First-in-Humans PET Imaging of KRAS G12C Mutation Status in Non-Small Cell Lung and Colorectal Cancer Patients Using [ 18 F]PFPMD.

Kirsten rat sarcoma ( KRAS ) mutations are an important marker for tumor-targeted therapy. In this study, we sought to develop a KRASG12C oncoprotein-targeted PET tracer and to evaluate its translational potential for noninvasive imaging of the KRASG12C mutation in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) patients. Methods: [18 F]PFPMD was synthesized on the basis of AMG510 (sotorasib) by attaching a polyethylene glycol chain to the quinazolinone structure. The binding selectivity and imaging potential of [18 F]PFPMD were verified by cellular uptake, internalization, and blocking (H358: KRASG12C mutation; A549: non- KRASG12C mutation) studies, as well as by a small-animal PET/CT imaging study on tumor-bearing mice. Five healthy volunteers were enrolled to assess the safety, biodistribution, and dosimetry of [18 F]PFPMD. Subsequently, 14 NSCLC or CRC patients with or without the KRASG12C mutation underwent [18 F]PFPMD and [18 F]FDG PET/CT imaging. The SUVmax of tumor uptake of [18 F]PFPMD was measured and compared between patients with and without the KRASG12C mutation. Results: [18 F]PFPMD was obtained with a high radiochemical yield, radiochemical purity, and stability. The protein-binding assay showed that [18 F]PFPMD selectively binds to the KRASG12C protein. [18 F]PFPMD uptake was significantly higher in H358 than in A549 and was decreased by pretreatment with AMG510 (H358 vs. A549: 3.22% ± 0.28% vs. 2.50% ± 0.25%, P < 0.05; block: 2.06% ± 0.13%, P < 0.01). Similar results were observed in tumor-bearing mice on PET imaging (H358 vs. A549: 3.93% ± 0.24% vs. 2.47% ± 0.26% injected dose/g, P < 0.01; block: 2.89% ± 0.29% injected dose/g; P < 0.05). [18 F]PFPMD was safe in humans and was excreted primarily by the gallbladder and intestines. The whole-body effective dose was comparable to that of [18 F]FDG. The accumulation of [18 F]PFPMD in KRASG12C mutation tumors was significantly higher than that in non- KRASG12C mutation tumors (SUVmax : 3.73 ± 0.58 vs. 2.39 ± 0.22, P < 0.01) in NSCLC and CRC patients. Conclusion: [18 F]PFPMD is a safe and promising PET tracer for noninvasive screening of the KRASG12C mutation status in NSCLC and CRC patients.