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J. Remon



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    MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      MA 05.03 - The Early Monitoring of Derived Neutrophil-To Lymphocyte Ratio (dNLR) Could Be a Surrogate Marker of Benefit of Immunotherapy in NSCLC  (ID 10147)

      15:45 - 17:30  |  Author(s): J. Remon

      • Abstract
      • Presentation
      • Slides

      Background:
      Baseline high derived NLR (dNLR>3, neutrophils/(leucocytes-neutrophils) ratio) has recently correlated with no benefit to immune checkpoint inhibitors (ICI) in advanced NSCLC, but the dynamic monitoring of dNLR has not been assessed in this population.

      Method:
      dNLR at baseline, at 2[nd] cycle and at progressive disease were retrospectively collected in advanced NSCLC patients treated with ICI from November 2012 to April 2017, in a multicentric cohort (N= 292) from 4 European centers. The primary endpoint was overall survival (OS), and secondary endpoints were progression free survival (PFS), response rate (RR) and disease control rate (DCR).

      Result:
      Out of 292 patients (67%) were males, 264 (92%) smokers and 239 (83%) with PS ≤1, with median age 64 years; 153 (52%) had adenocarcinoma and 114 (30%) squamous; 44 (15%) were KRASmut, 11 (4%) EGFRmut and 3 (1%) ALK positive. PDL1 was ≥ 1% by immunohistochemistry in 67 (76%), negative in 21 (24%) and unknown in 204 patients. The median of prior lines was 1 (0-10). The median follow-up was 12 months (m) [11-14]. The median PFS and OS were 4m [3-5] and 11m [9-15]. Baseline dNLR was>3 in 106 patients (36%) and at 2[nd] cycle in 90 patients (32%). dNLR>3 at baseline and at 2[nd] cycle were associated with poor PFS (p<0.0001 and p=0.0008, respectively), poor OS (both p<0.0001) and progressive disease (p=0.002 and p=0.005, respectively). At 2[nd] cycle of ICI, the dNLR status (> high or ≤ 3 low) changed in 63 patients: in 38 (14%) dNLR decreased; in 25 (9%) dNLR increased. According to the dNLR monitoring (combining dNLR at baseline et at 2[nd] cycle), the median OS was 17m (95%CI 13-NA) when dNLR remained low (n=153), 10m (95%CI 7-NA) when dNLR changed (n=64) and 4m (95%CI 3-7) when dNLR remained high (dNLR>3, n=64, p<0.0001).The dNLR monitoring was also associated with PFS (p=0.002), RR and DCR (p=0.003 and p=0.013, respectively).

      Conclusion:
      Monitoring dNLR at baseline and at 2[nd] cycle could be a routinely tool to early assess benefit to ICI in NSCLC patients on treatment. The dNLR monitoring showed a strong correlation with OS and PFS. Modification of dNLR between baseline and 2[nd] cycle impacts outcomes in NSCLC patients treated with ICI.

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    MA 11 - Emerging Diagnostic/Biomarkers in NSCLC (ID 668)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA 11.01 - Liquid Biopsies for Monitoring BRAF Mutation (V600E) in Advanced BRAF (V600E) Non-Small Cell Lung Cancer (NSCLC) (ID 10232)

      11:00 - 12:30  |  Author(s): J. Remon

      • Abstract
      • Presentation
      • Slides

      Background:
      Circulating tumor DNA (ctDNA) has been shown beneficial in monitoring EGFR mutations in blood, especially for the detection of resistance mutations, like T790M in NSCLC patients. However, the role of BRAF (V600E) ctDNA for monitoring the patient’s response has not been studied yet. The aim of this study was to determine the clinical relevance of BRAF (V600E) ctDNA for monitoring the response to BRAF inhibitors in a prospective cohort of advanced NSCLC BRAF (V600E) patients.

      Method:
      We prospectively enrolled advanced NSCLC patients with BRAF (V600E) treated with BRAF +/- MEK inhibitors in our institution. A blood sample was collected at different time points, including at baseline, during treatment and at progressive disease. ctDNA BRAF analysis was performed using the Inivata InVision platform (enhanced tagged-amplicon next-generation sequencing (eTAM-Seq).

      Result:
      Between June 2016 and June 2017, 14 patients have been included. Eight patients (57%) were females, 9 (64%) non-smokers, with a median age of 63 years (35-70). All the patients had adenocarcinoma and BRAF (V600E) mutation in tissue analysis. Thirteen patients (93%) had stage IV at diagnosis, 7 patients (50%) with bone, 6 (43%) pleural and 4 (29%) lung metastasis. The median of lines of treatment received was 2 (1-4). Thirteen patients (93%) received BRAF + MEK inhibitor and 1 patient (14%) BRAF inhibitor, with an objective response rate of 64% (1 complete, 8 partial response) and disease control rate of 86%. BRAF mutation detection was tested under treatment in 12 patients (86%). Longitudinal analysis was performed from the serial sampling in 6 patients to date: 4 patients (67%) were ctDNA positive for BRAF (V600E) at time of progression, with a range of allelic frequency of 0.11-6.16%. BRAF mutation was not detectable in patients with objective response (2/6, 33%) at time of sample collection(s). Additional BRAF (V600E) NSCLC patient samples are being analyzed.

      Conclusion:
      Liquid biopsy for monitoring BRAF (V600E) using ctDNA appears to be feasible and useful in advanced NSCLC patients. Updated longitudinal results for the complete patient cohort will be presented at the meeting.

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    P1.03 - Chemotherapy/Targeted Therapy (ID 689)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      P1.03-013 - Monitoring of ALK Fusions and Mutations in Advanced ALK Positive Non-Small Cell Lung Cancer (NSCLC) Patients (ID 10208)

      09:30 - 16:00  |  Author(s): J. Remon

      • Abstract

      Background:
      Co-isolated exosomal RNA and cfDNA from plasma can be used for detection of genomic alteration such as EML4-ALK fusion RNA and ALK resistance mutations in NSCLC patients. The clinical utility of this liquid biopsy for response monitoring is under investigation. The aim of this study was to evaluate liquid biopsy as tool for monitoring response to treatment in a prospective cohort of ALK-positive NSCLC patients.

      Method:
      Consecutive ALK positive NSCLC patients treated with systemic therapies in our institution were enrolled. After informed consent, blood samples were prospectively collected for longitudinal analysis during treatment and at progression. Exosomal RNA and cfDNA co-isolated from plasma was used for detection of EML4-ALK fusion RNAs by the qPCR-based ExoDx Lung(ALK)™-test as well as for analysis of ALK-resistance mutations by ExoDx NGS sequencing.

      Result:
      From Aug 2016 to date, 23 patients were enrolled in the study, 14 (61%) were females, 15 (65%) non-smokers, median age of 50 years (23-76). All patients had adenocarcinoma and were tissue positive for ALK by immunohistochemistry 14 (61%) and/or FISH 16 (70%). Nineteen patients (83%) had stage IV disease at diagnosis, with brain involvement in 7 patients (37%), bone in 11 (48%) and liver in 2 (11%). The median number of ALK inhibitors received was 2 (0-4). Twenty-one patients (91%) received ALK inhibitors (5 crizotinib, 3 ceritinib, 13 next-generation inhibitors) and 2 chemotherapy, with an objective response rate of 48%. Five out of 8 patients (63%) that were treatment naïve (baseline) or progressive disease (PD) at the time of collection, were positive for EML4-ALK by liquid biopsy, 1 of 4 samples (25%) at baseline, and 4 of 4 samples (100%) at PD, were positive by liquid biopsy. EML4-ALK variant 1 was detected in two (40%) and variant 3 in three patients (60%). All 26 samples collected during objective response or stable disease (100%) were negative for EML4-ALK by liquid biopsy. The ALK resistance mutation panel was performed on 2 samples from patients with PD, and both were detected positive for ALK resistance mutations, L1196M (variant 1) and G1202R (variant 3), respectively.

      Conclusion:
      The monitoring of ALK fusions on exosomal RNA by liquid biopsy is applicable in the clinic and closely correlated to disease control. ALK mutations detection using liquid biopsy can be an accurate tool for assessing the resistance to ALK inhibitors. Updated results from up to 30 patients will be available for the final presentation.

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    P2.07 - Immunology and Immunotherapy (ID 708)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      P2.07-060 - Response Assessment and Subgroups Analysis According to the Lung Immune Prognostic Index (LIPI) for Immunotherapy in Advanced NSCLC Patients (ID 10179)

      09:30 - 16:00  |  Author(s): J. Remon

      • Abstract

      Background:
      LIPI is a score that combine dNLR (neutrophils/(leucocytes-neutrophils) and lactate dehydrogenase (LDH) and correlate with prognosis of NSCLC patients treated with immune checkpoint inhibitors (ICI). We report the predictive role of LIPI on response and in various subgroups of patients.

      Method:
      Baseline dNLR and LDH were retrospectively collected in 431 patients treated with ICI from Nov. 2012 to Jan. 2017, from 8 European centers. LIPI delineates 3 groups: good (dNLR<3+LDH3 or LDH>ULN), poor (dNLR>3+LDH>ULN). Response rate (RR) and disease control rate (DCR) were assessed according to the investigator’s criteria. The subgroup analysis was performed according to the age, histology, performance status (PS) and PD-L1 status by immunohistochemistry (positivity if ≥ 1% on tumor cells).

      Result:
      With a median follow-up of 12.8 months (m.) [95%CI 11.9-14], 431 patients were included. Baseline characteristics are summarized in table 1. The median overall survival (OS) and progression-free survival (PFS) were 10.5m. [95%CI 9.5-13] and 3.9m. [3-4.4], respectively. The median OS was 4.8m. vs. 10 m. vs. 16.5m., and median PFS was 2m. vs. 3.1m. vs. 5m. for the poor, intermediate and good LIPI groups, respectively (both p<0.0001). LIPI was correlated with response rate (p<0.0001). In multivariate analysis, the intermediate and poor group were associated with progressive disease, with an OR of 2.20 [CI95% 1.26-3.84] p=0.005) and an OR of 3.04 [CI95% 1.46-6.36] p=0.003), respectively. LIPI was correlated with OS, regardless the age (<70 years (p<0.0001) vs. older (p=0.0006) and the histology non-squamous (p<0.0001) vs. squamous (p=0.02). In PS 0-1 and in smoker population, LIPI correlated with OS (both p<0.0001), but not in PS ≥2 (12%) and non-smokers (8%). LIPI was correlated with OS for positivity (p=0.01) and unknown PD-L1 (p=0.0001), but not negativity.

      LIPI 0 Good (N=162, 37%) LIPI 1 Intermediate (N=206, 48%) LIPI 2 Poor (N= 63, 15%) All population cohort N = 431 (%)
      Sex
      Male 102 (63) 131 (64) 42 (67) 275 (64)
      Age at diagnosis
      Median (years, range) 62 (36;86) 63 (29;86) 62 (39;84) 62 (29;86)
      Smoking status
      Non-smoker 13 (8) 18 (9) 5 (8) 36 (8)
      Former 80 (49) 115 (56) 46 (73) 241 (56)
      Current 67 (42) 69 (33) 11 (17) 147 (34)
      Unknown 2 4 1 7
      Histology
      Non-squamous 111 (69) 132 (64) 41 (65) 284 (66)
      Squamous 51 (31) 74 (36) 22 (35) 147 (34)
      Molecular alteration
      EGFR mutation 3 (2) 13 (6) 3 (5) 19 (4)
      ALK rearrangement 2 (1) 2 (1) 1 (2) 5 (1)
      KRAS mutation 34 (21) 31 (15) 8 (13) 73 (17)
      PDL1 status
      Negative 16 (36) 14 (25) 1 (5) 31 (25)
      Positive 28 (64) 43 (75) 20 (95) 91 (75)
      Unknown 118 149 42 337
      Performance Status
      0 51 (32) 45 (22) 10 (16) 106 (25)
      1 96 (60) 132 (64) 42 (67) 270 (63)
      ≥ 2 12 (8) 28 (14) 11 (17) 51 (12)
      Stage at diagnosis
      IIIb 18 (11) 33 (16) 14 (22) 65 (15)
      IV 101 (62) 135 (66) 38 (60) 274 (64)
      Metastases sites
      Median (Range) 2 (0;6) 2 (0;7) 2 (1;7) 2 (0-7)
      Bone 43 (27) 58 (28) 20 (32) 121 (28)
      Liver 28 (17) 39 (19) 16 (25) 83 (19)
      Brain 22 (14) 19 (9) 9 (14) 50 (12)
      Immunotherapy
      PD1 inhibitor 133 (82) 167 (81) 48 (76) 348 (81)
      PDL1 inhibitor 19 (12) 34 (17) 12 (19) 65 (15)
      PDL1 inhibitor- CTLA4 inhibitor 10 (6) 5 (2) 3 (5) 18 (4)
      Immunotherapy line
      Median (Range) 2 (1;11) 2 (1;12) 2 (1;8) 2 (1-12)
      Response rate
      Complete response (CR) 6 (4) 3 (1) 0 (0) 8 (2)
      Partial response (PR) 42 (26) 53 (26) 18 (28) 113 (26)
      Stable disease (SD) 66 (41) 59 (29) 8 (13) 133 (31)
      Progression 40 (25) 81 (39) 33 (52) 154 (36)
      NA 8 10 4 25
      Dissociated response 14 (9) 15 (7) 2 (3) 31 (7)


      Conclusion:
      Baseline LIPI predicts response to ICI, and was correlated with OS regardless of age and histology.