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Tom John



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    IBS17 - Undertaking Nursing and Allied Health Research...How to Survive It and Get Published (Ticketed Session) (ID 48)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Nursing and Allied Professionals
    • Presentations: 1
    • Now Available
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      IBS17.02 - How to Get Your Research Published (Now Available) (ID 3367)

      07:00 - 08:00  |  Presenting Author(s): Tom John

      • Abstract
      • Presentation
      • Slides

      Abstract

      It is becoming increasingly important for researchers to not only ask and answer questions, but to disseminate the information gained to the wider community. One of the most important and indeed respected means of disseminating information is publish your results in a peer reviewed journal. While this may sound very straightforward, those who have tried to publish their data will be familiar with the frustration with peer reviewers, of rejection without peer review, rejection following extensive peer review or the need to submit a completely revised manuscript.

      Here I will discuss some of the key principles of getting your paper published, based on my experience as an author, reviewer and associate editor.

      I will go cover a range of areas from writing a good cover letter, what to include in the paper, to how to respond to reviewers.

      There are no guarantees to getting your paper published where you want the first time round, but these pointers will hopefully enable you to pick the right type of publication, the right journal and the best way to frame your paper.

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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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      MA14.02 - Entrectinib in Patients with ROS1-Positive NSCLC or NTRK Fusion-Positive Solid Tumors with CNS Metastases (Now Available) (ID 1631)

      15:45 - 17:15  |  Author(s): Tom John

      • Abstract
      • Presentation
      • Slides

      Background

      Entrectinib potently inhibits kinases encoded by NTRK and ROS1 genes. It achieves therapeutic levels in the CNS with antitumor activity in intracranial tumor models. We report integrated analysis data (31 May 2018 data cut-off) from three Phase 1/2 entrectinib trials (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]) for a large cohort of adult patients with NTRK fusion-positive solid tumors (NTRK+) or ROS1 fusion-positive NSCLC (ROS1+), with baseline CNS metastases.

      Method

      Patients had locally advanced/metastatic NTRK+ solid tumors or ROS1+ NSCLC by nucleic acid-based assays confirmation. Baseline CNS metastases were identified by CT/MRI. Tumor assessments were performed at baseline, week 4, and then every 8 weeks by blinded independent central review (RECIST v1.1). Primary endpoints were overall response rate (ORR), duration of response (DOR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), intracranial efficacy in patients with CNS metastases, safety.

      Result

      Most patients were treated first-line or after one line of prior therapy; baseline characteristics relating to measurable CNS metastases for patients with NTRK+ solid tumors and ROS1+ NSCLC are presented (Table). Intracranial outcomes for the NTRK+ solid tumors (n=54; 18% NSCLC) and ROS1+ NSCLC (n=53) efficacy evaluable populations are reported (Table). Durability of treatment effect and potential delayed progression in the CNS was observed; time to CNS progression was 17.0 months (95% CI: 14.3–NE) for NTRK+ solid tumor patients and NE (95% CI: 15.1–NE) for ROS1+ NSCLC. In the subset of patients with NTRK+ NSCLC (n=10), 6 patients had CNS metastases at baseline (by BICR); IC-ORR was 66.7% (4/6), 2 CR; IC-DOR was NE. In both the NTRK+ and ROS1+ populations, entrectinib was tolerable with a manageable safety profile; most treatment-related AEs were grade 1–2.

      Conclusion

      Entrectinib induced clinically meaningful durable responses in patients with NTRK+ solid tumors or ROS1+ NSCLC with CNS disease at baseline.

      Funding: This study was funded by F. Hoffmann-La Roche

      table.jpg

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-136 - Uncommon EGFR Mutations in Non-Small Cell Lung Cancer: A Systematic Literature Review of Prevalence and Clinical Outcomes (ID 2175)

      09:45 - 18:00  |  Presenting Author(s): Tom John

      • Abstract
      • Slides

      Background

      Mutations in exons 18–21 of the epidermal growth factor receptor gene (EGFR) can confer sensitivity to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). About 90% of detected mutations are either deletions in exon 19 or the exon 21 L858R substitution. Comparatively few data are available on the prevalence, treatment sensitivity or clinical outcomes associated with the remaining 10%, termed ‘uncommon mutations’. To collate available published evidence, we conducted a systematic literature review (SLR) focussing on these uncommon EGFR mutations in metastatic and locally advanced NSCLC.

      Method

      Embase, MEDLINE and the Cochrane Library were searched using terms for NSCLC and EGFR; abstracts from relevant congresses were also reviewed. Screening identified clinical trials and observational studies published 2012–2019 that included patients with uncommon EGFR mutations (all mutations except exon 19 deletions, L858R and T790M). For prevalence data, only studies in which exons 18–21 were sequenced in their entirety were considered relevant; studies that used targeted methods to detect EGFR mutations were not included. We assessed the overall prevalence of uncommon EGFR mutations, and also compared response to treatment and progression-free survival (PFS) in patients with common and uncommon mutations.

      Result

      In total, 20 epidemiology and 90 clinical studies met the inclusion criteria, with broad variation in geography and study population. The prevalence of uncommon mutations varied widely across studies, between 1.0% and 18.2% of all EGFR mutations (Figure). The most frequently reported uncommon mutations, either singly or occurring in double/triple mutations, were G719X (0.9–4.8% of all EGFR mutations), exon 20 insertions (0.8–4.2%), L861X (0.5–3.5%) and S768I (0.5–2.5%). Patients with common mutations typically experienced better treatment response and longer PFS than patients with uncommon mutations when receiving TKIs. However, there was considerable heterogeneity across studies, which is likely to result partly from variations in TKI-sensitivity between different types of EGFR mutations and disparities in the uncommon mutation types represented in each study. In several studies, exon 20 insertions were associated with worse outcomes than other uncommon mutations, particularly mutations in exon 18.

      john et al_figure 1.jpg

      Conclusion

      This comprehensive SLR indicates that uncommon mutations may comprise a clinically significant proportion of the EGFR mutations occurring in NSCLC worldwide. As there are apparent disparities in TKI-sensitivity between some of the most frequently reported uncommon mutations, assessment and reporting of outcomes by specific mutation type will prove invaluable in identifying the most appropriate treatment strategy in each case.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-11 - Overcoming Resistance to Immunotherapy Using CVA21: Initial Results from a Phase II Study (Now Available) (ID 2070)

      10:15 - 18:15  |  Author(s): Tom John

      • Abstract
      • Slides

      Background

      Resistance develops in most non-small cell lung (NSCLC) patients treated with anti-PD-1/anti-PD-L1 based immunotherapy. CVA21 is an oncolytic coxsackie virus that targets ICAM over-expressing tumour cells. Pre-clinical models suggest that CVA21-induced tumour lysis may enhance the clinical efficacy of the anti-PD-1 antibody Pembrolizumab by inducing immune cell infiltration in patients that lack an immune cell rich tumour microenvironment. Previously, the Keynote 200 trial of CVA21 combined with Pembrolizumab reported an ORR of 23% in immunotherapy-naive NSCLC. We report the efficacy of Pembrolizumab in combination with CVA21 in a preliminary cohort of eight pre-treated NSCLC patients with secondary resistance to prior anti-PD-1/anti-PD-L1 therapy.

      Method

      On progression of prior therapy, IV CVA21 (1x109 TCID50) was administered on days 1, 3, 5, 8, then Q3W for 6 months, in combination with Pembrolizumab (200mg IV from day 8, then Q3W for up to 24 months). Repeat biopsies were mandated prior to cycle 2 of Pembrolizumab. Tumour measurements were calculated using immune-related RECIST. PD-L1 was tested on pre- and post-treatment biopsies using SP-263 (Ventana) and reported using the tumour proportion score (TPS).

      Result

      The majority of patients were female (n=7, 88%), median age 65 years (range 55-75), seven (88%) current or former smokers, five (63%) with 3+ lines of prior treatment, and only 1 anti-PD-1/anti-PD-L1 naive. Two patients were KRAS mutant, the remaining were wild type for EGFR, ROS1, ALK and BRAF.

      Two (25%) partial responses (PR) were observed, both in anti-PD-1/anti-PD-L1 pre-treated patients. Both responders were continuing at data cut-off, 240 and 120 days since commencement. Two achieved SD (overall clinical benefit 50%) and 3 were non-evaluable (1 early non-treatment-related death, 3 awaiting first scan). Early PD at 56 days occurred in the anti-PD-1/anti-PD-L1 naive patient (n=1).

      In the two PRs, PD-L1 TPS was 25% and 60% respectively. Preliminary IHC staining of paired biopsies showed an increase in PD-L1% in 2 (33%) evaluable patients at 21 days. PD-L1 TPS ranged from <1% to 80% in pre-treatment biopsies, but was not predictive of response or benefit from combination therapy. An increase in PD-L1 was associated with a trend toward longer disease stability (median 147 days).

      Combination treatment was well-tolerated with no observed G4/5 TRAE's.

      Conclusion

      Intravenous CVA21 in combination with pembrolizumab demonstrated encouraging clinical activity in patients who had progressed on prior anti-PD-1/anti-PD-L1 therapy, regardless of PD-L1 levels.

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    P2.06 - Mesothelioma (ID 170)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Mesothelioma
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.06-10 - ABT-806 Derived Antibody Drug Conjugates (ADCs) Inhibit Growth of Malignant Mesothelioma In-Vivo (ID 581)

      10:15 - 18:15  |  Author(s): Tom John

      • Abstract
      • Slides

      Background

      Malignant mesothelioma (MM) is an aggressive malignancy of the pleura with limited therapeutic options, and is associated with a poor prognosis. EGFR is known to be highly over-expressed in mesothelioma with reported EGFR overexpression between 44 to 97%. We have investigated an anti-EGFR antibody (ABT-806), which is tumour specific and robustly inhibits EGFR-expressing tumors. We have previously shown that ABT-806 ADCs demonstrate potent anti-tumor activity in 806 immunohistochemistry (IHC) positive MSTO-211H MM cell line xenograft model. We present data in MM using ABT-806 novel ADCs [ABT-414 (ABT-806- monomethyl auristatin F), ABBV-221 (ABT-806- monomethyl auristatin E), ABBV-322 (ABT-806- pyrrolobenzodiazepine)] and ABBV-321 (Affinity-matured ABT-806- pyrrolobenzodiazepine) in MM patient derived xenografts (PDX).

      Method

      We evaluated expression of EGFR and mAb 806 IHC in MM cell lines and PDXs. PDXs were implanted into 5 to 10 NOD-Scid mice per group and treated with control ADC, saline, cisplatin or ABT-806 ADCs and followed longitudinally with caliper measurements. Comparative statistics were performed in Graphpad prism. Quantitative biodistribution and imaging of mAb806 uptake (89Zr-ch806) were performed to allow correlation of mAb806 concentration in MM tumours.

      Result

      Three PDX models were selected according to their 806 IHC statuses (2 epithelioid 806 IHC positive, 1 biphasic histology 806 IHC negative). In one epithelioid PDX model, ABBV-322 resulted in significantly reduced tumor growth on day 27 post therapy with median tumour volumes of 180 mm3 (ADC control) compared with 78mm3 (ABBV-322; p=0.0159 two-sided). Moreover, the median survival was also significantly longer in ABBV-322 treated models (p=0.018).

      In the other epithelioid PDX model, ABBV-321 also resulted in significant responses (median 428mm3 (ADC control) vs 167mm3 (ABBV-321, p= 0.0201) [Figure 1].

      In the 806 IHC negative PDX model, the differences in tumor volumes between all groups were found to be non-statistically significant (ADC control vs ABT-414, ADC control vs ABBV-221, ADC-control vs ABBV-321 groups) with p=0.0597 for one-way ANOVA.

      MSTO211H cell line xenograft model also demonstrated significant anti-tumour response to both ABT-414 and ABBV-221 (p<0.01). Whole-body PET/MR images also confirmed localization of 89Zr-Ch806 to the established MSTO-211H xenograft tumours.figure 1 wclc abstract.jpg

      Conclusion

      In a disease with limited therapies, ABT-806 targeting ADCs in MM demonstrated significant responses in 806+ PDX and cell lines. These data support clinical expansion of these compounds in 806+ MM patients.

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