89Zr-trastuzumab and 89Zr-bevacizumab PET to evaluate the effect of the HSP90 inhibitor NVP-AUY922 in metastatic breast cancer patients

Purpose: HSP90 chaperones play a critical role in stabilizing key client proteins involved in the hallmarks of breast cancer growth and progression. This clinical trial primarily aimed to assess the feasibility of using 89Zr^{89}\text{Zr}-trastuzumab PET (for HER2-positive breast cancer) or 89Zr^{89}\text{Zr}-bevacizumab PET (for estrogen receptor [ER]-positive breast cancer) to evaluate in vivo degradation of client proteins induced by the novel HSP90 inhibitor NVP-AUY922.
Experimental Design: Patients with advanced HER2-positive or ER-positive breast cancer received 70 mg/m2^2 NVP-AUY922 administered intravenously on a weekly schedule. Biomarker analysis included serial PET imaging with 2-[18F^{18}\text{F}]fluoro-2-deoxy-D-glucose (FDG), 89Zr^{89}\text{Zr}-trastuzumab, and 89Zr^{89}\text{Zr}-bevacizumab. Tumor response was assessed using RECIST 1.0 criteria, with PET imaging data evaluated both visually and quantitatively by calculating maximum standardized uptake values (SUVmax). Serial blood samples were analyzed for HSP70 levels, the extracellular domain of HER2 (HER2-ECD), and pharmacokinetic/pharmacodynamic parameters.
Results: Sixteen patients (ten with HER2-positive and six with Luminespib ER-positive tumors) were enrolled. Among them, one achieved a partial response, and seven demonstrated stable disease. Changes in SUVmax on 89Zr^{89}\text{Zr}-trastuzumab PET from baseline to week 3 varied across tumor lesions and were correlated with changes in lesion size observed on CT after 8 weeks of treatment (r2=0.69;P=0.006r^2 = 0.69; P = 0.006). However, tumor responses measured by 89Zr^{89}\text{Zr}-bevacizumab PET and FDG-PET were not associated with CT responses.
Conclusions: NVP-AUY922 demonstrated proof-of-concept clinical activity in HER2-amplified metastatic breast cancer. Early changes detected with 89Zr^{89}\text{Zr}-trastuzumab PET were positively associated with lesion size reduction observed on CT, supporting the potential of PET imaging as a biomarker for treatment response.