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e21048 Background: The cGAS/STING pathway is an innate immune pathway that promotes cytokine production in response to cytoplasmic DNA, and its activation is important for the induction of anti-tumor immunity. However, predictivity of cGAS/STING tumor expression on the efficacy of PD-1/L1 inhibitors and subsequent immune responses (e.g., changes in serum cytokines) remain to be elucidated. Non-small cell lung cancer with PD-L1 tumor proportion score (TPS) of 50% or higher respond well to immune checkpoint inhibitor (ICI) monotherapy, but there is still a poor response group among them, and the extraction of such patients is an urgent issue. Methods: This is a post hoc analysis of prospective biomarker study, which enrolled 106 patients with advanced non-small cell lung cancer (NSCLC) who were treated with ICI monotherapy between December 2015 and September 2018. We investigated in 68 patients with preserved evaluable tissue samples taken before start of ICI treatment. cGAS, STING, and PD-L1 expression in tumors were stained by immunohistochemistry. cGAS and STING were evaluated by H-score. Using peripheral blood which was collected by the observational study, 41 serum proteins at the time of PD-1/L1 inhibitors initiation and in 4 – 6 weeks later were quantified. Results: The median cGAS and STING H-SCORE were 220 (5 – 300) and 190 (0 – 300), respectively. There were no differences in cGAS or STING H-SCORE between PD-L1 high (TPS ≥50) and low (TPS < 50) groups ( p= 0.990 and 0.283). Cases were divided into two groups according to median of the H-SCORE, respectively, and compared. Unexpectedly, cGAS high (H-SCORE ≥220) patients showed significantly shorter progression free survival of ICI when PD-L1 TPS ≥50 (median progression free survival (PFS); 143 days vs. not reached, p = 0.028) and progression free rate at 18 months was 7 and 53%, while no association was observed when PD-L1 TPS < 50 (median PFS; 47 vs. 61 days, p= 0.798). STING tumor expression was not associated with PFS regardless of PD-L1 TPS. In cytokine analysis, cGAS high was associated with significantly higher serum concentrations of TGF-β1 and β2 before ICI initiation (47.5 vs. 22.3hg/l, p= 0.023; 2118 vs. 882rg/ml, p= 0.037), and H-SCORE of cGAS, not STING, were significantly correlated with TGF-β1 and β2 basal levels (r = 0.447, p= 0.009; r = 0.373, p= 0.033). Analysis about fold change from baseline to 4 – 6 weeks later of 41 cytokines revealed that leptin significantly increased in cGAS high tumor while no difference was seen in all of cytokines between STING high and low tumor. Conclusions: Tumor expression (H-Score) of cGAS, not STING, is a candidate for predictor of poor response to ICI monotherapy in NSCLC with PD-L1 high (TPS ≥50). cGAS tumor expression may be associated with TGF-β producing, immune-suppressive tumor microenvironment in NSCLC. Clinical trial information: UMIN000024414.

11541 Background: PD-L1 expression on tumor tissue is associated with response to PD-1 blockade in NSCLC. Here, we conducted a serial evaluation of PD-1-expressing circulating tumor cells (CTCs) as a potential real-time diagnostic modality in NSCLC patients treated with nivolumab. Methods: Advanced NSCLC patients after failure of at least one prior chemotherapy regimen received nivolumab monotherapy (3mg/kg, q2W) until progressive disease (PD) or unacceptable toxicity. Peripheral whole blood (3 mL) was collected for CTC evaluation at baseline and at week 4. CTCs were detected using microcavity array system (Hitachi Chemical Co., Ltd, Chikusei, Japan). PD-L1 expression was immunohistochemically examined on both tumor tissues and CTCs. This study was registered at UMIN (ID: 000024414). Results: Thirty patients were registered in the study between January 2016 and September 2016 at Wakayama Medical University Hospital and 29 were included in the analysis. Demographics of the patients were as follows: median age 70 (range, 49 to 86); male 73 %; stage IV, 100 %; squamous/non-squamous, 27/73 %. At baseline, CTCs were detected in all patients (median, 15; range, 1 to 90) and PD-L1-expressing CTCs were detected in 87% of patients. Tumor proportion score (TPS) of PD-L1 expression on CTCs ranged from 6% to 100%, indicating intrapatient heterogeneity. Matched tumor tissues were available from 14 patients and 7 showed the PD-L1 TPS ≥ 50%. No positive correlation was observed on PD-L1 expression between tumor tissues and CTCs based on TPS (R2 = 0.0035). Overall response rate was 25% (7/29), and disease control rate was 54% (15/29). Total CTC count was significantly decreased after nivolumab treatment at week 4 (p < 0.05), but no significant change was observed in PD-L1 TPS on CTC. Patients harboring CTCs with PD-L1 TPS 50% or more at baseline were significantly more likely to achieve non-PD than those harboring CTCs with TPS less than 50% (p < 0.05). Conclusions: This is the first report on a serial monitoring of PD-L1 expression on CTCs in patients treated with nivolumab. PD-L1-expressing CTCs are suggested to hold potential for predicting clinical benefit. Clinical trial information: 000024414.