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Gabriella Sozzi



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    MA03 - Clinomics and Genomics (ID 119)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA03.10 - Prospective Evaluation of a Prognostic Clinico-Molecular Score (DEMo) to Predict Outcome of Advanced NSCLC Patients Treated with Immunotherapy (Now Available) (ID 1378)

      10:30 - 12:00  |  Author(s): Gabriella Sozzi

      • Abstract
      • Presentation
      • Slides

      Background

      We have already reported three different molecular (MSC: plasma miRNA-signature classifier, Boeri, Clin Cancer Res 2019) and clinico-biochemical scores (DiMaio: Di Maio, EJC 2010; EPSILoN: Ann.Onco 2018 supp) able to differently predict prognosis in advanced non-small cell lung cancer (aNSCLC) patients treated with immunotherapy (IO). Exploiting the ability of each test we developed a combined clinico-biological composite score called DEMo (DiMaio EPSILoN MSC). Objective of the study is to prospectively evaluate the prognostic value of DEMo in aNSCLC patients treated with IO.

      Method

      We enrolled 127 consecutive aNSCLC patients treated with IO in first (n=37) and further-lines (n=90) at Istituto Nazionale dei Tumori, Milan. All patients had complete clinico-laboratoristic data necessary for both scores: DiMaio (ECOG-PS, sex, histology, stage, uses of platinum-based therapy at first-line and response to first-line) and EPSILoN (ECOG-PS, Smoke, Liver, LDH, NLRatio). MSC was prospectively evaluated in plasma samples collected prior starting IO and the risk level were assessed. Progression-free survival (PFS) and overall survival (OS) in strata of MSC/DiMaio/EPSILoN alone or DEMo and overall response rate (ORR), were considered as endpoints. Kaplan Meier were used to generate survival curves and Cox hazard model were employed to perform multivariate analyses.

      Result

      In multivariate analyses, adjusted for age, sex, pack/year and ECOG-PS, patients with high MSC and high DiMaio and EPSILoN scores reported a lower PFS (MSC: HR 1.72 CI95% 1.06 – 2.77, p=0.027; DiMaio: HR 2.63 CI95% 1.40 – 5.00, p=0.002; EPSILoN: HR 2.17 CI95% 1.16 – 4.16, p=0.014) and OS (MSC: HR 2.17 CI95% 1.29 – 3.70, p=0.003; DiMaio: HR 3.57 CI95% 1.66 – 7.69, p=0.001; EPSILoN: HR 2.50 CI95% 1.15 – 5.26, p=0.020). DEMo stratified patients into four risk groups according to the presence of 3–2–1–0 bad markers (High MSC/DiMaio/EPSILoN or none). Groups had 0%–0%–32.2%–53.3% 1-year PFS (p<0.0001) and 4.4%– 19.4% – 66.9% – 75.4% 1-year OS (p<0.0001). We further compared 0/1 to 2/3 combined groups. At the multivariate Cox model group 2/3 had a mPFS 1.9 vs 9.4 mo compared to group 0/1 (HR 3.70 CI95% 2.08 – 6.67, p<0.0001) and mOS 4.1 vs 22.4 mo (HR 4.76 CI95% 2.56 – 9.10, p<0.0001). Regarding ORR, DEMo group 0/1 had a 3.86 (CI95% 1.76-8.47) fold higher probability to respond compare to 2/3 group (p=0.0007).

      Conclusion

      DEMo composite biomarker is able to predict better prognosis compared to each single score and can be a useful tool for guiding IO treatment choices. In particular, DEMo allowed a good selection for those patients who are less likely to benefit from IO.

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    MA07 - Clinical Questions and Potential Blood Markers for Immunotherapy (ID 125)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MA07.03 - A Circulating MicroRNAs-Based Test as Biomarker of Primary and Secondary Resistance in PD-L1 ≥50% NSCLC Treated with Immunotherapy (Now Available) (ID 2495)

      13:30 - 15:00  |  Author(s): Gabriella Sozzi

      • Abstract
      • Presentation
      • Slides

      Background

      PD-L1 represents the only clinically approved biomarker to select patients for immunotherapy. However, about 20-25% of PD-L1≥50% NSCLC patients do not benefit of ICIs treatment. We showed that a plasma microRNA signature classifier (MSC), reflecting the switch towards an immunosuppressive profile of immune cells, identifies NSCLC patients with worse prognosis after ICIs, irrespective from PD-L1 expression. Aim of this trial is to prospectively define the MSC role as biomarker of primary or secondary resistance in PD-L1≥50% NSCLC treated with ICIs.

      Method

      Fifty consecutive advanced NSCLC patients with PD-L1≥50% treated with ICI as first (n=32) or further line were enrolled. Plasma samples, as well as demographics information, smoking history and ECOG PS were collected before starting ICI treatment. The MSC test identified patients at high (H) risk vs intermediate/low (I/L) risk levels. According to RECIST 1.1 criteria, patients were classified as responders (R), patients with stable disease (SD), and progressors (P). Objective Response Rate (ORR), Progression Free Survival (PFS) and Overall Survival (OS) in MSC risk level strata at the baseline were considered as endpoints. For 26 R or SD patients with extended follow-up, additive, not mandatory plasma samples were collected and analyzed at the time of revaluations. To determine changes in the risk level during follow-up, we evaluated changes in the probability of having progressive disease after two consecutive MSC tests, considering all possible combinations.

      Result

      Overall 17 (34%) R, 17 (34%) patients with SD, 11 (22%) P and 5 (10%) not evaluable patients were identified. Considering the baseline blood samples 11 (22%) NSCLC patients were MSC H. ORR was 0% in MSC H vs 45% for other patients (p=0.0090). Median PFS was 2.3 months for MSC H vs 10.9 months for other patients (HR=0.38; 95%CI=0.17-0.84; p=0.0174). Median OS was 2.9 months for MSC H vs 22.0 months for other patients (HR=0.18; 95%CI=0.07-0.47; p=0.0004). Data remained significant adjusting for age, sex, pack-years and ECOG performance status: PFS HR=0.31 (95%CI=0.13-0.73; p=0.0072) and OS HR=0.13 (95%CI=0.04-0.39; p=0.0003). Among the 26 patients with longitudinal evaluation of MSC risk level, all the 12 patients reaching progression during treatment showed an increase in the risk level (Sign-test p-value=0.0039). Conversely, when considering the 14 NSCLC patients still maintaining SD or responding to ICIs at the time of the analysis, the risk level decreased for 9 (64%) of them (Sign-test p-value=0.1655).

      Conclusion

      These preliminary results suggest that MSC risk level at the baseline and during treatment could help to identify primary or secondary resistance in PD-L1≥50% NSCLC patients treated with ICIs. Ongoing clinical trials are validating these results.

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    MA13 - Going Back to the Roots! (ID 139)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA13.09 - Cisplatin Sustains Lung Cancer Metastasis Through the Systemic Activation of SDF-1/CXCR4 Axis (Now Available) (ID 2821)

      14:00 - 15:30  |  Author(s): Gabriella Sozzi

      • Abstract
      • Presentation
      • Slides

      Background

      Standard chemotherapy regimens have limited long-term efficacy in lung cancer patients due to chemoresistance and inefficacy in controlling metastatic disease. In pre-clinical models we have shown that cisplatin treatment enriches for the chemoresistant fraction of CD133+CXCR4+ lung cancer metastasis initiating cells (MICs), increasing distant metastasis development that can be prevented by CXCR4 blockade. Therefore, we hypothesize that the SDF-1/CXCR4 axis, implied in MICs maintenance/migration and in immune and stromal cells trafficking, could play a critical role in cisplatin-induced pro-metastatic effects.

      Method

      To study the effects of cisplatin in promoting a pre-metastatic niche, naïve SCID mice were treated with cisplatin plus/minus peptide R (5mg/kg), a novel inhibitor of CXCR4 and after 72h injected intravenously with metastatic H460 cell line. To assess the effect of the combination treatment in pre-clinical model, H460 subcutaneous xenografts were treated with cisplatin alone or with peptide R for three weeks. Content of MICs in xenografts, number and phenotype of lung metastasis and immune cells modulationt were evaluated by FACS and IHC

      Result

      We showed that cisplatin treatment of naïf SCID mice resulted in a rapid BM expansion of the subset of CCR2+CXCR4+Ly6Chigh inflammatory monocytes (IM), concomitantly with their recruitment to murine lungs guided by increased level of SFD-1 released by PDGFRβ+ stromal cells in response to cisplatin. Peptide R partially prevented these effects.

      Tail-vein injection of H460 human lung cancer cells 72h after cisplatin administration resulted in augmented number of lung metastases (p=0.003), that showed a 3.5-fold enrichment in CD133+CXCR4+ MICs (p=0.005) and increase of IM and derived macrophages. Pre-treatment with peptide R abolished these effects. We verified that the abundance of CXCR4+CCR2+IM together with increased endothelial permeability caused by cisplatin may favor tumor cells extravasations and expansion of MICs through SDF-1/CXCR4 axis activation which determined metastasis overgrowth.

      SDF-1 was also increased in cisplatin-treated subcutaneous H460 xenografts that expanded the subset of chemoresistant CD133+CXCR4+ MICs and recruited CXCR4+tumor associated macrophages which may allow MICs to escape primary tumor. At the metastatic site cisplatin treatment of H460 xenografts caused an increase in stromal SDF-1 and recruitment of both CXCR4+ inflammatory monocytes/macrophages (1.6-fold change p=0.01) and MICs subset (1.8-fold change p=0,04), overall resulting in a boost in micrometastases. CXCR4 inhibition prevented the co-recruitment and cross-talk of MICs and IM at distant site, counteracting the pro-metastatic effects of cisplatin.

      Matched case series of stage III chemo-naive NSCLC patients and cisplatin-based neo-adjuvant treated patients demonstrated a significant increased in SDF-1 after chemotherapy (p=0,0001). An high expression of tumoral SDF-1 ( Score: staining intensity x % positive tumor cells >6) induced by cisplatin neo-adjuvant treatment was associated with a shorter DFS (p=0,0056) and poor OS (p=0,029).

      Conclusion

      Conclusions: Our data reveal a paradoxical pro-metastatic effect of cisplatin that fosters MIC-IM recruitment and cross-talk via SDF-1/CXCR4 axis activation. A new combination strategy based on CXCR4 inhibition may disrupt these interactions, providing more effective and long-lasting results for lung cancer treatment

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    MS18 - Role of Biomarkers in Lung Cancer Screening (ID 81)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Screening and Early Detection
    • Presentations: 1
    • Now Available
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      MS18.02 - Circulating Nucleic Acid Biomarkers (Now Available) (ID 3545)

      14:30 - 16:00  |  Presenting Author(s): Gabriella Sozzi

      • Abstract
      • Presentation
      • Slides

      Abstract

      Encouraging results in lung cancer (LC) mortality reduction were obtained by the introduction of low dose computed tomography (LDCT) for lung cancer screening. The results of Nelson screening trial showed a 26% reduction in lung cancer mortality in the LDCT arm thus confirming the benefit of LC screening with LDCT already published by the NLST group (1).

      In MILD trial we showed that at 10 years follow up the mortality reduction was even higher (-39%) proving that extended LDCT screening is effective in reducing lung cancer mortality (2).

      Nonetheless, the development of non-invasive complementary biomarkers could be helpful to improve the efficacy of LDCT screening by improving LC risk prediction and defining personalised LDCT screening intervals as well as to decrease false positives identified by LDCT and monitor disease evolution in patients after curative resection.

      The value of circulating tumor DNA (ctDNA) as a biomarker in advanced tumor stages is well established. However, its role in early lung cancer detection is still uncertain. The biggest technical challenge is sensitivity. Current efforts to develop next-generation sequencing (NGS) technologies to study ctDNA in the context of early detection might improve sensitivity in this context.

      The scientific community is awaiting the results of the Circulating Cell-free Genome Atlas (CCGA) Study for early cancer detection, enrolling 15,000 participants in the United States and Canada. Plasma samples collected at baseline and during 5 years of follow-up will be analyzed by whole genome sequencing(WGS) for copy number variation(CNV), targeted DNA sequencing (a 507-gene panel), and whole genome methylome profiling. Preliminary results in an observational case-control setting include 95% specificity, high sensitivity for advanced lung cancer in 54 patients (85% for targeted sequencing, 91% for CNV WGS, and 93% for methylome profiling), and modest sensitivity for 63 patients with stage I to III lung cancer (48% for targeted NGS, 54% for CNV WGS, and 56% for methylome profiling)(3). Therefore, the generalizability of these findings to the screening setting is uncertain.

      In order to implement lung cancer screening programs, we focused on circulating microRNAs which may reflect the contribution not only of the tumor but also of its microenvironment and the host. We developed a plasma miRNA Classifier (MSC) composed of 24 miRNAs which showed high performance in terms of sensitivity (87%) and specificity (81%) in 940 subjects enrolled in the MILD screening trial. The classifier was able to identify, in longitudinal plasma samples of the patients, a risk profile to develop LC up to two years before a significant tumor burden was visible at LDCT(4). These results prompted us to launch in 2013 a prospective screening trial, called bioMILD, to test the efficacy of a combined LDCT-MSC approach as forefront screening tests in a large cohort of 4119 smokers, 50 yrs or older. We succesfully completed the baseline of all the volunteers and executed a LDCT in 11,012 and miRNA test in 9,156 subjects. BioMILD has now reached the 3 yrs follow up for all subjects and 4.2 year median follow up for the all cohort. Analyses of the results are ongoing and will be presented.

      Concerning the origin of the 24 miRNA, since the classifier was able to identify a risk profile to develop lung cancer up to two years before the radiological diagnosis, we hypothesized that that such circulating miRNAs could be released not merely by cancer cells but rather by the damaged lung microenvironment and the host response that may sustain tumor development. Using in vitro models and clinical samples we showed that c-miRNAs originated mostly from blood cells, with activated neutrophils showing modulation of the 24 miRNAs overlapping that observed in plasma of MSC positive subjects(5).

      The role of immunity in modulating the risk of disease development remains to be elucidated, while it could have enormous impact in terms of prevention and early intervention. Therefore we characterized peripheral blood immune cell profiles as possible complementary biomarkers for risk assessment and analyzed their relationship with MSC. In a case control study of 40 lung cancer patients and 20 controls we found immune cell subpopulations differentially expressed between screening detected lung cancer patients and controls. Of interest an MSC high risk profile in patients was associated with specific circulating immune cell subsets including higher numbers of exausted T cells and monocytes/MDSC and lower cytotoxic T and NK cells. These findings suggest that MSC high risk profile might reflect an immunosuppressive status and prompted us to study the possible utility of MSC in lung cancer immunotherapy settings. Using a prospective cohort of 140 consecutive advanced NSCLC patients treated with immune checkpoints inhibitors we found that MSC either alone or in combination with PD-L1 expression in the tumor was associated with patients survival(6). Therefore, plasma MSC, reflecting an impaired tumor immune contexture, could supplement PD-L1 tumor expression to identify a subgroup of patients who do not benefit from immunotherapy.

      References:

      D.R. Aberle, A.M. Adams, C.D. Berg, et al.Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med, 365 (2011), pp. 395-409

      Pastorino U, Silva M, Sestini S. et al. Prolonged Lung Cancer Screening Reduced 10-year Mortality in the MILD Trial. Ann Oncol. 2019 Apr 1.

      GR. Oxnard T. Maddala E. Hubbell et al. Genome-widesequencing for early stage lung cancer detection fromplasma cell-free DNA (cfDNA): the Circulating CancerGenome Atlas (CCGA) study. Paper presented at: 2018 American Society of Clinical Oncology Annual Meeting.June 1–5, 2018; Chicago, IL

      Sozzi G, Boeri M, Rossi M.et al. Clinical Utility of a Plasma-based microRNA Signature Classifier within Computed Tomography Lung Cancer Screening: A Correlative MILD Trial Study. J Clin Oncol. 2014 Mar 10;32(8):768-73.

      Fortunato O, Borzi C, Milione M, et al.Circulating mir-320a promotes immunosuppressive macrophages M2 phenotype associated with lung cancer risk. Int J Cancer. 2019 Jun 1;144(11):2746-2761. doi: 10.1002/ijc.31988. Epub 2019 Jan 6.

      Boeri M, Milione M, Proto C. et al. Circulating miRNAs and PD-L1 Tumor Expression Are Associated with Survival in Advanced NSCLC Patients Treated with Immunotherapy: a Prospective Study. Clin Cancer Res. 2019 Apr 1;25(7):2166-2173. doi: 10.1158/1078-0432.CCR-18-1981. Epub 2019 Jan 7.

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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      OA14.06 - Hyperprogressive Disease in Advanced Non–Small Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors (Now Available) (ID 1835)

      11:30 - 13:00  |  Author(s): Gabriella Sozzi

      • Abstract
      • Presentation
      • Slides

      Background

      Hyperprogressive disease (HPD) is a paradoxical boost in tumour growth described in a subset of cancer patients treated with immune checkpoint inhibitors (ICIs).

      Method

      We retrospectively collected data about all consecutive patients with advanced Non-Small Cell Lung Cancer (aNSCLC) treated with ICIs at our Institution between 04/2013 and 12/2018. Patients were classified according to our previously published clinical/radiological criteria for HPD (Lo Russo G, Clin Canc Res 2018). (Table). All ICIs administered for ≥1 cycle were admitted. Chi-square test was used to compare qualitative variables. Survival was estimated with Kaplan-Meier method. Log-rank test was used to compare curves. Multivariate analyses were performed with Cox hazard model.

      Table HPD definition on the basis of 3 concomitant out of the five possible criteria

      HPD CLINICAL & RADIOLOGICAL CRITERIA

      Time-to-treatment failure < 2 months

      Increase of ≥ 50% in the sum of target lesions major diameters between baseline and first radiological evaluation

      Appearance of at least two new lesions in an organ already involved between baseline and first radiological evaluation

      Spread of the disease to a new organ between baseline and first radiological evaluation

      Clinical deterioration with decrease in ECOG performance status ≥ 2 during the first 2 months of treatment

      Result

      We reviewed 301 cases and 257 were evaluable for response. We identified four categories: responders (R, 57 cases, 22.2%), patients with stable disease as best response (SD, 69 cases, 26.8%), patients with progressive disease as best response (P, 78 cases, 30.4%) and patients with HPD (53 cases, 20.6%). Clinical/pathological variables were uniformly distributed among groups, except for a higher rate of patients with Eastern Cooperative Oncology Group Performance Status (ECOG-PS) >1 in HPD group (p = 0.0141). After a median follow-up of 23.49 months (IQR 10.72–44.21 months), median Progression-Free Survival (mPFS) and median Overall Survival (mOS) were 14,2 vs 6,5 vs 2,3 vs 1,5 months ( p < 0.0001) and 32,5 vs 17,8 vs 7,8 vs 4,1months (p < 0.0001) in R, SD, P and HPD group, respectively. The multivariate analyses, between P and HPD groups, adjusted for ICIs line, number of metastatic sites and ECOG-PS according to PFS (HR 2.448, 95% CI 2.137-2.899, p<0.0001) and OS (HR 2.481, 95%CI 2.092-2.950, p < 0.0001) confirmed the worse outcome of HPD group.

      Conclusion

      Our updated analysis confirmed patients with HPD as a distinct category that performs significantly worse than other groups, including P patients. The incidence of HPD in our cohort is relevant. The ICIs’ detrimental effect has to be taken into account and further investigated.

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    PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track:
    • Presentations: 1
    • Now Available
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      PL02.04 - Blood MicroRNA and LDCT Reduce Unnecessary LDCT Repeats in Lung Cancer Screening: Results of Prospective BioMILD Trial (Now Available) (ID 907)

      08:00 - 10:15  |  Author(s): Gabriella Sozzi

      • Abstract
      • Presentation
      • Slides

      Background

      The National Lung Screening Trial (NLST) showed that lung cancer (LC) screening by three annual rounds of low-dose computed tomography (LDCT) reduced lung cancer mortality, and MILD trial provided additional evidence that extended intervention beyond 5 years, with annual or biennial rounds, enhanced the benefit of screening. The new bioMILD trial tested the additional value of blood microRNA (miRNA) assay at the time of LDCT on a large series of volunteers, with the aim of targeting next LDCT intervals on the basis of individual risk profile.

      Method

      BioMILD trial offered a lung cancer screening program combining LDCT and blood microRNA assay, to heavy smokers (current or former ≤10 years) aged 50-75 years (clinicaltrials.gov ID: NCT02247453). At baseline, LDCT and miRNA were tested independently with blind evaluation, choosing a 3-year interval for the next repeat in participants with double negative LDCT and miRNA.

      Result

      From January 2013 to March 2016, bioMILD prospectively enrolled 4,119 volunteers at Istituto Nazionale Tumori of Milan. The median age was 60 years, median pack-years 42, current smokers 79% and females 39%. According to baseline LDCT and miRNA profile, 2384 subjects (58%) with double negative LDCT and miRNA (2neg) were sent to 3-year LDCT repeat, 1526 (37%) with positive miRNA or indeterminate/positive LDCT (1pos) and 209 (5%) with positive miRNA and indeterminate/positive LDCT (2pos) were sent to annual or shorter LDCT repeat, depending on LDCT results. After four screening runs (LDCT 0/1/2/3), a total of 115 LCs were diagnosed (2.8%). Cumulative LC incidence was significantly different in the three groups: 0.6% for 2neg subjects, 3.8% for 1pos and 20.1% for 2pos (p<0.0001); LC mortality was 0.1%, 0.6% and 3.8% respectively (p<0.0001). Interval cancer incidence, proportion of stage I and resected LC were not statistically different among groups.

      Conclusion

      The combination of microRNA assay and LDCT is a valuable and safe tool to assess individual risk profile and reduce unnecessary LDCT repeats in lung cancer screening. Targeting LDCT intervals on individual risk profile did not cause any detrimental effects on LC detection or mortality.

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