Author of

• 10801

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  P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Medical Oncology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 10849

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    P1.11-049 - TSR-011: A Potent Inhibitor of ALK Including Crizotinib-Resistant Mutations in Phase 1-2 Development for ALK+ NSCLC (ID 3466)

    09:30 - 09:30  |  Author(s): R.E. Martell
    • Abstract

    Background
    Significant progress has been made in the identification of subsets of non-small cell lung cancer (NSCLC) driven by tyrosine kinase gene fusions (including gene fusions of ALK, RET, ROS1 and NTRK1). Despite approval of crizotinib for ALK+ NSCLC there are still significant challenges and high unmet need to develop new agents with durable efficacy against these kinase gene fusions that initiate NSCLCs. In order to address limitations of crizotinib, and to provide treatment option with increased activity against crizotinib resistance mutations and amplified EML4-ALK, TSR-011, a potent, small molecule, second generation ALK inhibitor is undergoing clinical evaluation. TSR-011 was designed using X-ray structure based drug design, and hence has high affinity for the ALK kinase domain (Kd = 0.36 nanomolar, [nM]). TSR-011 inhibits wild type, recombinant ALK kinase activity with an IC50 value of 0.7 nM and exhibits sustained potent inhibition of EML4-ALK-dependent tumor growth in mice. ALK amplification and mutations that are important drivers of tumor cell growth or crizotinib resistance are inhibited by TSR-011 at low nM (IC50 values of 0.1 to 2.2 nM) concentrations. TSR-011 is a similarly potent inhibitor of recombinant TRK kinases including suppressing proliferation of a NTRK1-rearranged colorectal cancer cell line in vitro. Collectively, the selective and potent activity of TSR-011 against ALK, and clinically observed crizotinib resistance mutations, coupled with pharmacologic properties that predict a low clearance, minimal risk for drug interactions, wide distribution and long half life, make TSR-011 a promising 2[nd] generation ALK inhibitor.

    Methods
    A Phase 1-2a dose escalation and cohort expansion study is underway to evaluate safety, tolerability, PK, and preliminary efficacy of TSR-011. Phase 1 is evaluating unselected patients with advanced solid tumors and lymphomas. The recommended Phase 2 dose will be evaluated in Phase 2a in patients required to have ALK+ tumors (defined by immunohistochemistry or fluorescent in-situ hybridization) including those with NSCLC progressing on, or naïve to, ALK inhibitor therapy.

    Results
    As of June 2013, patients have been enrolled at oral doses between 30 and 480 mg. Pharmacokinetic parameters have been dose responsive and human drug exposures in excess of that associated with efficacy in murine xenograft models are maintained for the entire dosing interval. Two of the first five patients have SD. A patient with EML4-ALK+ NSCLC with metastatic pericardial thickening and symptomatic disease, who progressed on crizotinib showed clinical improvement in symptoms and thinning of the pericardium by 6 weeks of treatment and continues on study.

    Conclusion
    Based on tight binding to ALK, potency at inhibiting enzymatic activity, as well as activity against crizotinib resistant mutations and early clinical data, TSR-011 is a promising agent for both ALK-dependent and crizotinib resistant NSCLC.