The current standard of care for treating patients with newly diagnosed GBM continues to be based on a randomized phase III trial published by Stupp et al. in 2005.1
In that study, patients were treated either with RT alone or with RT and concurrent temozolomide followed by adjuvant temozolomide given for 6 months. Median OS for the temozolomide-plus-RT arm was 14.6 months, compared with 12.1 months for the RT-only arm. The present study was powered for a primary end point of increasing survival at the historical median survival time of ~15 months (see Table ). In the current study, OS for patients treated with enzastaurin and temozolomide plus RT was slightly more favorable (74 weeks; 17.1 months) compared with the Stupp et al. historical standard. There is presumptive evidence that molecular profiles of brain cancers may predict response to molecular inhibitors in at least some subgroups of patients.2,3
A posthoc subgroup analysis of patients treated in the Stupp et al. 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.21
According to that analysis, patients with MGMT promoter methylation had significantly improved OS, compared with patients with unmethylated MGMT (21.7 months vs 15.3 months). Because the analysis was performed retrospectively, prospective validation is required before MGMT methylation can be used for clinical decisions about treatment with temozolomide. In the current study, we also found a significant difference in outcome between patients with promoter-methylated MGMT and those with unmethylated MGMT. Although not providing direct evidence, these results suggest that some patient groups may be identified and possibly have their treatment tailored by this specific molecular signature. These observations will require more testing, particularly in larger, prospective, controlled clinical studies, and currently should not be used to stratify patients.
The molecular correlative analyses in the current trial also suggest an association between enzastaurin and S6 biomarker status. However, these results must be viewed with the caution that this was a small phase II study conducted in a single institution. There are several other potential molecular markers that could affect cellular response to enzastaurin, temozolomide, or RT and serve as predictors of outcome. These preliminary results suggest that molecular correlative studies should be considered as part of future multimodal combination therapy trials for patients with GBM or gliosarcoma.
In the current study, we also performed a planned comparison of the survival outcome for patients given enzastaurin in combination with temozolomide plus RT (ETRT) to several historical phase II studies of other novel agents administered with temozolomide plus RT that were conducted at our institution and published in 2004 (TTRT; thalidomide),28
in 2005 (RTRT; cis–retinoic acid),29
and in 2009 (OTRT; erlotinib).30
The current trial produced significantly greater survival times, compared with both TTRT and RTRT. However, the survival results produced by the ETRT regimen in the current trial were comparable to those from our more recent phase II trial (OTRT; erlotinib). The 3 historical studies (OTRT, RTRT, and TTRT) were chosen as comparator trials on the basis of the similar use of a noncytotoxic agent with temozolomide therapy during and after RT. There were also similarities for these trials in terms of patient characteristics, eligibility requirements, and imaging standards. The differences observed between the current trial and the 3 historical control studies may have resulted from the novel agents themselves or changing patterns of care for GBM and gliosarcoma. Until these differences in survival outcomes are further clarified and understood, comparisons of phase II studies with published survival data for patients treated with temozolomide plus RT should be interpreted with caution. In fact, recent results for patients with newly diagnosed GBM treated with temozolomide plus RT and either single-agent talampanel, poly-ICLC, or cilengitide showed significantly longer survival, compared with patients treated with only temozolomide plus RT.26
The current study (ETRT) continues this trend by demonstrating encouraging OS and PFS results, compared with previous studies (RTRT andTTRT). However, it is unclear whether the novel agent or the improved care of patients with GBM has led to this trend or whether subsequent treatments, such as bevacizumab, have influenced results. Of course, the current study and the comparator trials done at the University of California, San Francisco, are limited by the nature of their design, which is single-arm phase II trials, rather than randomized phase II trials with an experimental treatment arm compared with a standard RT and temozolmide arm.
In conclusion, enzastaurin given in combination with temozolomide plus RT was well tolerated. The paucity of significant drug-associated toxicities associated with enzastaurin, the ease of use by oral administration, and the clinical data shown here as compared with a historical 15-month survival value, make enzastaurin a potentially attractive agent to evaluate in combination with other antiangiogenic and cytotoxic agents in patients with malignant glioma. However, when compared with other similar phase II trials that have a survival approaching 20 months, the combination of enzastaurin and temozolomide does not appear to provide additional benefit, and thus, future studies appear unrealistic. In addition, it is unclear whether the present study's improved survival compared with the 15-month historical standard is attributable to enzastaurin in combination with temozolomide, an improvement in care of patients with GBM, or subsequent treatment agents, such as bevacizumab. Future similar studies will need to consider whether a historical survival standard beyond 15 months is appropriate.
Conflict of interest statement. N.B. and S.M.C. have received clinical trial funding from Merck. M.H.–K., S.J.N., and D.E.T. are employees and shareholders of Eli Lilly.