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F. Fattah



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    P1.07 - Immunology and Immunotherapy (ID 693)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      P1.07-031 - Autoantibodies Associated with Risk of Subclinical Autoimmunity and Immune-Related Adverse Events from Checkpoint Inhibitor Therapy (ID 10153)

      09:30 - 09:30  |  Author(s): F. Fattah

      • Abstract

      Background:
      Immune checkpoint inhibitors have emerged as a highly promising treatment option for advanced lung cancer. However, a minority of patients develop unpredictable, potentially severe, and possibly permanent immune-related adverse events. We hypothesized that pre-existing subclinical autoimmunity predisposes patients to these toxicities.

      Method:
      We collected serum from patients treated with immune checkpoint inhibitors at multiple time-points: pre-treatment, 2-3 weeks, 6 weeks, 12 weeks, every 12 weeks thereafter, and at time of toxicity. We determined baseline and dynamic autoantibody profiles associated using an array panel of 125 antigens including nuclear, cytosolic, and tissue-specific antigens. Autoantibody levels between toxicity and no toxicity groups were compared using the quasi likelihood F test.

      Result:
      A total of 29 subjects were enrolled. Mean age was 69 years, 55% were women, and 83% had lung cancer. Immune-related adverse events occurred in 31% of cases as follows: pneumonitis (n=6), endocrinopathy (n=2), dermatitis (n=1). We also enrolled 11 healthy controls who underwent two blood draws 2-3 weeks apart. Across the entire cohort, there was substantial variation in baseline autoantibody levels. Patients receiving immunotherapy demonstrated a trend toward greater increase in autoantibody levels over time compared to the control group (P=0.23). In general, the greatest increases in autoantibody levels were noted among individuals with the highest baseline autoantibody levels. Broadly, elevated baseline levels of autoantibodies were associated with the development of immune-related adverse events, with 4 individual antibodies classically associated with systemic autoimmunity having significantly higher levels in the toxicity group (P<0.05). Immune-related adverse events were also more common among cases with greater post-treatment increase in antibody levels, with 10 individual antibodies having significant increases in the toxicity group (P<0.05).

      Conclusion:
      Subclinical autoimmunity occurs in a substantial proportion of patients with lung cancer and other malignancies. These clinically silent auto-antibodies may be associated with increased risk of immune-related adverse events from immune checkpoint inhibitor therapy.

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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 - 09:00  |  Author(s): F. Fattah

      • 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