PD-L1 imaging with [99mTc]NM-01 SPECT/CT predicts early metabolic response to pembrolizumab with or without chemotherapy in advanced non-small cell lung cancer (NSCLC) – results from the PECan study

Introduction: Immune checkpoint inhibition with anti-programmed cell death protein 1 (PD-1) / programmed death-ligand 1 (PD-L1) alone or in combination with chemotherapy is a standard of care in advanced non-small cell lung cancer (NSCLC). PD-L1 tumor proportion score (TPS) determined by immunohistochemistry on tissue is a predictive biomarker, but requires an invasive procedure and demonstrates spatiotemporal heterogeneity. [^99mTc]-labeled anti-PD-L1 single-domain antibody (NM-01) single-photon emission computed tomography (SPECT) has been shown to correlate with PD-L1 TPS. It, therefore, has the potential to non-invasively quantify total PD-L1 at multiple time points in the treatment pathway. We present results of the PECan study (NCT04436406), the primary aim of which was to assess the relationship between [^99mTc]NM-01 SPECT/CT and metabolic response determined by [¹⁸F]FDG-PET/CT to anti-PD-1 therapy. In addition, we hypothesized that PD-L1 expression measured with [^99mTc]NM-01 SPECT/CT correlated with PD-L1 TPS and would demonstrate interlesional heterogeneity, as well as, temporal heterogeneity following anti-PD-1 therapy.

Methods: This single-center exploratory study underwent UK ethics approval with all patients providing written informed consent. Inclusion criteria included diagnosis of advanced NSCLC, tissue available within 3 months for PD-L1 immunohistochemistry and prognosis >3 months. PD-L1 TPS was performed with the immunohistochemical SP263 assay. [^99mTc]NM-01 SPECT/CT and standard [¹⁸F]FDG-PET/CT were performed before and 9 weeks following anti-PD-1 pembrolizumab with or without chemotherapy. Patients were administered single dose 370-740 MBq [^99mTc]NM-01, with Siemens Intevo SPECT/CT at 2 hours. Tumor (T) to blood pool (BP) ROImax measurements were performed in primary and metastatic lesions using attenuation corrected images. Correlations of [^99mTc]NM-01 T:BP were subsequently made with PD-L1 IHC and [¹⁸F]FDG-PET/CT metabolic response, defined by EORTC criteria of ≥25% decrease in SUV_max at 9 weeks.

Results: Fifteen patients were included (median age 63 years, 9 male, 7 received single agent pembrolizumab). Intertumoral heterogeneity, ≥50% difference in [^99mTc]NM-01 T:BP between primary and metastasis, was evident in 10 (67%) patients. Mean [^99mTc]NM-01 T:BP demonstrated moderate correlation with mean PD-L1 TPS of corresponding lesions (r=0.45, p<0.05). Depth of metabolic response at 9 weeks following anti-PD-1 therapy (n=13), determined by [¹⁸F]FDG-PET/CT SUV_max, correlated strongly with baseline PD-L1 measured by [^99mTc]NM-01 T:BP (r=-0.73, p<0.05), but only moderately with PD-L1 TPS (r=-0.46, p=0.06). Stable or decreased [^99mTc]NM-01 T:BP at 9 weeks was associated with measurable metabolic response in 79% of corresponding lesions.

Conclusions: In this study, intertumoral heterogeneity and temporal heterogeneity of PD-L1 measured by [^99mTc]NM-01 SPECT/CT was demonstrated in patients with advanced NSCLC receiving anti-PD-1 therapy . Baseline [^99mTc]NM-01 T:BP also predicted early metabolic [¹⁸F]FDG-PET/CT response to anti-PD-1 therapy. [^99mTc]NM-01 SPECT/CT, therefore, has the potential to predict PD-L1 expression and response in NSCLC, with further investigation and studies ongoing.