[89Zr]Zr-DFO-avelumab accumulation in resectable non-small cell lung carcinoma indicates a suppressive tumor microenvironment amendable to neoadjuvant avelumab treatment

Background Immune checkpoint inhibitor treatment in non-small cell lung cancer (NSCLC) expands to early stages of disease. The neoadjuvant setting allows to investigate the mechanism-of-action of immune therapy using molecular imaging and tissue analysis. We investigated the safety and feasibility of programmed cell death ligand-1 (PD-L1) PET-imaging with 89Zr-labeled avelumab and neoadjuvant avelumab treatment in resectable NSCLC. Secondly, [89Zr]Zr-DFO-avelumab accumulation was correlated with features of the tumor immune microenvironment and pathological response. Methods This phase I-II study (NCT03514719) enrolled 20 patients with stage Ia-IIIa NSCLC who received 2 cycles of avelumab (10mg/kg Q2W) prior to surgery. In the imaging optimization part, [89Zr]Zr-DFO-avelumab PET was performed with protein doses of 2mg, 10mg or 50mg avelumab and imaging at day 2 and 4 post-injection. Subsequent patients were scanned with 10mg [89Zr]Zr-DFO-avelumab at day 4. Tracer-accumulation was correlated to PD-L1 expression and immune cell densities on pretreatment biopsies. Results [89Zr]Zr-DFO-avelumab PET/CT was successfully performed in 23/24 patients. 19/20 patients started neoadjuvant avelumab treatment, with no delays or conversions of surgical procedures. Six patients showed pathologic response, including two major pathologic responses. [89Zr]Zr-DFO-avelumab tumor-accumulation was not correlated to PD-L1 expression, but did correlate with regulatory T-cell density (r=0.72, p=0.030) and pathologic response (r=0.56, p=0.036); and was inversely correlated with CD303+ plasmacytoid dendritic cell density (r=-0.72, p=0.030). SUVpeak on baseline [18F]FDG-PET correlated with pretreatment PD-L1 expression but not with [89Zr]Zr-DFO-avelumab accumulation nor with pathologic response. Conclusion [89Zr]Zr-DFO-avelumab PET imaging is a safe and feasible approach in early-stage NSCLC. Higher [89Zr]Zr-DFO-avelumab tumor-accumulation at baseline strongly correlates with features of a suppressive tumor immune environment and response to neoadjuvant avelumab.