CLINICAL DEVELOPMENT OF A TYPE II EGFR KINASE INHIBITOR FOR GLIOBLASTOMAS
Led by Ingo K Mellinghoff, MD at Memorial Sloan Kettering Cancer
There is an urgent need for the development of new treatment paradigms for glioblastoma (GBM). This need could be met with a class of drugs that inhibit oncogenic kinases, enzymes that are overactive in glioblastoma cells due to mutation. Such “kinase inhibitors” already have shown activity in several other human cancers and have received regulatory approval for the treatment of certain hematologic malignancies (ABL-kinase, JAK kinases) and subsets of lung cancer (EGFR kinase, ALK kinase), sarcoma (KIT kinase, PDGFRA kinase), and melanoma (BRAF kinase). Clinical trials with kinase inhibitors in GBM have been disappointing thus far. The reason for this failure in the clinic has largely remained elusive (Mellinghoff et al., 2011). Recent work from my group has shed new light on this important question. Our work has focused on resistance to EGFR kinase inhibitors because of the extraordinarily high frequency of alterations in the EGFR gene in GBM (40-50%). We previously reported that EGFR mutations in GBM cluster in different regions of the receptor (extracellular domain) than EGFR mutations in lung cancer (kinase domain)(Lee et al., 2006). We recently observed that the EGFR mutants found in glioma are relatively insensitive to erlotinib (type I inhibitor), but are sensitive to lapatinib (type II inhibitor). In contrast, EGFR mutants found in lung cancer are more sensitive to erlotinib
than to lapatinib. This difference in drug response between EGFR mutants in GBM versus lung cancer is likely due to the distinct conformation of these receptors and may explain why erlotinib has clinical activity in lung cancer but only minimal activity in GBM (Vivanco et al., 2012). The key question now is whether lapatinib has clinical activity in GBM. To address this question, we examined tumor samples from patients who underwent surgery for GBM recurrence during lapatinib therapy. We found that lapatinib, when given at 750 mg po bid, fails to reach sufficiently high intratumoral drug concentrations to effectively inhibit EGFR (Vivanco et al., 2012). Based on these results, we are now conducting an investigator-initiated Phase II clinical trial with high-dose, intermittent (“pulsatile”) lapatinib. GlaxoSmithKline Oncology will provide lapatinib free of cost. In this proposal we would like to request funds to conduct correlative molecular studies of tumor samples collected in this trial.
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