The current standard of care for treating patients with newly diagnosed GBM is based on a randomized phase III trial published in 2005.2
In that study, patients were treated either with radiation alone or radiation with concurrent temozolomide followed by adjuvant temozolomide given for 6 months. Median survival for the temozolomide-plus-radiotherapy arm was 14.6 months as compared with 12.1 months for the radiotherapy-only arm. The 2-year survival rate for the temozolomide-treated group was 26%, compared with 10% for the radiation-only group. A posthoc subgroup analysis of patients treated in this trial correlating MGMT
promoter methylation with survival was conducted in an attempt to define patient groups that may be more or less sensitive to treatment.12
Patients with MGMT
promoter methylation had significantly improved median survival compared with patients with intact MGMT
(21.7 months v
As encouraging as these results are, however, most patients die of tumor progression. In this study we attempted to improve survival outcome over that seen with temozolomide and radiotherapy. Combining temozolomide with erlotinib and radiotherapy did reveal encouraging results. Compared with the historical phase II studies conducted at our institution, this new trial seems to show superior outcomes.10,11
We chose the two historical studies for comparator trials based on the similarity of the three trials in terms of patient characteristics, eligibility requirements, and imaging standards, as well as the use of temozolomide during and after radiotherapy. In addition, both historical studies added a noncytotoxic agent to radiation and temozolomide. The previous studies did not represent a significant improvement over that seen with radiotherapy and temozolomide alone. Of particular interest with the current study is the improvement in both progression-free and median survival. It should be noted that few patients were declared to have experienced disease progression at the initial postradiation assessment, well beyond the time frame when pseudoprogression may have occurred. We feel encouraged that the longer PFS in this study was due to a positive and sustained treatment effect.
The molecular correlative studies in this trial confirm the survival advantage seen in patients with MGMT promoter methylation and also suggest an interaction between MGMT and PTEN status. One significant observation was the inability to escalate the dose of erlotinib to our planned higher dose in patients treated with EIAEDs. It is possible that erlotinib exposure was reduced in this subset of patients. Whether higher doses or improved systemic exposure would have further increased survival in these patients is unknown, however, as pharmacokinetic data were not collected from these patients, the patient subset was small, and other patient factors may have influenced outcome. Our results must be viewed with the caution that this was a small, phase II study conducted in a single institution.
We and others have tested several agents in combination with temozolomide, using agents that showed in vitro and in vivo impact on specific molecular targets that seem relevant to glioma cell growth. Targeting EGFR
is a strategy based both on preclinical and preliminary clinical human data in patients with recurrent malignant glioma. Phase I testing of the combination of temozolomide and erlotinib documented tolerability, and preliminary evidence of efficacy of single-agent erlotinib, although modest at best, was encouraging.7
Studies of the combination of temozolomide and the EGFR
inhibitor gefitinib (Iressa; AstraZeneca, Wilmington, DE) have also been conducted, demonstrating tolerability and evidence of efficacy in recurrent disease.13
However, phase I and II studies of gefitinib and erlotinib used as single agents adjuvant to radiotherapy have shown no major improvements in survival for patients.14–16
None of these studies included temozolomide in the treatment regimen, and it seems that single-agent treatment with an EGFR
inhibitor in newly diagnosed disease may not be beneficial.
There is presumptive evidence that molecular profiles may predict response to EGFR
inhibitors in at least some subgroups of patients.8,17
In previous studies, patients with recurrent disease were more likely to respond to erlotinib or gefitinib if their tumors were found to be either EGFR
overexpressed, amplified, or mutated, plus intact for PTEN
, or without Akt phosphorylation. Other studies, however, have not shown such correlations.18
In this current study, we found a significant difference in outcome, both for median and 2-year survival expectations, between patients with promoter-methylated MGMT
and those with unmethylated MGMT
. This result is consistent with the subgroup analysis performed by the European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada phase III trial.12
In addition, patients who had MGMT
gene silencing and intact PTEN had a significant survival advantage. Although this is not direct evidence, it at least suggests that some patient groups may be influenced and possibly identified by this specific molecular signature. The MGMT
promoter methylation status was not evaluated in our previous two clinical trials, and we cannot directly compare survival outcomes within this molecular context. Attempts are ongoing to retrieve tumor blocks from those patients. However, there is no reason to believe that the general mix of tumor types will have changed substantially over this interval, and the absence of this information must be considered one of the random factors that need to be recognized in any clinical trial comparison using historical data sets. These observations need much more testing, particularly in larger, prospective, controlled clinical studies, and currently should not be used to stratify patients.
In conclusion, the current study shows encouraging PFS and median survival over that seen in our previous studies. We feel that further evaluation of this combination is warranted in a larger prospective trial, with additional molecular correlative studies.