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Posted May 25, 2008

Cediranib safe, effective for glioblastoma

AZD2171, an oral pan-VEGF receptor tyrosine kinase inhibitor, was a safe and effective treatment for patients with glioblastoma, according to Tracy T. Batchelor, MD.

Batchelor, executive director of the Center for Neuro-Oncology at Massachusetts General Hospital, and colleagues conducted a phase-2 trial of AZD2171 (cediranib, AstraZeneca) in 31 patients with glioblastoma who did not have a response to prior therapy with surgery, radiation or chemotherapy.

The primary outcome of the study was the proportion of patients alive with no disease progression at six months. “Our percentage at six months was 25.8%,” Batchelor said. “This compares favorably to historical controls, who are around 15%.”

The median progression-free survival was 117 days, and the median overall survival was 227 days.

More than half of the patients had a reduction in tumor mass and edema, which is higher than outcomes with other conventional chemotherapy drugs, Batchelor said. “Cediranib normalized the tumor blood vessels and alleviated the edema, which is a major cause of morbidity in this patient population,” he said.

The researchers observed a reduction in the edema mass effect using MRI. Fifteen of the 16 patients who were receiving steroids were able to reduce their dose. Five patients discontinued use of steroids.

Toxicity was manageable, according to Batchelor. Fifteen of 31 patients required at least one dose reduction.

The researchers observed no intracerebral hemorrhage in these patients, and there were no treatment-related deaths.

The prognosis for adults and children with malignant gliomas remains quite poor and this is especially true for patients with recurrent disease following conventional treatment with surgery, radiotherapy and often chemotherapy. The abstract by Batchelor concerning their experience with AZD2171, on oral pan-VEGF receptor kinase inhibitor, is interesting and adds to the growing body of experience with the use of anti-VEGF receptor therapy in patients with gliomas. The combination of bevacizumab, a VEGF-neutralizing antibody and the topoisomerase-1 inhibitor, irinotecan, has been demonstrated to be active in patients with recurrent malignant gliomas. Different drug schedules of this drug combination have been used and objective response has been dramatically high, ranging between 47% and 63%. Although, in studies the six month progression-free survival is encouraging at approximately 40%, the majority of patients with malignant gliomas ultimately will relapse a few (four to eight) months following the initiation of therapy and succumb to their disease. The relative contributions of the bevacizumab and irinotecan to tumor control remain to be clarified, although at first glance the drug combination seems to be better than the use of each individual agent alone. This is especially true for the irinotecan, which has been shown to have modest efficacy when used as single agent for patients with recurrent high grade gliomas.

In this perspective, the median progression free survival rate of 117 days and the median overall survival of 227 days with the use of AZD2171 is comparable. In addition, the drug reduced the peritumoral edema and allowed steroid taper. The early experience with AZD2171 suggests that this is a manageable drug, however, it does cause troublesome side effects such as fatigue, hypertension, and diarrhea. It is reassuring that no intracerebral hemorrhage was noted but the number of patients studied remains small and this continues to be a major concern, especially when coupled with the associated hypertension.

Despite these cautions, it does seem that the use of VEGF inhibitors have resulted in probably the best response rates seen, to date, for patients with recurrent glioblastoma multiforme. Future studies, no doubt, will utilize these agents, following surgery, either coupled with radiotherapy or immediately postcompletion of radiotherapy. The toxicities encountered in patients with newly diagnosed disease may be somewhat more difficult to manage than in those with recurrent disease and the issue of intracerebral hemorrhage will likely become even more significant. However, given the results reported by Batchelor, AZD2171, although not curative in patients with recurrent disease, should be added to the growing number of agents that should be investigated carefully in controlled studies in patients with newly diagnosed high grade gliomas.

– Roger Packer, MD

HemOnc Today Editorial Board member

For more information:

Batchelor T. #LB-247. Presented at: 2008 Annual Meeting of the AACR; April 12-16; San Diego.