Glioblastoma multiforme (GBM) is the most common and most malignant form of primary brain cancer. Approximately 9,500 cases of GBM are diagnosed each year in the U.S., representing roughly half of all malignant brain tumors. GBM is incurable and is the third deadliest form of cancer (after cancers of the lung and pancreas) with most patients dying within 2 years of diagnosis.

Treatment of GBM remains one of the most challenging fields in oncology. Current treatment involves surgical resection to the extent feasible, followed by radiotherapy given with or without chemotherapy. Until recent years, numerous trials evaluating different chemotherapy regimens have largely failed to show a clear survival benefit and thus, treatment of GBM consisted primarily of surgery and radiotherapy. However, two chemotherapeutic agents have recently received FDA approval: Temodar (Temozolomide; Schering-Plough), which is an oral agent given as an adjunct to radiotherapy; and Gliadel wafers (Carmustine wafers; MGI Pharma), which are directly placed within the tumor site to release the chemotherapeutic agent Carmustine. Both agents have shown a small, though significant, survival benefit. The survival benefit is greater with Temodar and given the dearth of active treatments for GBM, Temodar is now widely used as part of a triple modality regimen (alongside surgery and radiotherapy).

Despite the incremental improvements in survival with this treatment regimen, patients with GBM have a poor prognosis with less than 25% of patients surviving beyond 2 years. In patients with newly diagnosed disease, the median survival is 9 to 15 months. Even after successful initial treatment, GBM almost invariably recurs and in patients with recurrent disease, the median survival is 4 to 6 months.

There are several new drugs in development with the majority of these falling under 3 broad categories: immunotoxins, EGFR inhibitors, and angiogenesis inhibitors. Of these three, we believe that immunotoxins and angiogenesis inhibitors have the most compelling data. While EGFR mutations are the most common mutations seen in GBM, the lack of appropriate EGFR mutations (exon 19 and 21) in GBM tumors and the lack of activity seen with Iressa (Gefitinib; AstraZeneca) and Tarceva (Erlotinib; OSI Pharmaceuticals, Chugai, Genentech, and Roche) monotherapy make these agents unlikely treatment candidates. The immunotoxins are delivered to the brain tumor via Convection-Enhanced Delivery (CED), and of these, IL-13-PE (Cintredekin Besudotox; Neopharm) and TransMID (Transferrin-CRM107; Celtic Pharmaceuticals) appear to be the most promising. In contrast, angiogenesis inhibitors are given systemically and we believe that Avastin (Bevacizumab; Genentech) and Revlimid (Lenalidomide; Celgene) hold the most promise.

Overall, we expect the treatment of GBM to continue to consist of surgical resection, radiotherapy and Temodar, particularly in newly diagnosed patients. However, we expect some decline in the use of Temodar in newly diagnosed patients due to competition from new agents in development and we expect this decline to be more dramatic in recurrent GBM patients.

For patients with newly diagnosed GBM, we expect Temodar to continue to be widely used but we also expect a strong uptake of Revlimid in these patients. Although Revlimid is currently being evaluated as a monotherapy, we project that Revlimid will be more effective in combination with Temodar and will be used as such. We also expect some off-label use of Avastin and IL-13-PE in newly diagnosed patients. We expect this uptake of IL-13-PE in newly diagnosed patients to increase after 2010, when results of studies in newly diagnosed patients may become available. We also foresee a small uptake of TransMID in newly diagnosed patients who have non-operable disease (those not eligible for initial surgical resection of the tumor – generally due to poor health or because the tumor is in a critical area of the brain).

In patients with recurrent disease, we expect IL-13-PE to enjoy a wide adoption in patients who are eligible for reoperations. In recurrent patients who are ineligible for reoperations, we expect Avastin to dominate. However, we also project some uptake of TransMID and Revlimid in these patients.

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