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Alan G Dawson



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    P2.06 - Mesothelioma (ID 170)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Mesothelioma
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.06-02 - Mesothelioma Stratified Therapy (MiST): A Phase IIA Umbrella Trial for Accelerating the Development of Precision Medicines (ID 2465)

      10:15 - 18:15  |  Author(s): Alan G Dawson

      • Abstract

      Background

      There are currently no approved therapies for the treatment of relapsed mesothelioma. Recent advances in our understanding of inter-patient genomic heterogeneity, identification of potential drivers, and application of high throughput -omic technologies to clinical trial samples , has created opportunities to explore novel treatments in prospectively biomarker-enriched cohorts.

      Method

      MiST is a British Lung Foundation funded, University of Leicester sponsored multicentre national clinical trial. Patients (Pts) harbouring either pleural (any histological subtype) or peritoneal mesothelioma are eligible. Pts must have ECOG performance status 1 or 0, received prior standard chemotherapy and progressed from their last treatment (in any line). The study is designed in three stages. Stage 1 comprises prospective molecular profiling of the tumour suppressors BAP1, BRCA1, p16ink4A and the immune checkpoint inhibitor PDL1 (22C3), using automated immunohistochemistry. Stage 2: Patients meeting eligibility criteria are presently stratified into Arm 1: Rucaparib (PARP inhibitor) for BAP1 inactivated (cytoplasmic or loss of expression) /BRCA1 negative mesothelioma. Arm 2: Abemaciclib (CDK4/6 inhibitor) for p16ink4a negative tumour, Arm 3, Pembrolizumab (anti-PD1) and Bemcentinib (AXL) to patients without biomarker specification. Arm 4, Atezolizumab (anti-PDL1) and Avastin (anti-VEGF) for PDL1 positive MM. Further arms are in development. The primary endpoint is 12 week disease control (12wDCR), with the secondary endpoints, 24wDCR, response rate (modified RECIST1.1) and safety/tolerability. 12wDCR>50% will be considered worthy of further investigation. Stage 3: Genome wide somatic copy number analysis and transcriptomic analysis with in-silico deconvolution of immune cell infiltrates will be used to refine molecular correlates of response. Gut microbiome 16RNA sequencing will be conducted in arms 3 and 4. Patients exhibiting a response to treatment who then progress, will be re-biopsied to facilitate molecular interrogation of acquired resistance mechanisms. MiST is coupled to our laboratory functional genomics programme, aimed at exploring co-clinical trial models, to robustly define or validate mechanisms that underpin drug responses.

      Result

      Section not applicable

      Conclusion

      In summary, MiST is a new clinical research platform that will support proof-of-concept studies capable of testing biomarker enrichment/efficacy hypotheses, with the aim of advancing personalised therapy for mesothelioma.

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      P2.06-11 - MEDUSA: Phylogenetic Analysis of Mesothelioma Tumours by Multiregional Sampling, Whole Exome Sequencing, and Copy Number Analysis (ID 921)

      10:15 - 18:15  |  Author(s): Alan G Dawson

      • Abstract

      Background

      The Mesothelioma evolution: Drugging somatic alterations (MEDUSA) project aims to investigate the genomic evolution and heterogeneity of malignant pleural mesothelioma and identify genomic changes early in mesothelioma evolution that can be targeted by drugs. For 20 malignant pleural mesothelioma patients, we have analysed the exomes of at least four regions of the tumour and paired whole blood.

      Method

      Using paired tumour-normal analysis with the software Sequenza, we have called copy number alterations specific to the tumour, and used the software Tumult to reconstruct a phylogeny of the tumour for each of the 20 patients.

      Result

      We show that mesothelioma shows extensive heterogeneity in copy number changes, and accumulates typically between 100-200 copy number gains and losses while evolving in a branching pattern. We identify and validate copy number alterations that occur truncally, early in the evolution of the tumour, and are recurrent across patients, including homozygous loss of CDKN2A and MTAP in 4/20 patients, heterozygous loss of MTOR in 6/20 patients and heterozygous loss of BAP1 in 4/20 patients. Losses of these key genes are observed in some other patients, but only in a subset of regions, suggesting that they have occurred later in the evolution of the tumour compared to truncal changes.

      Conclusion

      As truncal changes are likely to be present throughout the tumour, identifying them highlights potential Achilles’ heels for drug targeting and treatment.