Molecular Imaging As a Tool for Drug Development and Trial Design
Authors: Elisabeth G.E. de Vries, Steven de Jong, Jourik A. Gietema
Journal: Journal of Clinical Oncology (2015)

In drug development and clinical trials, attention is paid not only to pharmacokinetic analysis of the drug, but increasingly to characteristics of the tumor, using techniques such as immunohistochemistry and genotyping. In the article that accompanies this editorial, Ciprotti et al have added another dimension to our understanding by radiolabeling the tumor necrosis factor–related apoptosis-inducing ligand receptor 2 (TRAIL-R2) agonistic antibody CS-1008 (tigatuzumab) and imaging the treated patients with single-photon emission computed tomography (SPECT). They obtained information on wholebody drug biodistribution and potentially on in vivo expression of the tumor characteristic of interest. The results illustrate the large gap between biopsy-based tumor characterization and what is actually happening in the various tumor lesions in a single patient. Three important issues in this respect are heterogeneity of tumor characteristics, whether the drug reaches the tumor lesions, and whether the optimal dose is administered. Heterogeneity of relevant tumor characteristics is increasingly being acknowledged; characteristics can differ within and across lesions in the same patient, so one biopsy of one lesion may not provide a representative profile for all tumor lesions. Fortunately, most hallmarks of cancer can now be imaged by specific tracers with SPECT and positron emission tomography (PET). PET scanning offers improved resolution and easier quantification. A wide array of radionuclide tracers are available, ranging from the well-known small-molecule PET tracer [F]fluorodeoxyglucose (FDG) to large molecules including antibodies. Targeted drugs can also be used as sensors to visualize their targets, as exemplified by Zr-trastuzumab in the case of human epidermal growth factor receptor 2 (HER2) and Zr-bevacizumab for vascular endothelial growth factor. These developments have made it possible to obtain noninvasive whole-body images of numerous relevant tumor characteristics in individual patients. The focus in drug development has been on measuring the drug or its active metabolites in the circulation. Most targeted agents are specifically designed to accumulate in the tumor, which makes it even more important to have information about the time course of drug presence in tumor lesions. Although a specific drug target is present in a tumor, the drug may fail to reach this target for a multitude of reasons. The drug must travel a long way to reach the tumor, and aspects such as tumor perfusion, presence of stroma, tumor interstitial fluid pressure, and anatomic location may play a role. Moreover, expression levels and the location of the target (eg, whether it is intracellular, at the cell surface, or secreted) can also affect drug uptake in tumors. Using SPECT imaging, Ciprotti et al detected tumor uptake of In-CS-1008 in only 63% of the patients, despite DR5 expression in all archival tumor tissues that were analyzed. DR5 imaging with In-CS-1008 revealed interand intrapatient heterogeneity of uptake between tumor lesions. Similar results were reported in a study that was designed to explore the role of molecular imaging to identify patients with HER2-positive metastatic breast cancer who are unlikely to benefit from the HER2-targeting antibody-drug conjugate trastuzumab-DM1. Determination of HER2 expression by tumors of patients with breast cancer using immunohistochemistry and fluorescent in situ hybridization is now well defined and standardized. In 16 of 52 (32%) patients with HER2-positive breast cancer, a Zr-trastuzumab PET/CT scan showed no or minimal tracer uptake in most of the metastatic tumor load, indicating substantial imaging heterogeneity between patients considered to have HER2-positive disease. Both studies suggest that either the drug target may not be expressed across all lesions or that the lesions may not be reachable for the drug; therefore, a significant percentage of presumed candidates may not benefit from monoclonal antibody–based treatment. If the antibody-imaging method was used for patient selection during drug development, this might prevent or reduce underestimation of drug activity in heterogeneous patient groups. Clearly, even if the drug reaches the target, antitumor efficacy may be absent. It is therefore interesting that both studies included early FDG-PET scanning as a functional effect sensor. Of the 19 patients who received CS-1008, one had a partial response and eight experienced stable disease. The disease control rate was 58% in patients with initial tumor uptake of In-CS-1008, compared with 28% in patients with no tracer tumor uptake. However, the study is small, with a low objective response rate, and it is unknown whether patients had progressive disease at study entry. Moreover, SPECT might not have been sensitive enough to detect antibody uptake in all lesions, and uptake might have been underestimated when the immunoreactivity of the clinical grade Inradiolabeled CS-1008 was similar to the 13.3% immunoreactivity reported in the preclinical study. Likely, there is room for improvement with PET instead of SPECT scanning and higher antibody tracer immunoreactivity. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 24 AUGUST 2