Enzastaurin (ENZ) before and concomitant with radiation therapy (RTX) followed by ENZ maintenance therapy in patients with newly diagnosed glioblastoma (GBM) without hypermethylation of the O6-methylguanyl DNA-methyltransferase (MGMT) promoter: A multicenter, open-label, uncontrolled phase II study

Reporter: J. Nicholas Lukens, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 5, 2011

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Presenter: Wolfgang Wick, MD
Presenter's Institution: University Hospital Heidelberg, Heidelberg, Germany

Background/Introduction

  • The standard of care for patients diagnosed with Glioblastoma multiforme (GBM) includes maximal safe surgical resection followed by chemoradiation with the alkylating agent temozolomide (TMZ) followed by more adjuvant TMZ.
  • Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair, and has been associated with improved survival of GBM patients treated with TMZ.
    • Among patients with methylated MGMT promoter, a survival advantage was observed for those treated with RT and TMZ compared to RT alone (median survival 21.7 months vs. 15.3 months, respectively)
    • Conversely, there was a small and insignificant benefit to the addition of TMZ to RT in patients with unmethylated MGMT promoter. (Hegi, NEJM 2005, 352)
  • Therefore, there is a need for novel therapeutics in the latter subset of patients with unmethylated MGMT promoters, in whom there is questionable benefit with TMZ.
  • Enzastaurin (ENZ) is a small molecule inhibitor of protein kinase C-? (PKC- ?) that has mild anti-angiogenic effects.
    • Pre-clinical data have demonstrated that combining cerebral RT with ENZ may lead to longer survival, as well as diminished upregulation of VEGF expression, in mouse models.
    • Initial Phase I/II studies of ENZ in combination with RT and TMZ for patients with GBM had shown good tolerability, and 50% of patients had a radiologic objective reduction in evaluable disease.
    • A subsequent Phase III trial of ENZ in patients with recurrent GBM, however, had failed to demonstrate a benefit with this agent.
  • The current Phase II trial was undertaken to evaluate ENZ with RT as first line therapy for the unfavorable subset of GBM patients with unmethylated MGMT.

Methods

  • This was a single arm (uncontrolled) Phase II study which enrolled newly diagnosed supratentorial GBM patients with unmethylated MGMT promoter by PCR analysis.
    • Patients were required to have an MRI within 72 hrs post-operatively.
    • Patients with biopsy alone were allowed to enter the study.
  • Schema: ENZ 250 mg BID was given during a 7 day lead-in period, then concomitant with RT (60 Gy in 2 Gy fractions), and as maintenance therapy until disease progression or development of adverse event.
  • The primary endpoint was 6-month progression free survival (PFS).
    • The described study was powered to detect an improvement to 55% compared to the 40% rate of 6 month PFS observed in the aforementioned Hegi analysis of patients with unmethylated MGMT.

Results

  • 57 pts were enrolled over a 2 year period
  • The extent of resection varied widely, as it often does in GBM patients:
    • Only 25 patients (44%) underwent complete resection
    • 9 patients (16%) underwent biopsy only
  • 53 patients went on to receive RT to 60 Gy
  • Toxicity:
    • Generally Enzastaurin was well-tolerated, with the most common side effect being fatigue
    • Two pts had grade 3/4 possibly drug-related lab adverse events.
    • One patient died of cerebral hemorrhage that was thought to be possibly related to ENZ, due to its anti-angiogenic mechanism of action.
  • Primary endpoint: the 6 month PFS rate was 51.8%, which did not meet the pre-specified endpoint of 55%.
  • There was significant variability in the 6-month PFS based on the extent of resection:
    • 6-month PFS was 20% for biopsy-alone patients, versus 68% for patients undergoing complete resection
  • 86% of patients discontinued the drug during the study, most often due to progressive disease.

Authors' Conclusions

  • While this study did not meet its primary endpoint of improvement in 6-month PFS, the results are "encouraging with a 6-month PFS survival rate of 52%, which compares favorably to the historical control used in this trial, the subset of unmethylated MGMT patients in the Hegi analysis, who had a 6-month PFS rate of 40%.
  • The extent of surgical resection has great prognostic significance, as has been demonstrated in other studies of GBM patients.
  • Further molecular analysis, for example an analysis of PKC-? or VEGF expression, may help identify a subset of patients who benefit from the addition of Enzastaurin to RT.
  • While Enzastaurin did not show activity as a single agent in the setting of recurrent GBM, its purported mechanism of action makes it reasonable to combine with radiation therapy in the front-line setting.

Clinical/Scientific Implications

  • Overall, this study represents an important investigation of potential treatment for a group of patients with few treatment options and overall poor prognosis.
  • There are several concerns about the design of this trial which confound its interpretation:
    • There was no control arm; rather the 6-month PFS rate was compared to historical controls. This is problematic insofar as this was a small study and there was wide variability in the extent of surgical resection, which we know has a profound impact on PFS in GBM patients. Therefore, a control group is important, even if control patients receive placebo rather than TMZ.
    • The primary endpoint of 6 month PFS is not ideal, because it is often difficult to differentiate progression from pseudo-progression in the months following chemoradiation. The endpoint was justified by the authors as a conservative one intended to get some signal of activity.
    • If the agent has no activity in the second-line setting for recurrent disease, is it ethical to test it as first line therapy? Based upon radiation biology and the potential activation of signaling pathways affected by this drug, it may be reasonable to consider this drug in the first-line setting with RT, despite its lack of efficacy as a single agent.
    • There was no molecular profiling to suggest PKC over-activation in the subset of GBM patients with unmethylated MGMT, so it is unclear whether this subset of patients represents a rational target population for this drug.
  • Enzastaurin may prove efficacious in the treatment of GBM patients, but there is a need for predictive biomarkers to define a subset of patients that is more likely to benefit from this agent.
  • There remains a great need for effective first-line therapeutics for patients diagnosed with GBM with unmethylated MGMT.