain metastasis of at least 8 mm, measured either on CT or MRI; (ii) minimal age 18 years old; (iii) informed consent given. Trial is in progress, with 3 HER2-postive and 1 HER2-negative patients enrolled so far. Clinical trial identification: EudraCT 2015-002328-24, NCT03331601. Legal entity responsible for the study: UZ Brussel. Funding: Scientific fund W. Gepts UZ Brussel, IWT-TBM, Kom Op tegen Kanker (stand up against cancer). Disclosure: M. Keyaerts: Travel and accomodation: Bayer; Research funding: Camel-IDS. C. Xavier: Patents on nanobody imaging and therapy. M. Vanhoeij: Research funding: Etherna. V. Caveliers: Research funding: Camel-IDS, IBA. T. Lahoutte: Co-founder, employee: Camel-IDS; Honoraria: Camel-IDS, IBA, Institut des Radioéléments (IRE). All other authors have declared no conflicts of interest.