[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 programed 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 two cycles of avelumab (10 mg/kg Q2W) prior to surgery. In the imaging optimization part, [89Zr]Zr-DFO-avelumab PET was performed with protein doses of 2, 10, or 50 mg avelumab and imaging at Day 2 and 4 postinjection. Subsequent patients were scanned with 10 mg [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 = .030) and pathologic response (r = 0.56, P = .036); and was inversely correlated with CD303+ plasmacytoid dendritic cell density (r = -0.72, P = .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.