89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors

Purpose: We evaluated biodistribution and tumor targeting of Zr-89-lumretuzumab before and during treatment with lumretuzumab, a human epidermal growth factor receptor 3 (HER3)targeting monoclonal antibody. Experimental Design: Twenty patients with histologically confirmed HER3-expressing tumors received Zr-89-lumretuzumab and underwent positron emission tomography (PET). In part A, (89)-Zr-lumretuzumab was given with additional, escalating doses of unlabeled lumretuzumab, and scans were performed 2, 4, and 7 days after injection to determine optimal imaging conditions. In part B, patients were scanned following tracer injection before (baseline) and after a pharmacodynamic (PD)-active lumretuzumab dose for saturation analysis. HER3 expression was determined immunohistochemically in skin biopsies. Tracer uptake was calculated as standardized uptake value (SUV). Results: Optimal PET conditions were found to be 4 and 7 days after administration of Zr-89-lumretuzumab with 100-mg unlabeled lumretuzumab. At baseline using 100-mg unlabeled lumretuzumab, the tumor SUVmax was 3.4(+/- 1.9) at 4 days after injection. SUVmean values for normal blood, liver, lung, and brain tissues were 4.9, 6.4, 0.9 and 0.2, respectively. Saturation analysis (n = 7) showed that 4 days after lumretuzumab administration, tumor uptake decreased by 11.9% (+/- 8.2), 10.0% (+/- 16.5), and 24.6% (+/- 20.9) at PD-active doses of 400, 800, and 1,600 mg, respectively, when compared with baseline. Membranous HER3 was completely downregulated in paired skin biopsies already at and above 400-mg lumretuzumab. Conclusions: PET imaging showed biodistribution and tumor-specific Zr-89-lumretuzumab uptake. Although, PD-active lumretuzumab doses decreased Zr-89-lumretuzumab uptake, there was no clear evidence of tumor saturation by PET imaging as the tumor SUV did not plateau with increasing doses. (C) 2017 AACR.