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Ludovic Lacroix



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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): Ludovic Lacroix

      • 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: 2
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-19 - Efficacy of Tyrosine Kinase Inhibitors in EGFR Mutated Non-Small Cell Lung Cancer with Leptomeningeal Metastases. (ID 13820)

      16:45 - 18:00  |  Author(s): Ludovic Lacroix

      • Abstract
      • Slides

      Background

      Leptomeningeal dissemination (LM) in patients with non-small cell lung carcinoma (NSCLC) is usually associated with dismal prognosis. However, survival data and optimal management of tyrosine kinase inhibitors (TKI) in EGFR-mutated (EGFRm) patients (pts) are unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Pts with EGFRm NSCLC with LM treated in 2 institutions were included. Clinical, pathological and radiological data were retrospectively collected. We performed overall survival (OS) analysis from LM diagnosis. We assessed survival, clinical response rate (CRR) and disease control rate (DCR; stable disease > 2 months or clinical response) in patients who received a subsequent TKI after experiencing LM progression with first-line TKI.

      4c3880bb027f159e801041b1021e88e8 Result

      Seventy pts were included between Apr. 2003 and Feb. 2018. Median age was 54 [26-79], 60 (85%) were non-smokers, 51 (73%) female and median number of prior systemic treatments before LM diagnosis was 2 [1-7].

      Median OS from LM diagnosis was 7 months (m) [95% CI 6-9], with a 1 year-OS of 29%. Pts received a median of 2 [1-6] lines of subsequent systemic therapy and 19 had additional intrathecal treatment.

      At first LM progression, 40 pts received subsequent TKI treatment with a median PFS of 3m [95% CI 2-not reached]. DCR and CRR were 73% and 38%, respectively. In patients without T790M mutation (N=36), median OS was 7 months [95% CI 4-7] with 2nd-line erlotinib (N=21) and 3 months [2-17] with 2nd-line afatinib or gefitinib (N=5). Eight patients received high-dose erlotinib as 2nd-line treatment after prior erlotinib with a median OS of 3 months [1-3] and a DCR of 75%. Four patients with T790M mutation received 2nd-line osimertinib with a median OS of 10 months [6-10] and a DCR of 100%.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pts with LM from EGFRm NSCLC have prolonged survival with 1st generation TKI. Second-line erlotinib after LM progression is an efficient approach in T790M-negative pts. Erlotinib dose increase is a suitable strategy in erlotinib-refractory T790M-negative pts.

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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): Ludovic Lacroix

      • 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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    P1.09 - Pathology (Not CME Accredited Session) (ID 941)

    • 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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      P1.09-17 - CTNNB1 (Beta-Catenin) Mutations in Non-Small Cell Lung Carcinoma: A Clinicopathological Study of 18 Cases (ID 12163)

      16:45 - 18:00  |  Author(s): Ludovic Lacroix

      • Abstract
      • Slides

      Background

      Beta-catenin, encoded by the CTNNB1 gene, plays an important role in a signaling pathway of progenitor cell proliferation and differentiation. Mutations of CTNNB1 are oncogenic in several tumor types and are often associated with a nuclear abnormal expression. However, such mutations have only rarely been reported in non-small cell lung carcinomas and their clinical signification is not well described. Otherwise, beta-catenin expression by immuno-histochemistry has been described as a prognostic factor in non-small cell lung carcinomas.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Our study was conducted on 18 CTNNB1-mutated non-small cell lung carcinomas. Tumors were routinely tested by next generation sequencing for mutations in exon 3 of CTNNB1 gene. Fifteen cases (2.6%) were from a series of 568 consecutive and contributive analyses performed between January 2017 and March 2018, on 417 adenocarcinomas, 60 squamous cell carcinomas and 91 large cell carcinomas. The 3 other cases dated from before this series. The hospital files of the 18 patients and pathological data from surgical samples (n=11), small biopsies (n=3) and trans-bronchial fine needle aspirations (n=4) were reviewed. Immuno-histochemistry was performed with an anti-beta-catenin antibody.

      4c3880bb027f159e801041b1021e88e8 Result

      There were 6 female and 12 male patients aged 54 to 83 (mean = 66). Six of the 18 patients were non-smokers (< 5 pack-years). There were 17 adenocarcinomas and 1 squamous cell carcinoma. Most adenocarcinomas were TTF1-positive (16/17) and had a papillary component accounting for more than 30% of their volume (n=11). Eight cases (44%) with CTNNB1 mutations showed associated EGFR mutations including exon 19 deletion (n=5) and L858R (n=2). Oncogenic KRAS mutations were only found in 3 cases (17%). The frequency of CTNNB1 mutations among EGFR mutated adenocarcinomas was 9% (7/79). The most frequent CTNNB1 mutations were S37F (n=7) and S45P (n=4). Immuno-histochemistry showed normal membrane expression with no nuclear or cytoplasmic abnormal expression in all cases.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study shows that CTNNB1 mutations are rare in non-small cell lung carcinomas and mostly occur in TTF1-positive adenocarcinomas with a papillary pattern. These mutations are similar to those observed in other tumor types but they probably do not play the same oncogenic role. Furthermore, in lung carcinomas, CTNNB1 mutations were often associated with EGFR mutations and may interfere in the mechanism of resistance to tyrosine kinase inhibitors. This should be thoroughly investigated in larges series evaluating the degree of response to EGFR tyrosine kinase inhibitors.

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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): Ludovic Lacroix

      • 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.

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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): Ludovic Lacroix

      • 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

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