Preclinical PET characterization of [68Ga]Ga-EMP-100 for non-invasive assessment of c-Met in NSCLC

The c-Met receptor is a key therapeutic target in non-small cell lung cancer (NSCLC). Current methods for assessing c-Met level, are limited by biopsy sampling, which fails to account for spatio-temporal and intra-tumour heterogeneity. This study aims to evaluate the use of PET/CT imaging for non-invasive, full-body quantification of c-Met expression in different subtypes of NSCLC, encompassing both ADC and squamous cell carcinoma and compare it to MET gene alterations and IHC c-Met scoring. [ 68 Ga]Ga-EMP-100, a PET radiotracer targeting c-Met, was radiolabelled and characterized. Cell-Derived Xenograft (CDX) models of NSCLC with different characteristics were developed and validated for PET/CT imaging using [ 68 Ga]Ga-EMP-100. Tumour uptake and heterogeneity were quantified and compared to c-Met expression determined by IHC (H-score using SP44 and EP1454Y antibodies) and MET gene amplification detected by FISH and NGS. Automated radiolabelling of [ 68 Ga]Ga-EMP-100 demonstrated a high radiochemical yield (RCY) and purity (RP). Pharmacokinetics studies revealed rapid excretion predominantly by the renal pathway. PET/CT imaging resulted in high contrast and enabled non-invasive classification of CDX models regarding c-Met receptor levels. The highest tumour uptake was observed in H1648 and EBC-1 models. Although MET gene alterations were not correlated with c-Met protein expression at the cell surface, a good correlation was found between SUVmax and c-Met expression, when using the EP1454Y antibody. PET/CT imaging using [ 68 Ga]Ga-EMP-100 successfully quantified c-Met expression in vivo, clearly adding up to conventional IHC and genetic methods. Our study adds novel comparative evidence across tumour histotypes, providing new insight into how tumour phenotype affects c-Met–targeted imaging. This radiotracer holds potential as a non-invasive tool for selecting patients for c-Met-targeted therapies and monitoring therapeutic response in NSCLC. Further clinical studies are warranted.