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Diego Signorelli



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    MA08 - Advances in Biomarkers for Immune Checkpoint Blockade and Targeted Therapy in Non Small Cell Lung Carcinoma (ID 166)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
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      MA08.04 - LIPI and Outcomes of Durvalumab as Consolidation Therapy after ChRT in Patients with Locally-Advanced NSCLC (ID 1969)

      16:45 - 17:45  |  Author(s): Diego Signorelli

      • Abstract
      • Presentation
      • Slides

      Introduction

      The lung immune prognostic index (LIPI), which combines pretreatment derived neutrophils/[leukocytes minus neutrophils] ratio (dNLR) >3 and lactate dehydrogenase (LDH) > upper limit of normal (ULN), is associated with outcomes in advanced non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICI). We aimed to assess whether pretreatment LIPI correlates with durvalumab efficacy after concurrent chemoradiotherapy in the locally advanced setting.

      Methods

      Multicenter retrospective study of locally advanced NSCLC patients treated with durvalumab consolidation in 21 European/US centers from 12/2015 to 5/2020. Clinical and biological data were collected before durvalumab treatment. PD-L1 expression by immunohistochemistry was also collected at diagnosis. LIPI was calculated according to previous reports and three groups were characterized: good (dNLR≤3+LDH≤ULN), intermediate (dNLR>3 or LDH>ULN) and poor (dNLR>3+LDH>ULN). The primary endpoint was progression-free survival (PFS). Response was assessed according to the clinical routine of each center.

      Results

      A total of 267 patients were enrolled. One hundred eighty-five (69%) patients were male, 252 (94%) smokers, with median age of 67 [range 59-73] and 223 (98%) with Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1. 260/266 (98%) were stage III, of which 96 were IIIA, 127 stage IIIB and 37 stage IIIC. 163 (63%) had non-squamous histology and 12/131 (27%) harbored driver alterations: 5 EGFR, 4 BRAF, 3 MET, 2 ALK; missing in 136 cases. PD-L1 was ≥1% in 191/233 (82%) patients both from Europe and US, missing in 34 cases. LIPI was evaluable in 143 patients: 90 were considered good (63%), 50 intermediate (35%) and 3 (2%) as poor LIPI group. dNLR >3 was found in 47/218 (22%) and LDH > ULN in 23/143 (16%) cases. Radiotherapy was delivered concurrent in 219 (82%) of cases. No differences in clinical characteristics were found between 3 LIPI groups, including the response to previous chemoradiotherapy.

      With a median follow-up of 13.4 months [95% confidence interval (CI), 12-15], the median PFS was 20 months [95% CI, 12.7-not reached (NR)]. Median PFS was 7.5 months [95% CI, 3.1-NR] for poor group vs. 10.7 months [95% CI, 5.1-NR] for intermediate group vs. 19.1 months [95% CI, 11.6-NR] for good LIPI group (P=0.020). Median overall survival (OS) was NR [95% CI 47-NR] in the entire cohort and therefore considered not mature. The first objective response rate under durvalumab was 44% (111/251), being 36% (18/50) for the intermediate-poor group and 38% (33/87) for the good group with no significant differences (P=0.099). No differences in PFS and OS between groups were found regarding PD-L1 status (P=0.5 and P=0.4, respectively).

      Conclusion

      Pretreatment LIPI is associated with clinical outcomes in locally advanced patients treated with durvalumab as consolidation after chemoradiotherapy. This cohort is still ongoing to confirm our preliminary findings in a larger cohort.

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    P33 - Pathology - Immunotherapy Biomarker (ID 101)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P33.01 - Circulating Extracellular Vesicles as Biomarkers for Immune-Checkpoint Inhibitors in Advanced NSCLC (ID 2311)

      00:00 - 00:00  |  Presenting Author(s): Diego Signorelli

      • Abstract
      • Slides

      Introduction

      Programmed death ligand-1 (PD-L1) expression is the only predictive biomarker in clinical practice for immune-checkpoints inhibitors (ICI) in NSCLC. Even if ICI efficacy is higher in PD-L1 strong positive tumours (Tumour Proportion Score, TPS>50%), also patients (pts) with low (TPS 1-49%) or absent (TPS<1%) PD-L1 expression can achieve a durable benefit. Extracellular vesicles (EVs) were used as biomarkers for cancer progression and could express PD-L1 on their surface (EVs-PD-L1). The main aim of this study was to evaluate EVs and EVs-PD-L1 in advanced NSCLC pts with low or absent TPS in order to find biomarkers for ICI in this pts subgroup.

      Methods

      EVs were isolated using ultracentrifuge from plasma of advanced NSCLC pts treated with ICI at our Institute. Pts were classified in responders (R) if they achieved a complete or partial response using RECIST 1.1 criteria, non-responders (NR) otherwise. EVs-PD-L1 was assessed by flow cytometry (FC). T cells of healthy donors were isolated and stimulated with CD3/CD28 Beads in presence of patients derived EVs, and analyzed by FC.

      Results

      Plasma samples were prospectively collected from 61 pts: 23 (37.7%) TPS low, 38 (62.3%) TPS absent, treated with ICI as first (n=23) or further (n=38) line; 19.7% were R, 80.3% NR. EVs-PD-L1 did not correlate with tumour PD-L1 expression. Stratifying baseline circulating EVs-PD-L1 levels according to median value, higher values were related to worse progression free survival (median: 2.2 vs 3.8 months, HR 1.78, 95%CI 1.03-3.08, p=0.036), without significant difference in overall survival (median: 8.3 vs 15.7 months, HR 1.50, 95%CI 0.79-2.88, p=0.213). In 20 patients (10 R, 10 NR), evaluated during ICI treatment (range: 3-13 weeks), EVs-PD-L1 levels increased in R compared to NR (PD-L1 fold change: R= 1.89 ± 0.24 vs NR= 0.91 ± 0.15; p<0.01). EVs had larger size in NR compared to R (mean size: R 149 ± 5.5 nm vs NR 169 ± 5.1 nm; n=6 for each group; p<0.05). No differences were observed in total particles count and expression of EVs-markers. Profiling 37 specific cell-type surface markers, Epcam surface expression was increased on R-EVs surface (median fluorescence: R=2114 vs NR=540, p<0.05), suggesting an epithelial origin of these EVs. We cultured in vitro CD8 T cells and CD4 T cells with EVs isolated from NR (n=12) or R (n=8) pts. EVs from both cohorts increased T cell proliferation compared to control T cells stimulated alone. Compared to NR-EVs, R-EVs induced higher T cell activation, evaluated as IFNγ and Granzyme B production, and reduced the frequency of CD4 Treg within cultures. No significant differences in checkpoint receptors expression on T cell surface (PD1, Tim3, Vista, Lag3) were detected.

      Conclusion

      Plasma EVs from NSCLC pts treated with ICI showed different features in terms of size, surface markers and activation of T cells. Increased T cell activation induced by R-EVs might reflect the presence of an activated immune-status in these pts. EVs-PD-L1 levels, assessed at baseline and during treatment, could represent a promising biomarker for ICI in NSCLC. Further studies including also PD-L1 TPS>50% NSCLC pts are warranted.

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