Phase I study examines biomarkers for response to erlotinib in glioma
Researchers have found two biomarkers that, in patients with a malignant type of brain tumor called glioblastoma multiforme, were associated with response to the cancer drug erlotinib (Tarceva). Patients with tumors that expressed high levels of epidermal growth factor receptor (EGFR) and low levels of phosphorylated PKB/Akt, an enzyme, responded better to erlotinib than patients with low levels of EGFR expression and high levels of phosphorylated PKB/Akt. The study findings appear in the June 15 issue of the Journal of the National Cancer Institute.
Efforts to improve treatment for gliomas have not substantially increased long-term survival. The EGFR tyrosine kinase inhibitor erlotinib has shown promising response rates in malignant gliomas. EGFR mutations in non–small-cell lung cancer tumors have been associated with better response to another tyrosine kinase inhibitor, gefitinib (Iressa). However, other tumor types do not carry similar mutations, which indicates that other molecular characteristics of EGFR or the tumor may be associated with response to tyrosine kinase inhibitors in these tumors.
To determine possible biomarkers of erlotinib response in gliomas, Daphne A. Haas-Kogan and David Stokoe, of the University of California, San Francisco, and colleagues studied tumor tissue samples from 41 participants in a phase I trial in which glioma patients were treated with erlotinib either alone or in combination with temozolomide. The tumors were examined to determine whether the expression of EGFR and its related proteins were associated with response to erlotinib.
Eight of the 41 glioma patients responded to erlotinib treatment. Response to erlotinib was associated with EGFR expression and amplification, and this association was stronger among the 29 patients initially diagnosed with glioblastoma multiforme. None of the 22 patients whose tumors had high levels of phosphorylated PKB/Akt responded to erlotinib, whereas eight of the 18 patients with low levels of phosphorylated PKB/Akt did respond. The level of phosphorylated PKB/Akt was also associated with time to progression. The researchers plan to use these results in the design of a phase II trial.
"Future trials of EGFR inhibitors should build on our current findings and with prospective molecular profiling should establish the most appropriate agent(s) for each individual patient. Clearly, in clinical trials testing signaling inhibitors, selection of patients with appropriate molecular characteristics will not only help to assess the true efficacy of specific novel agents but will also maximize benefits to individual patients," the authors write.
In an editorial, Federico Cappuzzo, M.D., of Bellaria Hospital in Bologna, Italy, discusses these latest findings and their relation to previous studies that have looked for biomarkers for response to tyrosine kinase inhibitors. "[E]rlotinib may be active in a small fraction of gliomas with EGFR expression or amplification. Although there is an inverse association between Akt activation and response to erlotinib, it seems unlikely that sensitive patients have no EGFR-dependent Akt activation," he writes. "The results of this preliminary study, thus, should stimulate further prospective studies to identify predictive markers for EGFR-TKI sensitivity in gliomas before their use in clinical decisions."
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