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M. Yule



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    MA 02 - Emerging Targets (ID 656)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Clinical Design, Statistics and Clinical Trials
    • Presentations: 1
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      MA 02.09 - A Ph I/II Study of BGB324, a Selective AXL Inhibitor as Monotherapy and in Combination with Erlotinib in Advanced NSCLC (ID 10388)

      11:00 - 12:30  |  Author(s): M. Yule

      • Abstract
      • Presentation
      • Slides

      Background:
      BGB324 is an orally available selective inhibitor of the receptor tyrosine kinase AXL (Biochemical IC50 0.4nM). In animal models of NSCLC exposure, BGB324 restricts cellular plasticity and prevents the development of resistance to Epithelial Growth Factor Receptor (EGFR) inhibitors through mesenchymal transformation.

      Method:
      BGB324 was administered at an oral loading dose (600 mg) on days one and two followed by a daily maintenance dose (200 mg) to eight patients with previously treated NSCLC (EGFR mutant or wildtype). The tolerability of two different loading doses BGB324 (600 mg on days one and two or 400 mg on days one two and three) were then explored in combination with erlotinib at a dose of 150 mg daily in patients with EGFR mutated NSCLC.

      Result:
      Two of eight patients treated with BGB324 monotherapy achieved at least six months of stable disease. Both dose levels of BGB324 were tolerated in combination with erlotinib although most patients experienced a transient worsening in gastrointestinal toxicity during the loading dose prior to returning to baseline. A three day loading dose was preferred. Treatment with BGB324 was accompanied by increases in patient serum levels of soluble AXL receptorconsistent with receptor inhibition. One patient who previously experienced progression during treatment with another EGFR inhibitor remains on treatment with erlotinib plus BGB324 for more than eighteen months with a best response of stable disease. The most common treatment related adverse events were increased serum creatinine, diarrhea, nausea and dysguesia.

      Conclusion:
      Conclusion BGB324 can be safely administered to patients with advanced NSCLC for prolonged periods at doses that abrogate AXL signalling either as monotherapy or in combination with erlotinib. A proportion of patients achieve durable disease stabilisation following treatment with BGB324 alone further exploration of the efficacy of the combination is ongoing.

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    P2.01 - Advanced NSCLC (ID 618)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P2.01-047 - A Phase 1 Trial of Dose Escalated BGB324 in Combination with Docetaxel for Previously Treated Advanced NSCLC (ID 10230)

      09:00 - 16:00  |  Author(s): M. Yule

      • Abstract

      Background:
      AXL is a member of the TAM family of receptor tyrosine kinases that regulate multiple cellular responses including cell survival, proliferation, and migration. AXL expression is associated with a variety of human cancers including NSCLC, and is predictive of poor patient overall survival. AXL is associated with epithelial-to-mesenchymal transition (EMT) and is required to maintain invasiveness and metastasis. Importantly, AXL confers resistance to both chemotherapeutic agents as well as EGFR tyrosine kinase inhibitors. BGB324 is a selective clinical-stage small molecule AXL kinase inhibitor. We found in a colony formation assay with NCI-H1299 cells (AXL[+], EGFR wt) that BGB324 displayed anti-proliferative activity as single agent (IC50 348nM). In a 3D organotypic assay, BGB324 prevented 3D-growth, and formation of aggregates and migration. In a mouse xenograft NCI-H1299 model non-responsive to docetaxel, BGB324 treatment significantly enhanced the antitumor activity of docetaxel. This suggested that BGB324 could overcome acquired resistance in in vivo models of NSCLC and provided a translational rationale for combining AXL targeted therapy with docetaxel in NSCLC to enhance anti-cancer response

      Method:
      This is a multi-centre, open-label phase Ib study of BGB324 in combination with docetaxel in advanced NSCLC. The study consists of a dose escalation and expansion phase. BGB324 is administered as monotherapy for 1week after which BGB324 and Docetaxel are co-administered as a continuous treatment with 21‑day treatment cycles. It is anticipated that a maximum of two BGB324 dose levels will be evaluated, with up to 12 patients enrolled in the dose-escalation phase. BGB324 is administered orally with a loading dose/maintenance dose regimen with the first three doses (200mg or 400mg) in Cycle 1 serving as the ‘loading’ dose and a maintenance dose of either 100mg or 200mg daily thereafter. Docetaxel 75 mg/m[2 ]is administered as a one-hour IV infusion every 21 days. The BGB324 dose will be escalated in a standard 3+3 fashion until a MTD or RP2D is reached. DLT will be assessed using the NCI CTCAE version 4.03 during the first cycle of treatment (7-day lead-in plus 21 days of combination therapy). Efficacy endpoints include the response rate, progression-free survival and overall survival. Blood and archival tumor tissue samples are taken to assess the pharmacokinetic profile of BGB324 and docetaxel, and for the investigation of pharmacodynamic effects of BGB324, including tissue epithelial markers, mesenchymal markers, and AXL expression; circulating Gas6 (AXL ligand), and systemic immune response. Enrollment began in December 2016

      Result:
      Section not applicable

      Conclusion:
      Section not applicable

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    P2.07 - Immunology and Immunotherapy (ID 708)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      P2.07-062c - A Phase II Study of BGB324 in Combination with Pembrolizumab in Patients with Previously Treated Advanced Lung Adenocarcinoma (ID 10315)

      09:30 - 16:00  |  Presenting Author(s): M. Yule

      • Abstract

      Abstract not provided