The PACIFIC randomised trial of radical chemoradiation +/- adjuvant immune checkpoint inhibitor immunotherapy with the anti-PD-L1 antibody durvalumab showed significant improvements in disease control and survival for immunotherapy-treated patients with locoregionally advanced non-small cell lung cancer (NSCLC). Benefits were seen even in patients with a baseline tumour cell PD-L1 of only 1%. However, sequential PD-L1 testing was not performed during the study and the dynamics of PD-L1 induction during chemoradiotherapy are unknown. It is known that radiation can rapidly induce PD-L1 expression. To investigate potential relationships between changes in PD-L1 expression and chemo-radiotherapy treatment, we developed a novel PET tracer for human use. Durvalumab is a humanised monclonal antibody that is known to bind to the PD-L1 molecule in patients with cancer and formed the basis for our imaging agent. The positron emitting isotope 89Zr was attached to the durvalumab molecule using a novel squaramide ester-desferrioxamine linking molecule. The resulting tracer has shown excellent radiotracer characteristics, both in vitro and in imaging studies of mice implanted with PD-L1 positive and PD-L1 negative human xenografts.
A clinical trial has been designed in 2 phases, and it will start recruiting in 2021. In phase 0, the 89Zr tracer will be administered to 5 patients with advanced NSCLC for biodistribution, pharmacokinetic and safety studies, allowing us to develop an optimised imaging protocol for the Phase I study. In the Phase I, 20 patients with stage III NSCLC will receive standard 6-week curative-intent radical chemo-radiation and will undergo sequential PD-L1 and FDG-PET imaging before and during treatment. Patients will be imaged at baseline, and during and at the end of radiotherapy. Together with translational analyses including ctDNA analysis, we hope that this study will allow us to characterise dynamic changes in PD-L1 in the tumour and investigate their correlates in the circulation. In a subset of patients, we will characterise changes in the tumour immune microenvironment between baseline and on-treatment tumour biopsies.