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  • pharmainvestor11 pharmainvestor11 May 16, 2012 7:38 PM Flag

    ASSO Abstracts Info Out Tonight

    Abstract:4006

    Background: Tivantinib (T) is a selective, oral inhibitor of c-Met, the tyrosine kinase receptor for hepatocyte growth factor involved in tumor cell migration, invasion, proliferation and angiogenesis. T has shown promising results in HCC in phase 1 studies as monotherapy and in combination with sorafenib. Methods: This multi-center RCT, enrolled pts with unresectable HCC, 1 failed systemic therapy, ECOG PS <2. Child-Pugh B-C were excluded. Pts were randomized 2:1 to oral T {360 mg bid (A), 240 mg bid (B)} or placebo (P), stratifying by PS and vascular invasion (VI). Treatment continued until disease progression (PD) or unacceptable toxicity. RECIST 1.1 response was evaluated by CT / MRI every 6 weeks. Crossover to open-label T was allowed after PD. Primary endpoint was time to tumor progression (TTP) in the intent-to-treat (ITT) population by central radiology review. Other endpoints included disease control rate (DCR), PFS, OS, efficacy in Met+ (Met ≥ 2+ in >50% of tumor at immunohistochemistry) pts, safety.

    Results: Characteristics of the 107 enrolled HCC pts (A= 38, B= 33, P= 36) in T/P: 58/28 male; median age 70/68; PS 0 41/21; VI 22/13; Met+ 22/15; Met- 27/13. Dose A was reduced to B in all pts due to G≥3 neutropenia (NEUT) rate. Major TTP, DCR and PFS benefits were obtained in Met+ pts, with preliminary OS trend favoring T (HR=0.47) and no detrimental effect in Met- pts. DCR (95% CI) in T/P was 44 (31-56) / 31(16-48)% for ITT and 50 (28-72) / 20 (4-48)% in Met+ pts. Most common AEs in T were asthenia (26.8%), NEUT (25.4%), low appetite (25.4%); most common drug-related AEs were NEUT (25.4%), anemia (15.5%). Most frequent drug-related serious AE was neutropenic sepsis (4.2%). Efficacy was similar in A / B with less frequent NEUT in B (21.1% / 6.1%). Final OS, PK, biomarker data will be presented.

    Conclusions: Compared to P, T significantly benefited second-line HCC pts, especially if Met+, with manageable safety profile at 240 mg BID.



    Median: T arm P arm HR Log-rank p value
    TTP (mos)
    ITT 1.6 1.4 0.64 0.04
    Met + 2.9 1.5 0.43 0.03

    PFS (mos)
    ITT 1.7 1.5 0.67 0.06
    Met + 2.4 1.5 0.45 0.02

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    • 2nd-line HCC is a new indication for me. However,

      "benefits were obtained in Met+ pts, with preliminary OS trend favoring T (HR=0.47) and no detrimental effect in Met- pts"

      HR and p-values are very solid,

      PS
      I wish to see the same results in the NSCLC trial.

      What is OS for 2nd-line HCC patients?

 
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