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Dean A Fennell



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    MA12 - Mesothelioma Surgery and Novel Targets for Prognosis and Therapy (ID 913)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 202 BD
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      MA12.05 - Phase 1 Study of HSP90 Inhibitor Ganetespib with Pemetrexed and Cisplatin/Carboplatin Chemotherapy for Pleural Mesothelioma (Now Available) (ID 11921)

      11:00 - 11:05  |  Presenting Author(s): Dean A Fennell

      • Abstract
      • Presentation
      • Slides

      Background

      There have been no new licenced therapies for mesothelioma in over a decade. Ganetespib is a small-molecule heat-shock protein 90 (Hsp90) inhibitor, with significant activity for down-regulating Hsp90 client protein levels. Prior evidence indicates efficacy for ganetespib in mesothelioma through critical survival pathways and synergies with antifolates and platinum chemotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We conducted a dose-escalation study of ganetespib in patients with pleural malignant mesothelioma and ECOG 0-1. Ganetespib was combined with standard pemetrexed/platinum therapy, using either cisplatin (GCisP), or carboplatin (GCarbP). Three ganetespib cohorts were: 100, 150 & 200mg/m2 given days 1 and 15, every 21 days. GCisP was evaluated using a 3+3 design. GCarbP followed an accelerated titration run-in using single patients, switching to a 3+3 design after one dose limiting toxicity (DLT). DLT was assessed during cycles 1-2 for GCisP and cycle 1 for GCarbP. Genomic instability was inferred by array-based analysis of somatic copy number.

      4c3880bb027f159e801041b1021e88e8 Result

      27 patients were treated (GCisP, n=16; GCarbP, n=11). Median age 66 (range 37-76), 6 PS-0/21 PS-1, and 25 male. Only 3 patients experienced DLTs, all at 200mg/m2: grade 3 nausea (GCisP, n=1; GCarbP, n=1); grade 2 infusion-related reaction (GCarbP, n=1). This dose was the maximum tolerated dose. Partial tumour response rate was 61% (14/23 evaluable patients); 7 patients had tumour burden reduction of >50% (Figure). PFS was better using 200mg/m2 versus 100mg/m2 (hazard ratio 0.32, 95%CI 0.11-0.95, p=0.04). One patient remains progression-free even after 37 months. Total loss of heterozygosity (LOH) was correlated with increased tumour burden (n=7, correlation=0.7, p=0.078).

      meso02abstract_bestresponse.png

      Figure. Best tumour response (% change in tumour burden from baseline)

      8eea62084ca7e541d918e823422bd82e Conclusion

      Ganetespib plus pemetrexed and platinum chemotherapy was well-tolerated in patients with pleural mesothelioma, with evidence of activity, particularly at the recommended dose of 200mg/m2. LOH correlated with poorer response to this triplet combination.

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    P2.06 - Mesothelioma (Not CME Accredited Session) (ID 955)

    • 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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      P2.06-09 - MiST3: A Phase II Study of Oral Selective AXL Inhibitor Bemcentinib (BGB324) in Combination with Pembrolizumab in pts with Malignant Mesothelioma (ID 12548)

      16:45 - 18:00  |  Presenting Author(s): Dean A Fennell

      • Abstract

      Background

      Mesothelioma is a cancer with significant unmet need, with only one line of therapy licenced in the UK. AXL is a member of the TAM (Tyro3, AXL, Mer) family of receptor tyrosine kinases that regulate multiple cellular processes including survival, proliferation and migration. An analysis of AXL expression in patients with mesothelioma reported an overexpression in 74% of the tumours examined. Several cell types associated with the suppressive tumour immune microenvironment express AXL, including natural killer cells and tumour-associated macrophages. AXL is an important regulator of tumour plasticity related to epithelial-to-mesenchymal transition, thereby contributing to evasion of antitumour immune response. Hence, AXL signalling contributes uniquely to tumour intrinsic and microenvironmental immune suppression. Bemcentinib (BGB324), a potent, selective orally bioavailable small molecule inhibitor of AXL, has demonstrated effective inhibition in pre-clinical models and is currently being trialled in combination with pembrolizumab in patients with advanced non-small-cell lung cancer, breast cancer and melanoma.

      Pembrolizumab has high affinity and potent receptor blocking activity for PD-1, therefore inhibiting the interaction with PD-L1. Recent data showed that the combination of bemcentinib with anti-PD-1 blockade profoundly enhanced anti-tumour activity in the syngeneic Lewis Lung (LL/2) lung carcinoma model.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a single arm phase IIA clinical trial of bemcentinib and pembrolizumab in patients with relapsed mesothelioma. MiST3 is one arm of a broader umbrella study- a stratified multi-arm phase IIA clinical trial to enable accelerated evaluation of targeted therapies for relapsed malignant mesothelioma. 25 patients recruited to MiST3 will receive a loading dose of 400mg bemcentinib, followed by daily doses of 200mg, alongside IV infusions of 200mg pembrolizumab on day-one of each 21-day cycle. The primary objective is to establish 12 week disease control rate (DCR), secondary objectives include safety and tolerability, objective response rate and 24 week DCR, as assessed by modified RECIST. Patients will continue therapy until disease progression, unacceptable toxicity or a maximum 2-year duration. A pre-treatment biopsy and serial plasma samples will be mandatory for exploratory research.

      Exploratory objectives include; correlation of PD-L1 and AXL expression levels with response to treatment, tumour mutation burden to interrogate the genomic correlates of treatment response, immune regulated gene signature in RNA extracted from tumour samples, to correlate the impact of tumour infiltrating lymphocytes with response, and correlations between gut microbiome composition and response to therapy will be sought using 16sRNA sequencing. First patient first visit is anticipated- Q3 2018.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    PL02 - Presidential Symposium - Top 5 Abstracts (ID 850)

    • Event: WCLC 2018
    • Type: Plenary Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 08:15 - 09:45, Plenary Hall
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      PL02.09 - Nintedanib + Pemetrexed/Cisplatin in Patients with Unresectable MPM: Phase III Results from the LUME-Meso Trial (Now Available) (ID 11192)

      09:15 - 09:25  |  Author(s): Dean A Fennell

      • Abstract
      • Presentation
      • Slides

      Background

      Nintedanib targets VEGFR 1–3, PDGFR α/β, FGFR 1–3, Src and Abl kinases, all implicated in malignant pleural mesothelioma (MPM) pathophysiology. This global Phase II/III, randomised, double-blind study investigated pemetrexed/cisplatin in combination with nintedanib or pemetrexed/cisplatin in combination with placebo, followed by nintedanib or placebo maintenance, in patients with unresectable MPM. In the double-blind, randomised Phase II part, nintedanib plus pemetrexed/cisplatin improved PFS vs placebo (HR=0.56; 95% CI: 0.34–0.91; p=0.017; median 9.4 vs 5.7 months).

      In Phase III, chemotherapy-naïve patients with epithelioid MPM (ECOG PS 0–1) were randomised 1:1 to receive up to six cycles of pemetrexed (500 mg/m2)/cisplatin (75 mg/m2) on Day 1, plus nintedanib (200 mg bid) or matched placebo on Days 2–21. After combination treatment, patients without disease progression received nintedanib or placebo maintenance. The primary endpoint (PFS by investigator assessment) and key secondary endpoint (OS) were planned to be analysed by hierarchical testing, with an interim OS analysis at the time of the primary PFS analysis. PFS was also assessed by independent central review. Based on the assumed treatment effect (HR=0.63), the study had 90% power to detect a statistically significant and clinically meaningful improvement in PFS.

      In total, 458 patients were randomised. Baseline patient characteristics and oncological history were similar between treatment arms. Median duration of nintedanib or placebo administration was 5.3 and 5.1 months, respectively. After 250 events, there was no difference in PFS between nintedanib and placebo arms (HR=1.01; 95% CI: 0.79–1.30; p=0.91; median 6.8 vs 7.0 months, respectively). PFS by central independent review was similar (242 events; HR=0.99; 95% CI: 0.77–1.28; p=0.96; median 6.8 months in each arm). In the interim OS analysis (127 deaths [28% of events]), median OS was 14.4 vs 16.1 months (nintedanib vs placebo; HR=1.12; 95% CI: 0.79–1.58; p=0.54). There were no unexpected safety findings. The proportion of patients with Grade ≥3 AEs was higher with nintedanib than with placebo (72% vs 62%). The most frequently reported Grade ≥3 AE by medical concept in both treatment arms was neutropenia (nintedanib: 32%; placebo: 24%). The proportion of deaths due to serious AEs was 4.0% (nintedanib) and 7.5% (placebo).

      The primary endpoint of the Phase III part of LUME-Meso was not met ‒ Phase II findings were not confirmed. The reported safety profile was consistent with the known safety profiles of nintedanib and pemetrexed/cisplatin.

      a9ded1e5ce5d75814730bb4caaf49419

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    YI01 - Young Investigators Session (ID 988)

    • Event: WCLC 2018
    • Type: Young Investigator Session
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/23/2018, 08:00 - 11:30, Room 106
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      YI01.14 - How to write a Successful Grant Application (Now Available) (ID 14683)

      10:45 - 11:00  |  Presenting Author(s): Dean A Fennell

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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