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Etienne Rouleau



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    MA16 - Novel Mechanisms for Molecular Profiling (ID 917)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD
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      MA16.09 - Feasibility, Clinical Relevance of ALK/ROS1 Fusion Variant Detection by Liquid Biopsy in Advanced Non-Small Cell Lung Cancer (ID 13492)

      14:30 - 14:35  |  Author(s): Etienne Rouleau

      • Abstract
      • Presentation
      • Slides

      Background

      Liquid biopsy offers an alternative non-invasive approach to reflect the tumor genomic landscape of NSCLC patients; however, the potential of liquid biopsies for ALK/ROS1 fusion detection is poorly described. Herein, we evaluated an amplicon-based NGS assay for ctDNA detection of ALK and ROS1 fusions in a large cohort of ALK and ROS1 NSCLC patients and correlation of variants with clinical data.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      ALK- and ROS1-translocated advanced NSCLC patients, were prospectively enrolled from October 2015 to April 2018 in 9 French institutions. ALK or ROS1 positivity was as confirmed by immunochemistry and FISH or RNAseq. ALK (EML4 variants v1, v2, v3), ROS1 (CD74, SLC34A2, SDC4 and EZR) fusions, and mutations in a panel of 36 NSCLC-associated genes were investigated in ctDNA using InVisionFirst™ (Plagnol V PLoS ONE, 2018).

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 120 patients were included: 96 ALK and 24 ROS1. 30 samples were collected from patients who were TKI-treatment-naive, 257 during follow-up and 73 at progressive disease (PD) under TKI. The median age was 55 years-old (range 23-75); most patients were female (57%) and had a non-smoking history (59%). At diagnosis, 20% of patients presented with brain metastasis. All patients received at least 1 ALK-TKI (median: 1.6; range:1-6).

      Preliminary results are available for the first 54 patients: 21 at diagnosis and 33 at PD under TKI. ALK/ROS1 fusions were detected in 13/21 patients (62%) at diagnosis: 12/20 ALK-fusions (7 v1, 2 v2 and 3 v3) and in 1/1 ROS1-fusion (CD74-ROS1). No fusion was detected in 8 patients, which may be due to partner genes or variants not covered by this panel. However, 5 of these 8 patients had exclusive thoracic or brain PD.

      Liquid biopsies collected at the radiographic evaluation under therapy revealed complete ctDNA clearance of the fusion when patients experienced PR (n=4). In samples at PD, fusion was detected in 44% of patients (24/55) with evidence of acquired resistance in patients both positive and negative for fusion.

      Results for the remaining samples, correlation between fusion variant and survival, fusion variant and mechanism of resistance will be presented at the Congress.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results suggest that ctDNA profiling is a promising non-invasive tool for identification of ALK/ROS1 fusions and monitoring of response in advanced NSCLC patients. Systematic identification of the fusion partner may help to better understand the heterogeneity and evolution (sensitivity profile to targeted inhibitors and associated-mechanisms of resistance) of NSCLC driven by ALK and ROS1 rearrangement.

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-67 - Clinical Relevance of ALK/ROS1 Resistance Mutations and Other Acquired Mutations Detected by Liquid Biopsy in Advanced NSCLC Patients (ID 14279)

      16:45 - 18:00  |  Author(s): Etienne Rouleau

      • Abstract

      Background

      Liquid biopsies (LB) for circulating tumor DNA (ctDNA) can be a tool for somatic mutation detectionin NSCLC patients. However, the applicability and clinical relevance of ALK/ROS1 and other acquired mutation detected by LB is poorly described. We evaluated ALK/ROS1 and other acquired mutations detected by ctDNA in a large cohort of ALK/ROS1+ NSCLC patients described to date.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Advanced ALK/ROS1+ NSCLC patients were prospectively enrolled from October 15 to April 2018 in 9 French institutions. ctDNA anlaysis was performed using ctDNA using InVisionFirst™ (36-gene panel) for ALK (EML4 variants v1, v2, v3), ROS1 (CD74, SLC34A2, SDC4 and EZR) fusions, and other somatic mutations.

      4c3880bb027f159e801041b1021e88e8 Result

      120 patients were included: 96 ALK, 24 ROS1. The median prior tyrosine kinase inhibitors (TKI) received was 2 (0-4). Blood samples (n=402) were collected: tyrosine kinase inhibitors (TKI)-naive (n=30), during (n=257) or at progression (PD) under TKI (n=73. Prior treated patients received at least 1 TKI (1-6). Preliminary results are available for the first 54 patients; ALK/ROS1 status was confirmed by ALK IHC (39), FISH (56) and RNAseq (2).

      ALK mutations were detected in 36% of blood samples at PD to TKI (12/33): 8% (1/13) post-crizotinib and 55% (11/20) post next-generation TKI (F1174/F1174V/D1203N/R1192P/G1202R (6)/F1174L+G1202/G1202R+F1174L+C1156Y). Complex ALK mutations were observed in 2/12 samples (17%) post next-generation TKI (G1202R+F1174L+C1156Y/F1174L+G1202R). Other acquired mutations were found in 36% (12/33) of samples at PD: TP53 (10), NFE2L2 (4), PTEN (2), PI3KCA (1), CDKN2A (1). Complex ALK mut.+ non-ALK mut. were found in 6/33 (18%) samples, 1 post crizotinib (G1269A+R1264K+L1196Q+F1164L+C1156Y+NFE2L2(4)), and 5 samples post next-gen TKI (G1202R+PTEN/G1202R+TP53/F1174L+G1202R+TP53/TP53(2)+D1203N/TP53+R1192P). Non-ALK mut. were exclusive and could explain TKI resistance in 6/33 (18%) samples.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Routine liquid biopsies can assess the heterogeneity of the TKI resistance, detecting ALK resistance and other acquired mutations in pretreated advanced ALK & ROS1 NSCLC patients. This could have an impact on clinical outcomes. The association of ALK mut. and complex ALK mut. +/- other acquired mut. with clinical outcomes will be presented at the congress.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.03 - Biology (Not CME Accredited Session) (ID 969)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.03-27 - Somatic BRCA1/2 Mutations in Advanced NSCLC Patients: Description of a Sub-Population from the Ongoing Unicancer SAFIR02-Lung / IFCT-1301 Trial (ID 13332)

      12:00 - 13:30  |  Author(s): Etienne Rouleau

      • Abstract
      • Slides

      Background

      Molecular profiling is considered standard of care in advanced NSCLC. Identification of druggable molecular alterations may enhance the percentage of patients suitable for personalized treatment.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From 04/2014 to 03/2017, 602 newly diagnosed,advanced NSCLC patients (pts) were enrolled in SAFIR02-Lung trial (NCT02117167). Molecular profile provided information on copy number alterations and mutations on 71 oncogenes and tumor suppressor genes. The profile was performed for 420 pts (70%) on archival tissue or frozen tissue collected from a new biopsy performed before the 3rd cycle (tissue or liquid) of chemotherapy. The frequency of BRCA mutation (mut) was assessed and clinicopathologic data collected. A homologous recombinant deficiency (HRD) score was performed on the copy number variations (CNV) data and the germline status was based on blood analysis. The BRCAshare database was the reference for the variants classification.

      4c3880bb027f159e801041b1021e88e8 Result

      18 pts were identified with BRCA alterations. BRCA variants of unknown significance were detected in 11 pts (2.6%). Response to chemotherapy according to RECIST 1.1 by investigator was: 6 stable disease (SD), 1 partial response, and 4 progressive disease (PD). CNV profile was evaluable for HRD in 6 out of 11 pts, with 50% positive.

      Seven pts (1.7%) were identified with deleterious BRCA-mut. 2 pts (0.5%) harboured germline BRCA2-mut (1 with breast cancer familiar history). Both pts had SD to chemotherapy. Somatic BRCA-mut was identified in 5 pts (1.2%, 2 BRCA1- and 3 BRCA2-mut). All were male, 100% adenocarcinoma, 75% smokers of 40 pack/year, 1 pt with familial cancer history, and 80% of pts had bone metastases. Response to chemotherapy was: 4 SD, and 1 PD. Three of 7 corresponding CNV profiles were evaluable for HRD score analysis with 100% positive.

      N=420

      BRCA alterations (N=18)

      BRCA VUS

      N=11

      BRCA deleterious

      N=7

      Somatic

      6

      5

      Germline

      5

      2

      HRD positive- Somatic

      Germline

      3/6*

      2

      1

      3/3*

      3

      0

      VUS: variants of unknown significance

      *Amongst patients with available samples for analysis
      8eea62084ca7e541d918e823422bd82e Conclusion

      Pathogenic BRCA1/2 mutations occur in 1.7% of advanced NSCLC with 71% of somatic mutations suggesting its value for exploring new therapeutic strategies in this population

      6f8b794f3246b0c1e1780bb4d4d5dc53

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