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Cecile Jovelet



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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): Cecile Jovelet

      • 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 InVisionFirstâ„¢ (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): Cecile Jovelet

      • 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 InVisionFirstâ„¢ (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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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-24 - Prospective Efficacy of Osimertinib in Circulating Tumour DNA (ctDNA) T790M-Mutant NSCLC Patients (ID 14031)

      16:45 - 18:00  |  Author(s): Cecile Jovelet

      • Abstract
      • Slides

      Background

      Liquid biopsy circulating tumor DNA (ctDNA) analysis in advanced EGFR-mutant NSCLC patients is an approved tool for molecular profiling and disease surveillance when tissue is not available. Long-term efficacy of osimertinib in patients with the T790M resistance mutation positive detected only by ctDNA (without tissue information) has not been fully validated.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In a prospective study, EGFR-mutant advanced NSCLC patients with acquired resistance to EGFR TKI, in whom a repeat tissue biopsy was not feasible, were assessed for ctDNA T790M mutational status using InVisionSeqTM. T790M-positive NSCLC patients received osimertinib (80 mg daily; extended access program or approval) at RECIST progression. The objectives were to assess: proportion of patients with acquired ctDNA-T790M positive; overall survival (OS) of the overall EGFR-mutant population as well as OS comparison for T790M +ve/-ve. Also, for those T790M-positive NSCLC patients who received osimertinib in a real world data we assessed: response rate (RR) according to RECIST 1.1 by investigator and progression free survival (PFS), calculated from the date of osimertinib initiation until the date of progression or death (whichever came first), or the date of last follow-up are also reported.

      4c3880bb027f159e801041b1021e88e8 Result

      We recruited 82 patients (71% female, median age 64 years, 72% Del19 EGFR mutation, 71% never-smokers). The ctDNA T790M mutation was detected in 55% (N=45) of NSCLC patients. Median OS of EGFR-mutant population was 38.2 months (mo.). According to T790M status, median OS was 41.2 months and 30.4 mo. for T790M-positive and T790M-negative NSCLC patients, respectively. Both cohorts had already received a median of 3 previous treatment lines. In 40 T790M-positive NSCLC patients who receive osimertinib, RR was 55% (PR: 55%, SD 27.5% and PD: 12.5%) and median PFS of 8.5 mo. Median OS on osimertinib among 10 patients with brain and/or leptomeningeal metastases at baseline was of 13.4 months.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In patients with acquired resistance to first- or second-generation EGFR TKIs, ctDNA T790M detection by InVisionSeqâ„¢ is equivalent to what has been reported in tissue biopsy. Osimertinib has clinical benefit in patients for which the T790M resistance mutation is detected only through a liquid biopsy procedure.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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