Lay Summary: Gleevec is not active in glioblastoma but may have promise in combination with other drugs.
Despite optimal treatment, the prognosis of patients with malignant gliomas remains poor. Patients with glioblastoma multiforme have a median survival of 9 to 14 months, whereas those with anaplastic astrocytomas have a median survival of 24 to 36 months. Once patients develop tumor progression, conventional chemotherapy is generally ineffective, with a median time to tumor progression of 9 to 13 weeks. There is a need for more effective therapies.
Tyrosine kinases play a fundamental role in signal transduction, and deregulated activity of these enzymes has been observed in an increasing number of cancers. There is growing evidence that specific inhibitors of these tyrosine kinases have potential therapeutic applications in oncology and Gleevec is being actively investigated in this disease. in one phase II component, the 6M-PFS for glioblastoma multiforme patients was 3%, whereas that for anaplastic glioma was 10%. In comparison, a retrospective review of negative phase II trials in recurrent malignant gliomas from the M.D. Anderson Cancer Center found a 6M-PFS of 15% for glioblastoma multiforme and 31% for anaplastic glioma. The results are especially disappointing for anaplastic gliomas where the relative importance of PDGF raised the possibility of potential benefit from imatinib.
The European Organization for Research and Treatment of Cancer and the North Central Cancer Treatment Group are also conducting phase II studies of imatinib in recurrent gliomas. In the European Organization for Research and Treatment of Cancer study, glioblastoma multiforme and anaplastic glioma patients were initially treated with imatinib at a dose of 300 mg twice daily, increasing after 8 weeks to 400 mg twice daily if no grade II toxicity was observed. Subsequently, the protocol was amended to treat patients initially with 400 mg imatinib twice daily, increasing to 500 mg twice daily if no toxicity was observed after 8 weeks. The majority of these patients were on EIAED, and there was no attempt to adjust the dose according to the type of AED. Preliminary results of the European Organization for Research and Treatment of Cancer phase II study in glioblastoma multiforme patients showed 3 partial response and 5 stable disease over 6 months in 51 patients, with a 6M-PFS of 15.7%. In anaplastic glioma patients, there was only 1 partial response in 36 anaplastic oligodendroglioma/anaplastic oligoastrocytoma patients and 1 partial response in 25 anaplastic astrocytoma patients. These results are consistent and suggest that imatinib has minimal single-agent activity in malignant gliomas.
The next step was studying Gleevec in combiantion with other drugs. As an example of the trend, I will focus on Gleevec and Hydrea data. Researchers from Germany have reported clinical benefit in 57% of patients with refractory glioblastoma multiforme treated with Gleevec (imatinib) and hydroxyurea. The details of this phase II study appeared in the September 2005 issue of Annals of Oncology. The current trial included 30 patients with progressive glioblastoma multniorme refractory to chemotherapy and radiation therapy. The combination of Gleevec and hydroxyurea led to a 20% response rate and a disease stabilization rate of 37%. The median time to disease progression was 10 weeks and the overall survival was 19 weeks. Three patients continue on therapy for 106 or more weeks. The two-year progression-free survival was 16% with 32% of patients surviving at least six months. These authors suggest that this combination shows promise. Clearly much more investigation needs to be done before this combination can be routinely prescribed.
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