Abstract
Introduction:Tumors over-expressing the human epithelial receptor 2 (HER2) or exhibiting amplification or mutation of its proto-oncogene have a poorer prognosis. Using trastuzumab and/or other HER2 targeted therapies can increase overall survival in patients with HER2(+) tumors making it critical to accurately identify patients who may benefit. We report on a Phase 0 study of the imaging agent, 111In-CHX-A”-DTPA trastuzumab, in patients with known HER2 status to evaluate its safety and biodistribution and to obtain preliminary data regarding its ability to provide an accurate, whole-body, non-invasive means to determine HER2 status.Methods:111In-CHX-A”-DTPA trastuzumab was radiolabeled on-site and slowly infused into 11 patients who underwent single (n=5) or multiple (n=6) ɣ-camera (n=6) and/or SPECT (n=8) imaging sessions.Results:No safety issues were identified. Visual and semi-quantitative imaging data were concordant with tissue HER2 expression profiling in all but 1 patient. The biodistribution showed intense peak liver activity at the initial imaging timepoint (3.3h) and a single-phase clearance fit of the average time-activity curve (TAC) estimated t1/2=46.9h (R2=0.97; 95%CI 41.8 to 53h). This was followed by high gastrointestinal (GI) tract activity peaking by 52h. Linear regression predicted GI clearance by 201.2h (R2 =0.96; 95%CI 188.5 to 216.9h). Blood pool had lower activity with its maximum on the initial images. Non-linear regression fit projected a t1/2=34.2h (R2 =0.96; 95%CI 25.3 to 46.3h). Assuming linear whole-body clearance, linear regression projected complete elimination (x-intercept) at 256.5hr (R2=0.96; 95%CI 186.1 to 489.2h).Conclusion:111In-CHX-A”-DTPA trastuzumab can be safely imaged in humans. The biodistribution allowed for visual and semiquantitative analysis with results concordant with tissue expression profiling in 10 of 11 patients. Advances in Knowledge and Implications for Patient Care Using readily available components and on-site radiolabeling 111In-CHX-A”-DTPA trastuzumab SPECT imaging may provide an economical, non-invasive means to detect HER2 over-expression.
Highlights
Tumors over-expressing the human epithelial receptor 2 (HER2) or exhibiting amplification or mutation of its proto-oncogene have a poorer prognosis
We present preliminary results of a Phase 0 111In-CHX-A”-DTPA trastuzumab imaging study in cancer patients, including an evaluation of its safety, physiologic biodistribution over time, and comparison of lesion uptake with pathologic HER2 status
One patient withdrew prior to receiving 111In-CHX-A”-DTPA trastuzumab and another patient received the dose but died from her disease prior to imaging
Summary
Tumors over-expressing the human epithelial receptor 2 (HER2) or exhibiting amplification or mutation of its proto-oncogene have a poorer prognosis. Amplification of the proto-oncogene, HER2/neu (aka: c-erb-B2) may increase the number of human epithelial receptor 2 (HER2) transmembrane protein receptors [1,2]. A member of the Epithelial Growth Factor Receptor (EGFR) subgroup (erbB1-4, a.k.a. EGFR/ HER1, HER2, HER3 and HER4), HER2 is a 185kD transmembrane receptor tyrosine kinase (TK) [3] with a prominent extramembrane binding domain (EBD), a hydrophobic trans-membrane component and a smaller intracellular (cytoplasmic) component containing the TK domain. EGFR/ HER1, HER2, HER3 and HER4), HER2 is a 185kD transmembrane receptor tyrosine kinase (TK) [3] with a prominent extramembrane binding domain (EBD), a hydrophobic trans-membrane component and a smaller intracellular (cytoplasmic) component containing the TK domain While it has no known natural ligands. Trastuzumab is currently FDA-approved for use only in patients whose tumors overexpress HER2
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