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Ernest Nadal



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    FP07 - Pathology (ID 109)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP07.06 - Lung Immune Prognostic Index (LIPI) in Advanced NSCLC Patients Treated with Immunotherapy, Chemotherapy and both Combined Upfront. (ID 823)

      00:00 - 00:00  |  Author(s): Ernest Nadal

      • Abstract
      • Slides

      Introduction

      The Lung Immune Prognostic Index (LIPI) that combines the neutrophils/[leucocytes minus neutrophils] ratio (dNLR) and lactate dehydrogenase (LDH), is associated with outcomes in pretreated advanced NSCLC patients receiving single agent immune checkpoint inhibitors (ICI). However, its role in first line treatment of advanced NSCLC patients has not been explored yet. We assessed the value of baseline LIPI in the first line setting, for ICI-monotherapy, ICI-combination or platinum-based chemotherapy alone (CT).

      Methods

      We retrospectively collected data of patients treated with first-line ICI between 2016 and 2019 as single agent if PD-L1 ≥50% (ICI-cohort), or in combination with a CTLA4-inhibitor (ICI+ICI cohort), or with chemotherapy (ICI+CT cohort), from 18 centers worldwide. A control cohort of patients treated with platinum-based CT (CT-cohort) was also collected between 2011 and 2019 from 2 centers. Baseline LIPI was calculated as previously reported and correlated with overall survival (OS) and progression-free survival (PFS) in each treatment cohort.

      Results

      Overall, 930 patients were enrolled, 561 in the ICI-cohort, 186 in the combo ICI+CT, 55 in the ICI+ICI and 128 in the CT-cohort. Median (m) follow-up was 12.5 months. In the whole cohort, median age was 66 years, 70% male, 80% had non-squamous histology, and 84% had PS ≤1. Based on LIPI (available for 792 patients): 305 (38%) were considered good, 331 (42%) intermediate and 156 (20%) poor group.

      Treatment outcomes according to LIPI scores are depicted in Table 1. The LIPI poor population had significantly worse OS compared with other LIPI groups, in the whole cohort (P<0.001) as well as in the ICI monotherapy and combo ICI+CT cohorts (both P<0.0001); and in the CT cohort (P=0.004). In term of PFS, we observed correlation between LIPI groups and outcomes in the whole cohort (P<0.001) and in the ICI- monotherapy cohort (P=0.008); however, no differences were observed in the cohorts of patients receiving chemotherapy regimens, alone (P=0.08) or combined with ICI (P=0.08). The analysis by PD-L1 expression in 756 patients with available data will be presented in the Congress.

      Table 1: Median OS and PFS according to LIPI subgroups. NR = non reached.

      Outcomes

      LIPI

      subgroups

      Overall cohort

      N= 925

      ICI-cohort

      N=558

      ICI + CT-cohort

      N= 185

      ICI + ICI cohort

      N= 55

      CT-cohort

      N=127

      Median OS

      (95% CI)

      All

      16.3 (14.7-18.8)

      21.0 (17.1-NR)

      24.7 (16.9-27.1)

      20.5 (14.1-NR)

      9.79 (8.3-14.4)

      LIPI good, 38.5%

      19.8 (17.2-25.7)

      NR (NR-NR)

      25.7 (25.6-NR)

      33.6 (14.7-NR)

      14.42 (8.9-17.9)

      LIPI interm, 41.8%

      15.8 (14.3-20.3)

      21.2 (17.1-NR)

      20.3 (12.8-NR)

      14.6 (5.5-NR)

      9.30 (7.0-14.5)

      LIPI poor, 19.7%

      6.96 (5.6-12.5)

      8.5 (3.4-13.7)

      6.1 (4.9-NR)

      14.1 (10.3-NR)

      6.1 (5.0-NR)

      Global LogRank P value

      <0.0001

      <0.0001

      <0.0001

      0.4

      0.004

      Overall cohort

      N= 909

      ICI-cohort

      N=543

      ICI + CT-cohort

      N= 185

      ICI + ICI cohort

      N= 54

      CT-cohort

      N=127

      Median PFS

      (95% CI)

      All

      6.5 (5.9-7.1)

      6.3 (5.0-7.6)

      8.9 (6.80-10.9)

      7.2 (5.7-30.6)

      5.7 (5.3-6.4)

      LIPI good, 38.7%

      7.0 (5.9-8.5)

      6.4 (4.5-10.8)

      9.8 (7.8-13.0)

      9.2 (5.7-NR)

      6.0 (5.3-7.8)

      LIPI interm, 41.6%

      6.6 (6.1-7.6)

      6.6 (5.6-8.1)

      10.4 (6.4-12.4)

      5.5 (2.5-NR)

      6.1 (4.3-7.6)

      LIPI poor, 19.7%

      3.6 (3.1-5.6)

      3.3 (1.9-6.7)

      4.5 (2.8-8.2)

      7.1 (2.56- NR)

      3.7 (3.4-NR)

      Global LogRank P value

      <0.0001

      0.008

      0.08

      0.4

      0.08

      Conclusion

      Pretreatment LIPI was prognostic in untreated advanced NSCLC patients regardless of the type of therapy. However, LIPI was associated with PFS only in patients receiving ICI-monotherapy, with no statistically significant differences in CT-containing cohorts (alone or combined with ICI). This value of LIPI to guide treatment selection should be further explored in prospective studies.

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    FP12 - Tumor Biology and Systems Biology - Basic and Translational Science (ID 188)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP12.09 - Molecular Insight into NADIM Clinical Trial: Potential Immune Biomarkers of Pathological Response for NSCLC Patients. (ID 3552)

      00:00 - 00:00  |  Author(s): Ernest Nadal

      • Abstract
      • Presentation
      • Slides

      Introduction

      Many studies have demonstrated that chemo-immunotherapy is a promising approach for NSCLC patients but still exists a lack of prediction biomarkers of survival. We have recently showed that pathological response is a surrogate of progression free survival (PFS) including infiltrating immune cells as potential biomarker of pathological response in NADIM clinical trial (Provencio et al., 2020. Lancet Oncology, in press).

      New biomarkers in peripheral blood are being described, focused on the immune system response. Preliminary data was presented at WCLC 2019 however additional results are included in this report. Here we describe the effect of chemo-immune neoadjuvant treatment on resectable NSCLC stage III patients’ immune system and describe blood biomarkers that could help to identify responders to this combination therapy.

      Methods

      Peripheral mononuclear cells (PBMCs) and plasma from NADIM clinical trial patients before and after chemo-immune neoadjuvant treatment were used. Phenotyping and activation levels of immune cell populations were analyzed by flow cytometry, focused on CD4 T cells, CD8 T cells, T cells NK like and NK cells. Moreover, characterization of the immune response was evaluated by a cytokine array.

      Clinical evaluation of pathological response, classified patients in 3 groups, complete (CPR, 0% tumor cells), major (MPR, <10% viable tumor) and incomplete (IPR, >10% viable tumor). Wilcoxon and Kruskall-Wallis statistic tests were used.

      Results

      Even though we have previously described a decrease of T lymphocytes on tissue after treatment, we do not see these changes on blood. Thus, percentages of PBMCs (T cells, B cells, NK cells and macrophages) did not vary after neoadjuvant treatment. However, lower levels of activated CD4 T cells and NK cells were observed. Interestingly, this decrease was exclusively statistically significant for patients who achieved a CPR, but no differences were observed for MPR or IPR. As expected, detection of PD1+ cells after neoadjuvant Nivolumab (anti-PD1) treatment was almost completely abrogated, however, a trend for higher PD1+ cell proportions was observed in patients achieving CPR at diagnosis.

      Furthermore, many cytokines involved in immune response and described as putative biomarkers for immunotherapy in NSCLC as IL-2, IL-15, IL-6, IL-13 or IFN-gamma, among others, were decreased after neoadjuvant treatment. Notably, stratifying by pathological responses, this decrease was statistically significant only for non-complete responses.

      Conclusion

      The analysis of immune cell markers on blood samples could be a source for potential surrogate markers of pathological response to neoadjuvant treatment on NSCLC patients.

      Similarly, to what occurs in tissue, CPRs showed differences compared to MPR or IPR in some blood markers, both at the cellular and cytokine level. Thus, after treatment, patients achieving CPRs do not seem to reduce their levels of cytokines such as IL-2, IL-15, IL-6, IL-13 or IFN-g associated with anti-tumor response, but they do reduce their levels of activated CD4 and NK cells

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    MA06 - Molecular Developments and Novel Treatments in Mesothelioma and Thymoma (ID 134)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Mesothelioma, Thymoma and Other Thoracic Malignancies
    • Presentations: 1
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      MA06.03 - Phosphorylated Ribosomal Protein S6, Correlation With Characteristics and Clinical Outcome in Patients With MPM: Results from ETOP Mesoscape (ID 2260)

      14:15 - 15:15  |  Author(s): Ernest Nadal

      • Abstract
      • Presentation
      • Slides

      Introduction

      Malignant pleural mesothelioma (MPM) is an aggressive malignancy with increasing prevalence and poor prognosis. The European Thoracic Oncology Platform (ETOP) Mesoscape project was designed to address clinical, pathological, and molecular characteristics of MPM patients and their impact on outcome, along with having formalin-fixed paraffin embedded tumour tissue available for central analysis. In previous studies the phosphorylated ribosomal protein S6 (pS6), which is a downstream target of PI3K /mTORC1 signaling, was associated with clinical outcome, and low pS6 immunoreactivity was significantly correlated with longer progression free survival in other MPM patients. Correlating pS6 with the clinical as well as pathological information in Mesoscape allows researchers to improve the knowledge and facilitate decision-making in patients with MPM.

      Methods

      A biobank with fully annotated tissue samples was established for ETOP Mesoscape, and Tissue Micro Arrays (TMAs) were constructed. Expression of phospho-S6 (p-S6, Ser240/244, Cell Signaling Technology, 1:50 dilution) was explored in the ETOP Mesoscape cohort. Immunohistochemical evaluation of the TMAs was conducted by two independent observers in a blinded manner. The staining intensity was semi-quantitatively scored 0 (negative), 1 (weak), 2 (moderate), or 3 (strong). Furthermore, the percentage of cells with any positivity was proportionally scored 0 (0%), 0.1 (1%–9%), 0.5 (10%–49%), or 1.0 (50% and more). An aggregate H-score was obtained by multiplication of intensity with percentage staining (final range: 0-3 per core). The final H-score was determined by averaging the H-scores of all the cores from the same patient. Patients’ classification as pS6-high/low, was based on median H-score.

      Results

      Up to 14 July 2020, the ETOP Mesoscape included pS6 IHC results on 269 of the 499 patients from 10 centers, diagnosed between 1999-2018. The remaining cases are currently undergoing pS6 scoring.

      Overall, patients in the Mesoscape database are primarily men (84%), of 0/1 ECOG Performance status (46/46%), with known previous exposure to asbestos (75%) and a median age of 64 years. The primary histology of included tumours is epithelioid (72%), followed by biphasic (22%) and sarcomatoid (6%). Clinical staging is available for 77%. The stage distribution (I/II/III/IV) is 14/29/42/15%.

      Calretinin and WT1 are detected in the vast majority of patients tested (Calretinin: 97%; WT1: 89%). Also, 90% (of those tested) are CK5/6 positive, 91% D2-40 positive and 97% Pan-CK positive. Palliative treatment has been administered in 41%.

      PS6-high patients (128 patients with H-score>1.375) are significantly associated with higher age, more T-stage of 3/4, and higher percentage of right localization compared to pS6-low patients (141 patients with H-score≤1.375). Overall survival (OS) is non-significantly different between pS6-low and pS6-high patients (medians: 21.4 months; 95%CI:[15.3-23.4] and 17.8 months; 95%CI:[15.1-20.7], respectively; log-rank p=0.61]. In the multivariate Cox model, pS6 is also non-significant (p=0.31), while gender, histology, and treatment strategy are the only significant survival predictors.

      Conclusion

      Based on preliminary data, high pS6 expression is associated with higher age and T-stage; effect in survival is non-significant. Updated and additional results on the expression and clinical significance of pS6 from the full ETOP Mesoscape cohort will be presented at the conference.

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    P60 - Tumor Biology and Systems Biology - Basic and Translational Science - Immune Bio (ID 198)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 2
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P60.07 - TMB and Selected Mutations in Resectable Stage IIIA NSCLC Patients Receiving Neo-Adjuvant Chemo-Immunotherapy from NADIM Trial (ID 2142)

      00:00 - 00:00  |  Author(s): Ernest Nadal

      • Abstract
      • Slides

      Introduction

      Tumor Mutational Burden (TMB) assessment and identification of specific mutations associated to anti-PD1 blockade therapy resistance have become a novel approach to predict the clinical benefit to anti-PD1/PDL1 therapy. However, the clinical relevance of these parameters in terms of pathological response and PFS in neo-adjuvant chemo-immunotherapy has not been established. To answer this question we analysed samples from the NADIM study (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant chemo-immunotherapy with Nivolumab.

      Methods

      Pretreatment TMB, defined as the number of nonsynonymous variants (missense and nonsense single nucleotide variants (SNVs)), plus insertion and deletion variants (INDELs) detected per megabase (Mb) of exonic sequence, was estimated from 27 patients that had enough diagnostic material for next generation sequencing using the Oncomine Tumor mutation Load assay (ThermoFisher) following manufacturer’s instructions. The panel covers 1.7 Mb of 409 genes with known cancer associations. Regarding pathological responses, patients were classified into 3 groups: pathologic complete response (pCR) (0% viable tumour at any localization tested), major pathologic response (MPR, <10% viable tumour) and pathologic incomplete response (pIR) (>10% of viable tumour). At data analysis, median follow-up time was 22.7 months.

      Results

      Median TMB was 5.89 (range 1.68 – 73.95). No differences in TMB value between histologies (adenocarcinoma vs squamous cell), smoking status (former vs current), age or sex were observed. Somatic mutations were identified in lung cancer driver genes such as TP53, KRAS, EGFR, CDKN2A, NOTCH1, BRAF and in specific genes associated with resistance to immunotherapy such as STK11, KEAP1, and RB1. No genomic alterations in ALK, ROS1, PTEN or ERBB2 were found.

      Based on literature, a poor prognosis mutation signature (presence of EGFR, STK11, KEAP1 or RB1 mutations) was generated. A third of the sequenced patients (9/27) harboured at least one mutation in one of these genes.

      Pathological response data was available from 23 out of 27 patients sequenced. Both the TMB value and the presence of these resistance mutations were not associated with the degree of pathological response.

      Regarding PFS, TMB alone was not predictive of disease progression using different thresholds. However, the presence of these resistance mutations was associated with shorter PFS (log-rank p-value=0.032). The median PFS for mutated patients was 21.4 months (95% CI 16-26 months) while median PFS was not reached in non-mutated patients.

      Additionally, the combination of this mutational signature with TMB (absence of resistance mutations and TMB-Higher than median) was able to distinguish patients that strongly benefit from this therapy. Although the median PFS was not reached in both groups yet, statistically significant differences were observed (log-rank p-value=0.046). PFS at 18 and 24 months was 100% (95% CI not estimable) for Non-mutated patients with TMB-High vs 70% (95% CI 50-89%) and 58% (95% CI 35-81%) for the rest of patients (mutated patients plus Non-mutated patients with TMB-Low).

      Conclusion

      TMB did not predict benefit from chemo-immunotherapy induction in our cohort. However, the presence of EGFR/STK11/KEAP1/RB1 mutations alone, or in combination with TMB, may help identify patients that unlikely benefit from neo-adjuvant chemo-immunotherapy

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      P60.11 - TCR Repertoire Predicts Pathological Response in NSCLC Patients Receiving Neoadjuvant Chemoimmunotherapy from NADIM Trial (ID 3417)

      00:00 - 00:00  |  Author(s): Ernest Nadal

      • Abstract
      • Slides

      Introduction

      Characterization of the T-cell receptor (TCR) repertoire has become a novel approach to monitor immunotherapy responses, however there is lack of knowledge about its clinical relevance as predictive biomarker of pathological response in neoadjuvant chemoimmunotherapy. For this purpose, we analysed samples from the NADIM study (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant Paclitaxel + Carboplatin + Nivolumab for 3 cycles, achieving a 63% of complete pathologic responses (CPR). PD-L1 TPS and TMB as CPR biomarkers showed AUC ROC of 0.77 and 0.55, respectively, reinforcing the need for new biomarkers (Provencio, M. et al. 2020).

      Methods

      TCR repertoires from primary tumours or lymph nodes of 19 NSCLC patients were obtained, at both time points: diagnosis and after neoadjuvant treatment. TCR repertoire was analysed in terms of convergence, diversity, evenness and clonal space, defined as the summed frequency of clones belonging to a frecuency group (top 1%, top 1% to 2%, 2% to 5%, and >5%) relative to the total T-cell repertoire. The results were correlated with pathological response groups and ROC curve analysis was performed to test if TCR repertoire-derived parameters could identify patients with CPR.

      Results

      There were no statistically significant differences observed in TCR repertoire in biopsy samples in terms of diversity (p = 0,797) or convergence (p = 0,202) between the three pathological response groups or between biopsy and surgery samples. However, we observed differences in terms of evenness in biopsy samples between the pathologic response groups (p=0.037), which were lower in those patients who achieved CPR. The AUC for evenness was 0.844 (IC: 0.667-1.000), p=0,011. An evenness value of <0.8639 showed a sensitivity of 50% and specificity of 100% identifying patients with CPR.

      Moreover, the clonal space of the TOP 1% clones in diagnostic samples was higher in patients that achieved CPR (p=0.002). The AUC of this novel biomarker was 0.9667 (IC: 0.897-1.036) (p=0.0006). A TOP 1% clonal space higher than 0.1607 showed a sensitivity of 90% and specificity of 88.9% identifying patients with CPR.

      nadim trasl_tcr_image.jpg

      Conclusion

      Our results support the association between the uneven distribution of T-lymphocytes clones proportions present in the tissue at diagnosis and response to chemoimmunotherapy. Specifically, higher clonal space occupied by the TOP 1% clones seems to outperform PD-L1 and TMB as predictive biomarker of CPR in NSCLC patients receiving neoadjuvant chemoimmunotherapy.

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