ROCKVILLE, MarylandThe Food and Drug Administration (FDA) has approved a
new indication for Temodar capsules (temozolomide, Schering-Plough) for use
concurrently with radiotherapy for the treatment of adults with newly diagnosed
glioblastoma multiforme (GBM) and as maintenance therapy after radiotherapy.
The FDA based its decision on study data that showed a statistically
significant overall survival benefit in such patients.
The FDA also granted Temodar full marketing approval for the treatment of
adult patients with refractory anaplastic astrocytoma, for which it initially
received accelerated approval in 1999.
Temodar is an oral cytotoxic alkylating agent designed to prevent the
replication of rapidly dividing cells through the alkylation of DNA by the
diazomethane precursor MTIC, a compound to which the drug is converted.
Physicians diagnose between 8,000 and 10,000 new cases of GBM annually.
Researchers have not demonstrated that the drug is effective in treating
FDA granted priority review last September to the company’s application for
the drug’s indication in GBM, meaning that Temodar, if approved, would provide
a significant advance in treating an unmet medical need.
Schering-Plough submitted a 573-patient phase III trial conducted by the
European Organization for Research and Treatment of Cancer (EORTC) to support
Temodar’s GBM indication (N Engl J Med 352:987-996, 2005).
Researchers randomized 287 newly diagnosed GBM patients to Temodar plus
radiotherapy and 286 to radiotherapy only. The Temodar-treated group received
75 mg/m2 of the drug once daily from their first day until their last day of 42
radiotherapy treatments. This schedule was followed by six cycles of Temodar
alone (150 to 200 mg/m2) on days 1 to 5 of every 28-day cycle starting 4 weeks
after the last radiotherapy session. Control patients received the same
radiotherapy schedule without Temodar.
At the time of disease progression, Temodar was given as salvage therapy to
161 patients (57%) in the radiotherapy-only arm and 62 patients (22%) in the
Temodar plus radiotherapy arm.
The addition of concomitant and maintenance Temodar to radiotherapy showed a
significant improvement in overall survival, compared with radiotherapy alone:
14.6 months vs 12.1 months (hazard ratio 0.63; P < .0001). "After 26 years of
practicing neuro-oncology, I view Temodar as a significant advancement in battling GBM," said
Henry Friedman, MD, co-director of the Clinical Neuro-Oncology Program at Duke
University’s Brain Tumor Center.
The company also submitted a single-arm, multicenter trial as confirmatory
evidence of Temodar’s safety and efficacy in treating refractory anaplastic
astrocytoma, which FDA required as part of granting the drug accelerated
approval for use in the brain cancer. The study enrolled 162 patients, 54 with
refractory disease. In this subgroup, 12 patients (22%) responded and 5 (9%)
had a complete response. Response duration in these 12 patients ranged from 16
to 114 weeks (median, 50 weeks); complete responders had a response duration of
52 to 114 weeks (median, 64 weeks).
Progression-free survival in responders was 45% at 6 months and 29% at 12
months. Median progression-free survival was 4.4 months, and median overall
survival was 15.9 months.
During the concomitant phase (Temodar plus radiotherapy) of the European
GBM study, adverse events that were more common in the Temodar group included
thrombocytopenia, nausea, vomiting, anorexia, and constipation. The most common
adverse events across the experience of Temodar use are alopecia, nausea,
vomiting, anorexia, headache, and constipation, according to Schering-Plough.
Myelosuppression was the dose-limiting adverse event in the GBM study. When
the researchers combined laboratory abnormalities and adverse events, grade 3-4
neutrophil abnormalities, including neutropenia, occurred in 8% of the Temodar
patients and grade 3-4 platelet abnormalities, including thrombocytopenic
events, were observed in 14%.