Pharmacokinetics, Biodistribution, and Radiation Dosimetry for ⁸⁹Zr-Trastuzumab in Patients with Esophagogastric Cancer

Abstract

Trastuzumab with chemotherapy improves clinical outcomes in patients with human epidermal growth factor receptor 2 (HER2)-positive esophagogastric adenocarcinoma (EGA). Despite the therapeutic benefit, responses are rarely complete, and most patients develop progression. To our knowledge, this is the first report evaluating Zr-trastuzumab in HER2-positive EGA; here, we evaluate the safety, pharmacokinetics, biodistribution, and dosimetryZr-trastuzumab. Trastuzumab was conjugated with deferoxamine and radiolabeled withZr. A mean activity of 184 MBq was administered to 10 patients with metastatic HER2-positive EGA. PET imaging, whole-body probe counts, and blood draws were performed to assess pharmacokinetics, biodistribution, and dosimetry. No clinically significant toxicities were observed. At the end of infusion, the estimatedZr-trastuzumab in plasma volume was a median 102% (range, 78%-113%) of the injected dose. The median biologic half-life T was 111 h (range, 78-193 h). The median biologic whole-body retention half-life was 370 h (range, 257-578 h). PET images showed optimal tumor visualization at 5-8 d after injection. The maximum tumor SUV ranged from no to minimal uptake in 3 patients to a median of 6.8 (range, 2.9-22.7) for 20 lesions in 7 patients. Dosimetry estimates from OLINDA showed that the organs receiving the highest absorbed doses were the liver and heart wall, with median values of 1.37 and 1.12 mGy/MBq, respectively. Zr-trastuzumab imaging tracer is safe and provides high-quality images in patients with HER2-positive EGA, with an optimal imaging time of 5-8 d after injection.

EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer

“…We previously reported that 89 Zr-trastuzumab localizes to HER2-positive EG tumors as measured by PET imaging (26). Furthermore, in contrast to 18 F-FDG and 18 F-FLT PET, 89 Zrtrastuzumab PET could noninvasively differentiate HER2positive from HER2-negative EG cancers preclinically (15).…”

111In-labeled anti-cadherin17 antibody D2101 has potential as a noninvasive imaging probe for diagnosing gastric cancer and lymph-node metastasis

“…HER2-targeted PET imaging using 89 Zr-trastuzumab has been investigated as an immuno-imaging method for gastric cancer. A clinical study showed a high degree of accumulation of 89 Zr-trastuzumab in the foci of esophagogastric cancer patients [25], and a preclinical study using gastric cancer xenograft mice showed the highest tumor uptake of 34.4% ID/g at 96 h p.i. [26].…”

Understanding the in vivo fate of radioimmunoconjugates for nuclear imaging

“…Readers interested in these efforts are directed to a comprehensive review by Heskamp et al 131 Though little clinical data is available on the metabolism of 89 Zr-labeled antibodies, it is interesting to note that the bone uptake patterns observed in mice are typically not seen in humans, leading many to believe that DFO is indeed a suitable chelator for 89 Zr in the clinic. 97,[132][133][134][135][136] Studies using 89 Zr-DFO-labeled trastuzumab in HER2-positive esophagogastric adenocarcinoma 136 and 89 Zr-labeled cmAb-U36 antibody in head and neck cancer 131 reported relatively low activity accumulation and retention in the liver and spleen. In contrast, higher activity concentrations were observed in both organs during trials with 89 Zr-huJ591, 97 89 Zrcetuximab, 133 and 89 Zr-rituximab.…”