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Virginie Westeel



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    MA07 - Clinical Questions and Potential Blood Markers for Immunotherapy (ID 125)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MA07.05 - Immune Checkpoint Inhibitor (ICPi) Re-Challenge: Outcomes Analysis in a French National Cohort of Non-Small-Cell Lung Cancer (NSCLC) Patients (Now Available) (ID 1903)

      13:30 - 15:00  |  Author(s): Virginie Westeel

      • Abstract
      • Presentation
      • Slides

      Background

      Anti-PD1/PDL1 deeply changed the NSCLC therapeutic algorithm in the past few years. Unfortunately, a majority of patients experiences disease progression. ICPis re-challenge could be an attractive option but no data supporting this strategy are available. Here we report outcomes of a large cohort of NSCLC patients treated with anti-PD1/PDL1 re-challenge.

      Method

      We retrospectively collected data about 144 advanced NSCLC patients (diagnosis between 2010 and 2018) from 26 French centers. Patients were re-challenged with ICPis after at least 12 weeks of discontinuation for toxicity, disease progression or clinical decision. Progression Free Survival (PFS) and Overall Survival (OS) were calculated from the start of first or second ICPi to disease progression (PFS1;PFSR) and death or last follow-up (OS1;OS2) respectively.

      Result

      Median age was 63 year [39 –83], most of patients were male (67%), smokers (87%), adenocarcinomas (62%) and stage IV at diagnosis (66%). Most of patients received the first ICPi round in first or second line (66%) and the second ICPi round in third line or later (79%). In both settings patients received preferentially an anti-PD1 (87%) and no differences were detected regarding brain metastasis or ECOG PS (P = 1.10-1 and P = 1.10-1 respectively). The Best Response during the re-challenge was not associated to that one achieved to the first ICPi (P = 1.10-1). The median PFS1 and PFSR were 13 months [95% CI 10-16.5] and 4.4 months [95% CI 3-6.5] respectively. PFSR was longer in patients discontinued because of clinical decision (6.5 months [95% CI 2.5-11.9]) or toxicity (5.8 months [95%CI 3.5-18]) compared to disease progression (2.9 months [95% CI 2.0-4.4]) (P = 2.10-2) and in those not receiving chemotherapy between the two ICPis (5.8 months [95%CI 4.1-10.5]) compared to those who did (3.0 months [95% CI 2.0-4.4])(P = 2.10-3). Median OS1 was 3.3 years [95% CI 2.9-3.9] without differences according to the discontinuation reason (P =2.10-1). Median OS2 was 1.5 y [95%CI 1.0-2.1] and was longer in patients discontinuing the first ICPi due to toxicity (2.1y [95%CI 1.4-NR]) compared to disease progression (1.0y [95%CI 0.4-1.5]) or clinical decision (1.5y [95%CI 0.4-NR]) (P = 3.10-2). Neither OS1 nor OS2 were affected by treatments received between the two ICPis (P = 3.10-1 and P = 1.10-1 respectively).

      Conclusion

      ICPis re-challenge might be a useful option mainly in patients discontinuing the first ICPi because of toxicity or clinical decision and in those able to keep a treatment-free period between the two ICPis.

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    MA14 - The Adequate MTarget Is Still the Issue (ID 140)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA14.12 - Discussant - MA14.09, MA14.10, MA14.11 (Now Available) (ID 3779)

      15:45 - 17:15  |  Presenting Author(s): Virginie Westeel

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA21 - Non EGFR/MET Targeted Therapies (ID 153)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA21.07 - Circulating Tumor DNA Analysis Depicts Potential Mechanisms of Resistance to BRAF-Targeted Therapies in BRAF+ Non-Small Cell Lung Cancer (Now Available) (ID 1365)

      14:30 - 16:00  |  Author(s): Virginie Westeel

      • Abstract
      • Presentation
      • Slides

      Background

      Oncogenic BRAF-V600 mutations are observed in 1-2% of non-small cell lung cancer (NSCLC). Targeted therapies including vemurafenib (V), dabrafenib (D) or combination of dabrafenib plus trametinib (D+T) are associated with favorable outcomes in these patients (pts). The mechanisms of resistance to BRAF-targeted therapies (BRAF-TT) in NSCLC are largely unknown.

      Method

      We performed genomic profiling of serial circulating-tumor DNA (ctDNA) in a cohort of 79 metastatic BRAF-mutant NSCLC pts (96% V600E, 4% non-V600). BRAFmutational status was ascertained based on local testing. Plasma samples were collected, from 2014-2018 in 27 Hospitals, from pts treated with V (n=34), D (n=2) or D+T (n=23). We collected 41 plasma samples at baseline to BRAF-TT, 40 at progressive disease (PD) and ~200 samples during treatment follow-up, concomitant to routine radiological evaluation. Inivata InVisionSeq™ assay was used to detect the presence of SNVs, indels and CNAs in 36-cancer related genes.

      Result

      At baseline, 72,5% of BRAF mutations (V600E and non-V600E) were detected in plasma. BRAF-V600E detection in plasma was associated with the presence of liver metastasis, versus BRAF-V600E-negative cases (22% vs. 7%, respectively). Co-occurring molecular alterations at baseline, besides BRAF-V600E, were observed in 18/26 (70%) cases: FGFR2 (1pt), PIK3CA (2pts), ERBB2 (1pt), CTNNB1 (2pts) and IDH1 (2pts). FGFR2, PIK3CA or CTNNB1 alterations were associated with PD as the best response to the subsequent BRAF-TT. TP53 and STK11 mutations were observed in 54% (14/26) and 8% (2/26) of pts, respectively. Complete clearance of BRAF-V600E in plasma at baseline was observed at the first CT-scan evaluation in 42% (3/7) and 82% (9/11) pts treated with V or D+T, respectively. These pts were in complete or partial response, suggesting that monitoring BRAF-V600E levels in plasma on treatment may be a clinically useful marker of tumor response. At PD, a consistent rebound in BRAF-V600E plasma levels was observed in 60% (24/40) pts. Resistance to V was associated with alterations in the MAPK pathway: 1pt (KRAS), 1pt (GNA11), 1pt (NRAS and GNAS) and 1pt (MAP2K1 and NFE2L2). Activating PI3KCA mutations were observed in 4 pts who progressed in <6 months on V treatment. ctDNA analyses at PD under D+T revealed that, similar to what we observed in patients who progressed on V, alterations in KRAS, NRAS, PIK3CA and CTNNB1 are associated with D+T resistance. Prediction of the impact of these alterations, at the protein level, was assessed using in silico structure modeling and will be presented.

      Conclusion

      ctDNA monitoring might be an informative tool for assessing disease response and resistance in NSCLC pts treated with BRAF-TT. MAPK reactivation remains an important resistance mechanism to BRAFi-monotherapy or to BRAFi and MEKi combination therapy.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-19 - Exome Analysis of Patients Treated with Afatinib Reveals Genetic Variations Discriminating Extreme Responders (Now Available) (ID 2298)

      09:45 - 18:00  |  Author(s): Virginie Westeel

      • Abstract
      • Slides

      Background

      Non-small cell lung cancer is a dramatic disease. For several years, molecular analyses highlighted several genetic alterations (mutations, gene fusions) enabling use of targeted therapies. Among targetable mutations, the most frequent (11% of lung adenocarcinomas) are EGFR mutations spanning from exon 18 to exon 21, except insertion in exon 20 and T790M mutation. In clinical practice, progression free survival under EGFR Tyrosine Kinase Inhibitor is between 12 and 14 months, but some patients rapidly progress in less than 6 months, whereas other patients are treated with EGFR TKI during more than 16 months, and even more in some cases.

      Method

      ALCAPONE clinical trial (NCT02281214) included 165 patients with a non-small cell lung cancer divided in 2 different groups: EGFR mutated (n=63) and EGFR wild-type tumors (n=102). All tumors at baseline had an exome analysis performed with SureSelect Human all exon v5 or v6 kit. After adapter trimming and quality check, GATK tools were applied to process the data. After variant calling (Haplotype Caller) and annotation, genetic variations were separated in 3 categories: intron variants, synonymous variants and transcripted variants. Only variants with a general population frequency <1% were conserved for statistical analyses. For the first analysis of the trial, we focused on a training set of 33 EGFR mutated patients homogenously treated by afatinib. We selected 18 extreme responders (10 short responders with PFS<180 days and 8 long responders with PFS>500 days) to select genetic markers predictive of extreme responses and used them to evaluate survival including 15 patients with PFS between 180 and 500 days.

      Result

      Thanks to 2 different predictive models, it appeared that 5 genes were able to discriminate short responders from long responders: AKR1B1, WNK1, IHH*, PLA2G16*, and SMYD3*, whose those with an asterisk selected by the 2 different predictive models. For these genes, the presence of a non-synonymous variant in transcripted (UTR and coding) sequences of the genes was associated with a worse response to afatinib. By studying PFS probability with the 33 EGFR mutated patients of the training set, it appeared that 2 genes discriminated responders from non-responders. Indeed, patients with a variation in IHH or in WNK1 gene had a significant worse PFS than patients with no variation (p=0.0003, median PFS=9 vs 16 months for IHH and p=0.0052, median PFS=9 vs 17 months for WNK1). Interestingly, in the literature, IHH (Indian HedgeHog) decreased expression are correlated with increased sensitivity to treatment, and WNK1 (With No lysine Kinase 1) activation are linked to cellular migration and epithelial mesenchymal transition in non-small cell lung cancer.

      Conclusion

      This first analysis from the ALCAPONE clinical trial identified 2 genes that could discriminate responders from non-responders. As the analysis was performed from 33 EGFR mutated patients, it will be confirmed thanks to a validation set of 30 new EGFR mutated patients treated with afatinib. If these results are confirmed, the analysis of genetic variations on both genes could be new biomarkers bringing new information to clinicians for the choice of EGFR TKI treatment sequence.

      ALCAPONE study was supported by Boehringer Ingelheim

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    SH02 - Highlight of the Previous Day (ID 99)

    • Event: WCLC 2019
    • Type: Highlight of the Previous Day Session
    • Track:
    • Presentations: 1
    • Now Available
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      SH02.03 - Thymoma and Other Thoracic Malignancies (Now Available) (ID 3664)

      11:30 - 13:00  |  Presenting Author(s): Virginie Westeel

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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