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Exelixis, Inc. Message Board

  • hbomb57108 hbomb57108 May 2, 2013 5:07 PM Flag

    Tivantinib (ARQ197) Displays Cytotoxic Activity That Is Independent of Its Ability to Bind MET

    Interesting read. So now they say Tivantinib is not a MET inhibitor? A more tolerable second generation docetaxel - I kid

    "Translational Relevance
    MET is one of the most frequently activated tyrosine kinases in human cancer. Although a variety of MET inhibitors have been developed, only a few have progressed to the clinic. The recent failure of a phase III trial with tivantinib, the most clinically advanced molecule, could raise concerns about the validity of MET as a therapeutic target. However, the data presented here provide evidence that tivantinib is not a MET inhibitor but an antimitotic agent that kills tumor cells independently of MET. Therefore, the negative results obtained with tivantinib should not be generalized to other MET inhibitors. Moreover, selection of patients undergoing tivantinib treatment should not be based on MET status, and future clinical trials should be designed acknowledging that MET is not the pharmacologic target of tivantinib. Finally, patients who could benefit of MET inhibition should not be subtracted from treatment with an authentic anti-MET drug."

    I also wanted to note that Tivantinib phase 2 HCC randomized trial demonstrated more robust activity in localized disease vs metastatic and vascular invastion.

    Tivantinib HCC OS data demonstrates an HR of 1.89 vs placebo involving vascular invasion, and HR of .6 without vascular invasion. If you look at distant metastasis, HR was 1.04 for Tivantinib vs placebo involving distant metastasis, and HR of .45 for Tivantinib without distant metastasis.

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    • "....and future clinical trials should be designed acknowledging that MET is not the pharmacologic target of tivantinib."

      Back to the drqwing board for Arqule. What do they do with their ongoing CRC trial recruiting high MET patients?

      • 1 Reply to erniewerner
      • "Back to the drqwing board for Arqule. What do they do with their ongoing CRC trial recruiting high MET patients?"

        On the other hand, Tivantinib did demonstrate a large survival benefit in high MET subgroup analysis in phase 2 HCC data. I posed this question on Biotech value boards. Poster's on that board present interesting thoughts on limitations of the assays involved. More specifically, whether those assays would capture C-MET mutants.--I'm still bothered by Tivantinib's subgroup analysis regarding distant metastasis, and vascular invasion. I was questioning whether C-MET alone would have impact on distant metastasis. Now I really don't know for sure whether Tivantinib inhibits C-MET at all. Right now I am extremely interested in Tivantinib subgroup analysis for that phase 3 lung cancer trial that I believe will be out mid year. ---I am a big fan of METMAB data, and would like to see if Tivantinib actually had potential in that area.

        Enabler,

        Tivantinib would likely compete against Cabo in post sorafenib HCC population assuming phase 3 approvals assigned to both drugs. If Tivantinib isn't a CMET inhibitor, that would differentiate the two that much more. I assume this is the answer you are looking for? If not, I would do my best to answer your question. I have a limited understanding of assays, and folks on that biotech value board are probably better suited to decipher than myself. I'm projectchris over there, for those interested in following the thread.

    • ARQ197's IC50 number for c-Met is 0.1 μM, compare that to Cabo's dramatically lower 1.3 nM according to Selleck chem. It makes sense in light of this; thanks for the link.

 
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