Page 82 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

Chapter 4
Tumor uptake was visible in 6 of 10 patients, of which 4 had clinical benefit. In a patient with 2 lung lesions, one lesion could be visualized, while the other could not, possibly indicating intra-individual heterogeneity of receptor expression or an effect of tumor size (the lesion not visualized was smaller). Of the remaining 4 out of 10 patients without tumor uptake, 3 had progressive disease and 1 had clinical benefit without visible 89Zr-cetuximab uptake. Possibly, the amount of cetuximab that reached the latter tumor was insufficient for visual detection, but did induce anti-tumor activity. This example indicates that for appropriate interpretation of tumor uptake-response relationships it is of paramount importance that 89Zr-cetuximab and unlabeled cetuximab show exactly the same biodistribution.
Altogether these results support further investigations in a larger cohort to assess whether 89Zr-cetuximab can discriminate between cetuximab responding and non-responding patients. Currently a follow-up study, including dose escalation for patients without visible tumor uptake of 89Zr-cetuximab and assessment of cetuximab concentrations in tumor biopsies, is ongoing (ClinicalTrials.gov Identifier: NCT02117466). A limitation of 89Zr-cetuximab- PET reported by the authors is its inability to detect tumor lesions in the liver. In contrast to 89Zr-trastuzumab, 89Zr-cetuximab specifically accumulates in normal liver tissue resulting in spillover when quantifying hepatic lesions. Important technical aspects to consider are whether the imaging dose (89Zr-labeled cetuximab) and the therapeutic dose (unlabeled cetuximab) show similar biodistribution, and if the degree of similarity can be influenced by the sequence of administration.
In this study patients were treated with a cold therapeutic dose of cetuximab (500 mg/m2), within 2 hours followed by the infusion of 37 MBq 89Zr-cetuximab (10 mg). It was assumed that within this time frame the therapeutic dose and the imaging dose behave as if injected simultaneously due to slow pharmacokinetics. Sequential administration was chosen to make radiation safety precautions during administration of 89Zr-cetuximab easier.
Previous studies with 111In-cetuximab (C225) in patients with squamous cell lung carcinoma have indicated a dose-dependent biodistribution, showing liver sequestration of 111In-cetuximab, which decreased with increasing doses of unlabeled cetuximab (up to 300 mg), while tumor uptake increased (36). To get better insight in the dose-dependent biodistribution of 89Zr-cetuximab, Menke- van der Houwen van Oordt et al. administered a scouting dose of 0.1 mg 89Zr- cetuximab before the dose of unlabeled cetuximab in 3 patients (35). Blood
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