Crizotinib
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Crizotinib

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  • Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res . 2004;64:7099-7109. Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006;66:11851-11858. Avila MA, Berasain C, Sangro B, Prieto J. New therapies for hepatocellular carcinoma. Oncogene . 2006;25:3866-3884. Semela D, Dufour JF. Angiogenesis and hepatocellular carcinoma. J Hepatol . 2004;41:864-880.

Crizotinib Presentation Transcript

  • 1. Crizotinib (PF-02341066 ) c-MET inhibitor in Patient with Alk ( anaplastic lymphoma kinase ) -positive NSCLC
    • MET is commonly overexpressed in lung cancer and its amplification may produce resistance to EGFR-TKI’s therapy
    • EML4 (Echinoderm Microtube associated protein Like4) Alk (Anaplastic lymphoma kinase) fusion frequency=4% adenocarcinoma (at least 7 fusion variants)
    • Crizotinib demonstrated potent growth inhibitory activity against H3122 (ALK fusion) cells
    • Patients with ALK -positive NSCLC Do not Appear to Respond to EGFR TKIs
    Inamura K et al. J Thorac Oncol 2008;3:13–17 Soda M et al. Proc Natl Acad Sci U S A 2008;105:19893–19897 Chiarle R et al. Nat Rev Cancer 2008;8(1):11–23; Mossé YP et al. Clin Cancer Res 2009;15(18):5609–5614 Shaw AT et al. J Clin Oncol 2009;27:4247–4253 ; Inversion Translocation OR Break-apart FISH assay for ALK -fusion genes Non-split signal Split signal
  • 2. Available data with crizotinib
    • Objective response rate (ORR): 57% (95% CI: 46, 68%)
      • 57% in patients with PS 2 or 3
    • Response duration: 1 to 15 months
    • Disease Control Rate (CR/PR/SD at 8 weeks): 87%
    • (95% CI: 77, 93%)
    • No grade 3 or 4 toxicities reported. 2% of grade 3 constipation and 1% grade 2 nausea, diarrhea and vomiting, respectively. 42% grade 1 visual disturbance (changes in light/dark accommodation, no abnormalities on ophthalmologic exam)
    ORR according to previous line therapies No. prior regimens* ORR % (n/N) 0 80 (4/5) 1 52 (14/27) 2 67 (10/15) ≥ 3 56 (19/34)
  • 3. Current crizotinib clinical trials Available at: www.clinicaltrials.gov . NCT00890825 . http://www.clinicaltrials.gov/ct2/show/NCT00890825?term=NCT00890825&rank=1
    • Key entry criteria (N=318)
    • Positive for ALK by central laboratory
    • 1 prior chemotherapy (platinum-based)
    PHASE III PHASE II
    • Key entry criteria (N=250)
    • Positive for ALK by central laboratory
    • Progressive disease in Arm B of study A8081007
    • >1 prior chemotherapy
        • Crizotinib 250 mg BID
    • Pemetrexed 500 mg/m 2 or
        • Docetaxel 75 mg/m 2
        • infused on day 1 of a 21-day cycle
    R
        • Crizotinib 250 mg BID
    PHASE III
    • Key entry criteria (N=344)
    • Positive non squamous carcinoma for ALK by central laboratory
    • Chemonaive patients
        • Crizotinib 250 mg BID
    • Pemetrexed 500 mg/m 2
        • Cisplatin 75 mg/m 2 or Carboplatin AUC5or6
        • infused on day 1 of a 21-day cycle
    R R
    • Pemetrexed 500 mg/m 2
        • Cisplatin 75 mg/m 2 or Carboplatin AUC5or6
        • infused on day 1 of a 21-day cycle
    Primary Endpoint: PFS Primary Endpoint: PFS Primary Endpoint: ORR
  • 4.