Bevacizumab/Erlotinib Combinations in the Treatment of Metastatic Renal Cell Carcinoma (RCC)

Reviewer: Neha Vapiwala, MD
University of Pennsylvania School of Medicine
Ultima Vez Modificado: 7 de noviembre del 2005

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Presenter: John D. Hainsworth, M.D.
Presenter's Affiliation: Sarah Cannon Research Institute, Nashville, TN
Type of Session: Scientific

Background

  • Most clear cell renal cancers have mutations or inactivations of the von Hippel Landau (VHL gene).
  • As a result, multiple tumor growth-signaling agents are overexpressed, including VEGF, EGF, TGF alpha, and PDGF beta.
  • Active tumors need access to nutrients and a blood supply, and the process of new blood vessel formation is called angiogenesis.
  • Considerable research has demonstrated the importance of angiogenesis for tumor growth and development.  
  • Growing tumors secrete molecules that signal for the initiation and maintenance of angiogenesis.
  • One of the main molecules that signals for angiogenesis is called vascular endothelial growth factor (VEGF).
  • Hypoxia, inflammatory molecules, and growth factors can all cause tumor cells to begin expressing VEGF.
  • VEGF has 3 known receptors by which it can transmit the signal for angiogenesis to occur.
  • A novel strategy to block tumor growth involves disrupting tumor angiogenesis by either decreasing VEGF levels or blocking VEGF receptors.
  • Bevacizumab, a humanized anti-VEGF antibody which binds to the major ligand of the VEGFR1 receptor, has shown single agent activity in refractory RCC, prolonging progression-free survival (PFS) from 2.5 months to 4.8 months when compared to placebo.
  • Additional inhibition of other pertinent signaling pathways, such as EGFR or PDGFR, may improve treatment efficacy.
  • Erlotinib is a small molecule inhibitor of the EGFR tyrosine kinase receptor.
  • Adding erlotinib to bevacizumab could potentially improve response rates in renal cell carcinoma.

     

  • Materials and Methods

    Results

    Author's Conclusions

    Clinical/Scientific Implications

    Dr. Hainsworth presented the results of two trials examining multi-drug combinations of targeted therapies for metastatic renal cell carcinoma.  These data illustrate a number of important points.  First, many clinicians have the incorrect idea that targeted therapies are always well tolerated, especially when compared with cytotoxic chemotherapy.  At least with the second trial (the 3 drug regimen), the rates of grade 3 or 4 toxicity were quite high.  It appears that if one adds together enough of these biologic agents, one can come up with a fairly toxic regimen. 

     

     
    The second important point to take away from these data is that simply because something "makes sense" in a laboratory setting, does not mean it will translate well to the clinic, in a human population.  The logic behind adding imatinib to the other two drugs is certainly sound, but in practice it did not appear to change outcomes.  Perhaps we need to learn more about exactly what these compounds do, and how various cellular pathways affect one another when inhibited, before we can be optimally “rational” about our drug design.  Imatinib is an excellent drug for CML, but at least in the way it was prescribed here, it did not significantly improve outcome. Furthermore, given the added cost of this agent, the 3-drug combination is likely going to be shelved (at least for now).  However, the preliminary results of the bevacizumab/erlotinib trial are certainly quite interesting, and there is little doubt that further research will eventually validate these findings.

     

     



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