First-in-Humans Evaluation of a PD-L1–Binding Peptide PET Radiotracer in Non–Small Cell Lung Cancer Patients

(68)Ga-NOTA-WL12 is a peptide-based PET imaging agent. We conducted a first-in-human study of (68)Ga-NOTA-WL12 for PET to study the in vivo biodistribution, metabolism, radiation dosimetry, safety, and potential for quantifying programmed death ligand-1 (PD-L1) expression levels in patients with advanced non–small cell lung cancer (NSCLC). Methods: In vitro assessment of the PD-L1 expression and cellular uptake of (68)Ga-NOTA-WL12 was performed, followed by in vivo evaluation of (68)Ga-NOTA-WL12 uptake in mouse models with tumors. Nine patients with NSCLC with lesions expressing PD-L1 were enrolled and monitored for adverse events during the study. (68)Ga-NOTA-WL12 and paired (18)F-FDG PET/CT imaging were performed. Uptake (SUV, SUL [SUV(lean)], and kBq/mL) values of tumors and normal organs were obtained. Radiopharmaceutical biodistribution, radiation dosimetry, and the relationship of tumor uptake to PD-L1 expression were evaluated. Follow-up (18)F-FDG PET/CT was performed in patients who had undergone treatment with a combination of pembrolizumab with chemotherapy. Results: (68)Ga-NOTA-WL12 exhibited PD-L1–specific uptake in vitro and in PD-L1–positive tumors in vivo. (68)Ga-NOTA-WL12 PET imaging proved safe with acceptable radiation dosimetry. Physiologic tracer uptake was mainly visible in the liver, spleen, small intestine, and kidney. Tumors were clearly visible, particularly in the lungs, with a tumor-to-lung ratio of 4.45 ± 1.89 at 1 h. One hour was a suitable time point for image acquisition because no significant differences were noted in tumor-to-background ratios between 1 and 2 h. A strong, positive correlation was found between tumor uptake (SUV(peak)) and PD-L1 immunohistochemistry results (r = 0.9349; P = 0.002). (68)Ga-NOTA-WL12 and (18)F-FDG PET studies suggest that PD-L1 PET before therapy may indicate the therapeutic efficacy of pembrolizumab plus chemotherapy combination treatment. Conclusion: Our first-in-human findings demonstrate the safety and feasibility of (68)Ga-NOTA-WL12 for noninvasive, in vivo detection of tumor PD-L1 expression levels, indicating potential benefits for clinical PD-L1 therapy.