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Bruno Coudert



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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
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      OA14.04 - Five-Year Outcomes From the Randomized, Phase 3 Trials CheckMate 017/057: Nivolumab vs Docetaxel in Previously Treated NSCLC (ID 894)

      11:30 - 13:00  |  Author(s): Bruno Coudert

      • Abstract
      • Slides

      Background

      Historically, outcomes for advanced non-small cell lung cancer (NSCLC) have been poor, with 5-year survival rates < 5% with conventional chemotherapy. Nivolumab, a programmed death-1 (PD-1) inhibitor, was approved in 2015 for patients with previously treated advanced NSCLC based on two randomized phase 3 trials, CheckMate 017 (NCT01642004; squamous) and CheckMate 057 (NCT01673867; non-squamous), which demonstrated improved overall survival (OS) vs docetaxel. We report 5-year pooled efficacy and safety from these trials, representing the longest survival follow-up for randomized phase 3 trials of an immune checkpoint inhibitor in advanced NSCLC.

      Method

      Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG performance status (PS) ≤ 1, and progression during or after first-line platinum-based chemotherapy, were randomized 1:1 to nivolumab 3 mg/kg Q2W or docetaxel 75 mg/m2 Q3W until progression or unacceptable toxicity. After completion of the primary analyses, patients in the docetaxel arm no longer receiving benefit could cross over to receive nivolumab. OS was the primary endpoint for both studies.

      Result

      At 5-year follow-up, 50 nivolumab patients and 9 docetaxel patients were alive. Baseline characteristics of 5-year survivors in both arms were similar to the overall population and patients who survived < 1 year, except for a higher percentage of patients with ECOG PS 0 or tumor programmed death ligand-1 (PD-L1) expression ≥ 1% on nivolumab and ECOG PS 0 and Stage IIIB NSCLC on docetaxel. Nivolumab continued to show long-term OS and progression-free survival (PFS) benefit vs docetaxel with 5-year OS rates 13% vs 3% (HR, 0.68 [95% CI, 0.59–0.78]) and PFS rates 8% vs 0% (0.79 [0.68–0.92]). OS benefit with nivolumab vs docetaxel was observed across subgroups including patients with tumor PD-L1 expression < 1%, baseline liver and adrenal metastases, neutrophil-to-lymphocyte ratio < median, lactate dehydrogenase ≥ upper limit of normal or no baseline proton-pump inhibitor use. Among patients with an objective response to nivolumab (20%) or docetaxel (11%), 32% remained in response at 5 years vs none on docetaxel, with a median duration of response of 19.9 vs 5.6 months, respectively. Of the 5-year nivolumab vs docetaxel survivors, 36% vs 0% were on study drug, 20% vs 67% received subsequent immunotherapy (on or off study), and 10% vs 0% were off study drug, progression free, with no subsequent therapy. No new safety signals were observed with longer follow-up. Between 3 and 5 years’ follow-up, 8 of the 31 (26%) nivolumab-treated patients reported a treatment-related adverse event, 1 (3%) grade 3–4. The most common select adverse events (events with a potential immunological cause) were related to skin, in 4 (13%) patients, none of which were grade 3–4.

      Conclusion

      CheckMate 017 and 057 are the first phase 3 trials to report 5-year outcomes for a PD-1 inhibitor in previously treated advanced NSCLC, demonstrating a greater than 4-fold increase in 5-year OS rates with nivolumab (13%) over docetaxel (3%). Nivolumab remained well tolerated with no new safety signals.

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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): Bruno Coudert

      • 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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