First-in-Human Human Epidermal Growth Factor Receptor 2-Targeted Imaging Using 89Zr-Pertuzumab PET/CT: Dosimetry and Clinical Application in Patients with Breast Cancer

Abstract

In what we believe to be a first-in-human study, we evaluated the safety and dosimetry of ⁸⁹Zr-pertuzumab PET/CT for human epidermal growth factor receptor 2 (HER2)-targeted imaging in patients with HER2-positive breast cancer. Methods: Patients with HER2-positive breast cancer and evidence of distant metastases were enrolled in an institutional review board-approved prospective clinical trial. Pertuzumab was conjugated with deferoxamine and radiolabeled with ⁸⁹Zr. Patients underwent PET/CT with 74 MBq of ⁸⁹Zr-pertuzumab in a total antibody mass of 20-50 mg of pertuzumab. PET/CT, whole-body probe counts, and blood drawing were performed over 8 d to assess pharmacokinetics, biodistribution, and dosimetry. PET/CT images were evaluated for the ability to visualize HER2-positive metastases. Results: Six patients with HER2-positive metastatic breast cancer were enrolled and administered ⁸⁹Zr-pertuzumab. No toxicities occurred. Dosimetry estimates from OLINDA demonstrated that the organs receiving the highest doses (mean ± SD) were the liver (1.75 ± 0.21 mGy/MBq), the kidneys (1.27 ± 0.28 mGy/MBq), and the heart wall (1.22 ± 0.16 mGy/MBq), with an average effective dose of 0.54 ± 0.07 mSv/MBq. PET/CT demonstrated optimal imaging 5-8 d after administration. ⁸⁹Zr-pertuzumab was able to image multiple sites of malignancy and suggested that they were HER2-positive. In 2 patients with both known HER2-positive and HER2-negative primary breast cancers and brain metastases, ⁸⁹Zr-pertuzumab PET/CT suggested that the brain metastases were HER2-positive. In 1 of the 2 patients, subsequent resection of a brain metastasis proved HER2-positive disease, confirming that the ⁸⁹Zr-pertuzumab avidity was a true-positive result for HER2-positive malignancy. Conclusion: This first-in-human study demonstrated safety, dosimetry, biodistribution, and successful HER2-targeted imaging with ⁸⁹Zr-pertuzumab PET/CT. Potential clinical applications include assessment of the HER2 status of lesions that may not be accessible to biopsy and assessment of HER2 heterogeneity.

Keywords: 89Zr-pertuzumab; PET/CT; breast cancer; dosimetry; oncology; radiobiology.

FIGURE 1.

Summed whole-body (WB) and serum biologic clearance data for ⁸⁹Zr-pertuzumab in 6 patients. Error bars indicate SE of mean. %ID/l = percentage injected dose/L.

FIGURE 2.

Comparative distributions of absorbed doses for ⁸⁹Zr-pertuzumab and ⁸⁹Zr-trastuzumab (16). Error bars denote SD. LLI = lower large intestinal; ULI = upper large intestinal.

FIGURE 3.

46-y-old woman with both HER2-positive and HER2-negative primary breast malignancies and recently diagnosed brain metastases. Sequential maximum-intensity-projection images 1 d (A), 2 d (B), 6 d (C), and 8 d (D) after administration of ⁸⁹Zr-pertuzumab. Blood-pool and liver background cleared on sequential images. Activity excreted by bowel was seen on days 1 and 2. Bilateral kidney activity was visualized on all days. Increasing activity in foci overlying skull was seen as time progressed (arrows). Decreasing activity was seen in blood pool of superior sagittal sinus (arrowheads). (E) Gadolinium-enhanced T1-weighed MR image of brain demonstrated enhancing brain metastases (arrows) and superior sagittal sinus (arrowhead). (F) Axial fused PET/CT, CT, and PET images 8 d after ⁸⁹Zr-pertuzumab administration demonstrated avidity in brain metastases (arrows) and minimal residual avidity in superior sagittal sinus (arrowhead).

FIGURE 4.

58-y-old woman with HER2-positive breast cancer and current left breast and left axillary nodal disease. (A) Maximum-intensity-projection image 6 d after administration of ⁸⁹Zr-pertuzumab demonstrated ⁸⁹Zr-pertuzumab–avid left breast (arrow) and left axillary nodal (arrowhead) disease. (B) Axial fused PET/CT, CT, and PET images obtained 6 d after ⁸⁹Zr-pertuzumab administration localized ⁸⁹Zr-pertuzumab avidity in left breast (arrow). (C) Axial fused PET/CT, CT, and PET images from ¹⁸F-FDG PET/CT scan 3 wk earlier demonstrated corresponding ¹⁸F-FDG–avid breast lesion (arrow).