Rationale <p>Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor II (TGF-βRII or TGF-β “trap”) and human immunoglobulin 1 antibody which blocks programmed cell death ligand 1 (PD-L1). This trial aimed to investigate the biodistribution of ⁸⁹Zr-bintrafusp alfa in patients with NSCLC with PD-L1 expressing tumors.</p> Methods <p>Five lung cancer patients were recruited with PD-L1 staining more than 1% of tumor cells. Patients underwent ⁸⁹Zr-bintrafusp alfa intravenous infusion (100&#xa0;mg IV) on Day 1 followed by sequential PET imaging to determine the biodistribution of ⁸⁹Zr-bintrafusp alfa. Patients then received treatment with bintrafusp alfa (1200&#xa0;mg IV) on day 15 and 29, with the latter including further ⁸⁹Zr-bintrafusp alfa to determine the effects of bintrafusp alfa treatment on receptor occupancy. Patients continued with bintrafusp alfa monotherapy, or in combination with chemotherapy for those without objective response to monotherapy, until disease progression or unacceptable toxicity. The study stopped after five patients due to the overall cessation of the bintrafusp alfa program.</p> Results <p>⁸⁹Zr-bintrafusp alfa imaging was feasible and well tolerated. All patients showed tumor specific uptake without normal tissue uptake. There was no correlation between uptake and tissue PD-L1 expression or outcomes, likely due to sample size. Inter- and intra-patient heterogeneity was observed and optimal treatment regimens will need to address this in future.</p> Conclusions <p>⁸⁹Zr-bintrafusp alfa imaging is safe, feasible and provides relevant tumor targeting information for patient selection and treatment.</p>