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T. John



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    MA 19 - Mesothelioma: Bench to Bedside (ID 680)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Mesothelioma
    • Presentations: 2
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      MA 19.03 - Nintedanib + Pemetrexed/Cisplatin in Malignant Pleural Mesothelioma (MPM): Phase II Biomarker Data from the LUME‑Meso Study (ID 8111)

      11:00 - 12:30  |  Author(s): T. John

      • Abstract
      • Presentation
      • Slides

      Background:
      Nintedanib is a triple angiokinase inhibitor. LUME-Meso (NCT01907100) is a randomised, Phase II/III study of ≤6 cycles of nintedanib+pemetrexed/cisplatin versus placebo+pemetrexed/cisplatin, followed by nintedanib or placebo maintenance, in chemo-naïve patients with MPM. In Phase II results, nintedanib+pemetrexed/cisplatin improved progression-free survival (PFS) versus control (hazard ratio [HR]=0.54; p=0.010), with a trend for prolonged overall survival (OS; HR=0.77; p=0.319). Benefit was most pronounced in patients with epithelioid tumours. Since no pharmacodynamic/predictive biomarkers are validated for anti-angiogenic therapies, exploratory analyses were conducted to investigate potential associations of plasma-derived angiogenic factors and genomic markers with treatment outcome in the LUME-Meso Phase II epithelioid population.

      Method:
      Blood samples were collected at baseline and, for patients receiving maintenance, at monotherapy Cycle 3 (C3mono) and end of monotherapy (EoTmono). Analyses focused on 58 angiogenic factors (Human AngiogenesisMAP[®] panel, Myriad RBM) and single-nucleotide polymorphisms (SNPs) in genes implicated in mesothelioma and/or associated with response to anti-angiogenic therapies in other tumour types (VEGFR1, VEGFR3 and mesothelin). Associations of biomarkers with treatment effect were evaluated by Cox regression and tested for interaction with false discovery rate (FDR) adjustment. Adjusted mean changes in angiogenic factor levels were compared between arms by ANCOVA. Analyses were exploratory, limited by small sample size, and considered hypothesis generating.

      Result:
      Of 77 patients with epithelioid tumours, angiogenic factor and genomic data were available for 71 and 67 patients, respectively. PFS/OS benefit of nintedanib appeared potentially more pronounced in patients with baseline plasma endoglin level below the median. There were possible weak associations between major homozygous genotypes for two VEGFR3 SNPs (rs307821 G/G and rs307826 A/A), and OS benefit and between VEGFR1 SNP rs9582036 A/A genotype and PFS benefit. Biomarker treatment associations were limited by small subgroup size, especially for low-frequency SNPs, and interaction tests were not significant after FDR adjustment. Regarding pharmacodynamic effects, adjusted mean change in interleukin-8 levels with nintedanib was greater from baseline to C3mono and lower from C3mono until EoTmono, compared with placebo. Nintedanib showed lower adjusted mean changes versus placebo for VEGFR2 from baseline to C3mono, and for VEGFR2 and VEGFR3 from baseline to EoTmono.

      Conclusion:
      These analyses represent the first biomarker results for nintedanib-treated MPM. While there seemed to be signals for greater PFS and OS improvement in patients with low plasma endoglin and major homozygous VEGFR1/3 genotypes, no biomarkers showed clear significant association with treatment benefit. These findings warrant further evaluation in the Phase III study.

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      MA 19.11 - Discussant - MA 19.09, MA 19.10 (ID 10831)

      11:00 - 12:30  |  Presenting Author(s): T. John

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA 14 - New Paradigms in Clinical Trials (ID 681)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Clinical Design, Statistics and Clinical Trials
    • Presentations: 1
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      OA 14.06 - Entrectinib in Patients with Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small Cell Lung Cancer (NSCLC) (ID 8564)

      11:00 - 12:30  |  Author(s): T. John

      • Abstract
      • Presentation
      • Slides

      Background:
      Entrectinib is a potent, investigational, CNS-active, oral inhibitor of ROS1 with a biochemical IC~50~ (0.2 nM) ~30 times more potent than crizotinib, the only agent approved for the treatment of ROS1-positive NSCLC. Previously, we reported an objective response rate of 85% in 13 ROS1 inhibitor-naïve NSCLC patients who were treated in Phase 1 studies (Drilon and Siena et al, Cancer Discov 2017), including 2 of 3 (67%) patients with CNS disease. Responses were durable, with 1 patient remaining on study for more than 3 years. Entrectinib was well tolerated, with predominantly Grades 1 or 2 adverse events that were reversible with dose modification.

      Method:
      Patients with ROS1 inhibitor-naïve NSCLC were enrolled across Phase 1 and 2 studies of entrectinib. Patients were screened for ROS1 gene fusions either locally or centrally at Ignyta’s diagnostic laboratory using next generation sequencing. Entrectinib was administered orally at 600 mg once-daily in 4-week cycles. Safety was assessed by monitoring adverse events, laboratory tests, and clinic visits. Tumor assessments were performed at the end of Cycle 1 and every 8 weeks thereafter. All scans were read locally (INV) and by blinded independent central review (BICR) using RECIST v1.1. INV results will be presented except where noted.

      Result:
      As of 24 May 2017, a total of 32 patients were evaluable for response (median age 52 years, 72% female). At a median follow-up of 12 months, objective responses were observed in 24 of 32 (75% [95% CI: 56.6, 88.5]; 3 complete responses) patients, including 7 of 11 (64% [95% CI: 30.8, 89.1]) patients with CNS disease at baseline. Five of 7 patients with evaluable CNS lesions by BICR experienced confirmed RECIST intracranial responses, for a CNS response rate of 71% (95% CI: 29.0, 96.3). With 19 (59%) patients remaining on study, the median duration of response was 17.2 months (95% CI: 6.5, 36.0) and progression-free survival was 19.1 months (95% CI: 6.5, 36.6). The most common (>15%) treatment-related adverse events were fatigue/asthenia (34%), dysgeusia (34%), dizziness (24%), weight increase (21%), paresthesia (19%), nausea (18%), constipation (18%), and diarrhea (16%). All data will be updated at the time of presentation.

      Conclusion:
      Entrectinib is well tolerated and has shown promising antitumor activity in ROS1 inhibitor-naïve NSCLC, including patients with CNS disease. Patients with ROS1+ NSCLC and other tumor types continue to be enrolled in STARTRK-2 (NCT02568267) in order to support a potential regulatory filing for entrectinib in this population.

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    P2.02 - Biology/Pathology (ID 616)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P2.02-039 - Spatial Heterogeneity of Immunological Markers Between Cores and Complete NSCLC Sections Using Multispectral Fluorescent IHC (ID 9728)

      09:30 - 16:00  |  Author(s): T. John

      • Abstract
      • Slides

      Background:
      Immunotherapy with immune checkpoint inhibitors have revolutionised the management of solid organ malignancy including melanoma and NSCLC. Direction has turned to the tumour immune microenvironment (TIM) to explore predictive biomarkers. The spatial arrangement of immune infiltrative cells has the potential to better explain the TIM. Vectra multispectral immunohistochemistry (IHC) allows accurate definition of the TIM and may help detect mechanisms of immune evasion.

      Method:
      Multispectral fluorescent immunohistochemistry with a panel including CKAE1/3, CD8, FOXP3 and PD-L1 (clone E1L3N, Cell Signalling Technology) was used to analyse the TIM in six patients (pts) with resected NSCLC (full face section from block). Respective tissue microarrays were collected in triplicate from each specimen and underwent conventional IHC scoring for PD-L1, tumour infiltrating lymphocytes (TILs), CD8, FOXP3 and scored (0,1,2,3). The spatial arrangement of lymphocytes relative to tumour cells, stroma and PD-L1 expression was examined.

      Result:
      All six pts had adenocarcinoma histology, with the following level of PD-L1 expression: low(0-5%;n=2), intermediate(5-50%;n=2) and high(>50%;n=2)Figure1. In PD-L1[hi] pts Vectra staining showed uniform staining of PD-L1 across the full face. CD8 lymphocytes were present mainly in tertiary lymphoid structures without evidence of clustering. In PD-L1[lo] pts, one had heterogenous staining of TILs with dense stromal clustering (3:1 ratio of stroma to intratumoural). Neither patient (PD-L1[lo]) demonstrated significant PD-L1 uptake on full section assessment. Of the PD-L1[int] pts, although heterogeneity in PD-L1 expression was evident across the full face, the majority of tumour rich areas stained positively and TILs were uniform in the stroma. FOXP3 had low expression across all 6 patients <1% almost uniformly in the stroma.Figure 1



      Conclusion:
      Although PD-L1 staining heterogeneity was limited in this small dataset, clear differences in immune-cell infiltrate were seen between full-face sections and limited cores. Multiplex Immunofluorescent IHC provides accurate quantification of immune infiltrates and spatial alterations within the TIM and may facilitate predictive biomarkers.

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    P3.02 - Biology/Pathology (ID 620)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P3.02-038 - Diagnosis of Leptomeningeal Disease and Clonal Heterogeneity with Digital Droplet PCR (ddPCR) in EGFR Mutated NSCLC (ID 8929)

      09:30 - 16:00  |  Author(s): T. John

      • Abstract
      • Slides

      Background:
      Non-small cell lung cancer (NSCLC) spread to the central nervous system (CNS) is associated with universally poor outcomes. Diagnosis of leptomeningeal (LM) disease is particularly challenging, with radiological and cytological assessment of CSF often negative. Examination of cell-free DNA (cfDNA) is promising method for the assessment of tumour mutation status and disease monitoring. We examine its utility in the diagnosis and management of LM disease.

      Method:
      Patients with EGFR mutated NSCLC with symptoms suggestive of LM disease underwent cerebrospinal fluid (CSF) sampling and ddPCR assessment. Matched plasma and/or tumour biopsy samples were obtained. Clinical data was collected retrospectively. Genomic DNA was extracted from 1 mL of CSF and 4 mL of plasma using the Qiagen QIAamp Circulating Nucleic Acid kit and T790M and L858R mutations were assessed by using the QX200 ddPCR assays. Survival was calculated from diagnosis and diagnosis of LM disease.

      Result:
      Seven patients (pts) were included in the analysis. Most pts, 6/7 (86%) developed LM either during or after EGFR tyrosine kinase inhibitor (TKI) therapy. EGFR mutations were demonstrated in CSF in 6 (86%) pts, but only 2 (29%) demonstrated the same mutation profile in both CSF and plasma. Causes of discrepancy were between CSF and plasma/tissue were: two cases were CSF positive but had no extrathoracic disease to biopsy, 1 case was negative in the CSF for T790M but positive in plasma and on biopsy and one case was wild type in CSF but positive on plasma and biopsy for G719A+T790M mutation. Six pts (86%) received therapy after diagnosis of LM disease and OS from LM diagnosis ranged from 1.0 -15.8 months.

      Sex/ Age Therapy at diagnosis of CNS disease Duration of response to prior TKI (months) Therapy after diagnosis of CNS disease OS from diagnosis (months) OS from diagnosis of LM (months) Baseline EGFR mutation Tissue biopsy mutation profile CSF EGFR mutation profile (ddPCR) Plasma EGFR mutation profile (ddPCR) CSF cytology
      M/64 Nivolumab Erlotinib: 12.4 Gefitinib: 2.5 AZD3759 WBRT Osimertinib 52.7* 15.8* L858R L858R L858R + T790M L858R + T790M Positive - carcinoma
      F/68 Osimertinib Erlotinib: 18.2 Osimertinib: 7.2 Nil 28.6 1.7 L858R L858R + T790M Sample 1: L858R Sample 2: L858R + T790M N/A Sample 1 - negative Sample 2 - positive
      F/50 Osimertinib Erlotinib: 6.4 Osimertinib: 6.1 Erlotinib (1500mg weekly) 15.7 1.0 L858R L858R + T790M L858R L858R + T790M + C797S Positive - carcinoma
      F/79 Nil N/A Erlotinib (1500mg weekly) 74.5* 9.5* Exon 19 deletion No site for biopsy Exon 19 deletion Wild type Positive - carcinoma
      M/64 Erlotinib Erlotinib: 10.5 Erlotinib (1500mg weekly) 15.0 9.1 L858R No site for biopsy L858R Wild type Not performed
      F/63 Erlotinib Erlotinib: 5.9 Osimertinib 7.8* 1.3* G719A G719A + T790M WT G719A Not performed
      M/60 Erlotinib Erlotinib: 22.0 Erlotinib (1500mg weekly) 31.0* 7.4* Exon 19 deletion No site for biopsy Exon 19 deletion Exon 19 deletion Negative


      Conclusion:
      ddPCR is able to detect cfDNA in CSF, where other diagnostic modalities may be negative, and demonstrates both initial and resistance mutations. Heterogeneous mutation status may guide therapy when LM disease remains sensitive to targeted therapy.

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