RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM)

Reporter: J Taylor Whaley, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 3, 2013

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Presenter: Mark R. Gilbert, MD
Presenter's Affiliation: University of Texas MD Anderson Cancer Center Department of Neuro-Oncology, Houston, Tx

Background

  • Glioblastoma Multiforme (GBM) is the most common primary malignant brain tumor in adults, accounting for 40% of primary CNS malignancies.
  • The standard of care for patients diagnosed with Glioblastoma multiforme includes maximal safe surgical resection followed by chemoradiation with the alkylating agent temozolomide (TMZ) with additional adjuvant TMZ (6-12 cycles) following completion of radiation.
  • Despite aggressive therapy, patients with GBM have a poor prognosis with observed survival typically 12-18 months.
    • Therefore, there is a need for novel therapeutics in this group of patients.
    • GBM is characterized by excessive angiogenesis, making this a potential target for treatment. Furthermore, improving blood flow may improve oxygenation for more effective radiation and improve drug delivery for chemotherapeutics.
    • Initial studies with Bevacizumab in the recurrent setting demonstrated remarkable radiographic responses, prompting trials in the newly diagnosed setting.
    • A Phase II study from Duke University demonstrated better than expected survival when combining Bevacizumab with TMZ and radiation for newly diagnosed patients. This trial revealed an unprecedented 21 month median overall survival, creating a significant amount of excitement in the neuro-oncology field.
  • Bevacizumab is a monoclonal antibody that binds to and inhibits the activity of vascular endothelial growth factor (VEGF). This prevents VEGF from interacting with its receptor on endothelial cells, subsequently, inhibiting the formation of new blood vessels, which slows the growth of tumor.
  • The current Phase III trial was undertaken to determine if the addition of Bevacizumab to standard CRT improves survival (OS) or progression-free survival (PFS) in newly diagnosed GBM.

Materials and Methods

  • This phase III multi-center international trial was conducted jointly by the RTOG, NCCTG, and ECOG.
  • In this international trial, entry criteria were as follows:
    • Neurologically stable pts > 18 yrs with KPS ? 70, and > 1cm3 tumor tissue block, and no multifocal disease
  • Patients were randomized to the following:
    • Arm 1: standard RT with TMZ plus placebo
    • Arm 2: standard RT with TMZ plus Bevacizumab (10 mg/kg IV every 2 weeks).
  • Experimental treatment began at week 4 of radiation then thru 6-12 cycles of maintenance chemotherapy.
  • Co-primary endpoints were overall survival (OS) and progression free survival (PFS), with significance levels of .023 and .002, respectively. The accrual target was selected for 25% reduction in death with 30% reduction in PFS.
  • Secondary endpoints included toxicity evaluation, symptom burden, quality of life evaluation, Net Clinical Benefit (NCB), evaluation of MGMT methylation and prognostic 9 gene signature status (either favorable or unfavorable).
  • At progression, treatment was unblinded and patients were allowed to crossover or continue Bevacizumab.
  • Symptom, QOL and neurocognitive (NCF) testing was performed for the majority of patients. Longitudinal neurocognitive function testing was performed at baseline, week 10, 22 and 34 of the trial using Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test (TMT) and Controlled Oral Word Association.

Results

  • Goal accrual was 942 patients. Actual accrual was 978 registered patients; 637 were randomized from 4/2009-5/2011.
  • Inadequate tissue (n=105) and blood on imaging (n=40) were key reasons for non-randomization.
  • Age, gender, race, KPS, neurocognitive function, and RPA were well balanced.
  • 60% of patients had gross total resection.
  • No difference was found between arms for median overall survival (median 16.1 vs. 15.7 months).
  • PFS was extended for Arm 2 (7.3 vs. 10.7 months, p = 0.004) but did not reach significance.
  • Patients with MGMT methylation had superior OS (23.2 vs. 14.3 mo, p < 0.001) and PFS (14.1 vs. 8.2 months, p < 0.001).
  • Neither the 9 gene signature nor MGMT predicted selective benefit for Bevacizumab treatment. The best prognosis patients (those with MGMT methylation and favorable 9-gene score) had a worse survival trend with Bevacizumab (15.7 vs 25 months p = 0.08).
  • No subgroup had improved overall survival with Bevacizumab treatment.
  • To date, 128 pts were unblinded on Arm 1 (salvage Bevacizumab in 86) and 87 pts on Arm 2 (continued Bevacizumab in 39). In total, 40% of patients on the placebo arm crossed over to the Bevacizumab treatment.
  • Treatment was well-tolerated with expected toxicity. Increased grade 3/4 toxicity was seen with Bevacizumab, mostly neutropenia, hypertension, and DVT/PE.
  • 504 patients participated in the neurocognitive testing. There were significant differences in the objective and patient reported outcomes with a progressive and significant decline in the Bevacizumab arm.

Author's Conclusions

  • The addition of Bevacizumab for newly diagnosed GBM did not improve overall survival.
  • Progression free survival was slightly improved but did not reach the significance criterion.
  • MGMT and 9 gene profile did not identify selective benefit, but risk subset results suggested strongly against the upfront use of Bevacizumab in the best prognosis patients.
  • Full interpretation of the PFS results incorporating symptom burden, QOL, and NCF is ongoing.
  • Additional molecular studies were performed on tumor samples with molecular profiles developed; however, these profiles require validating.

Clinical Implications

  • The authors presented a well designed, well-performed multi-center phase III randomized double-blind placebo-controlled trial evaluating the use Bevacizumab for patients with newly diagnosed Glioblastoma multiforme .
  • These unsatisfactory results have perplexed neuro-oncologists. Utilizing pathologic features, pre-clinical data, and promising phase II studies, anti-VEGF targeted therapy was expected to have significant improvements as GBM is known to be a very vascular tumor with high expression of VEGF.
  • Similarly, the initial use of Bevacizumab in the setting of recurrent GBM showed tremendous promise. Dramatic radiographic responses were seen with 30-60% response rates seen (which are radically different than 10% historical controls). Similarly, PFS showed 30-50% improvements in the recurrent setting as well.
  • This study is published alongside the parallel AVAglio study, which was presented at the Society for Neuro-Oncology in November 2012. The studies had very similar designs with comparable experimental arms. AVAglio revealed improvements in progression free survival with a 4.4 month difference in the two arms though no change was observed in overall survival. Unfortunately, the results were from the RTOG 0825 are disappointing with no change in progression free survival or overall survival.
  • The secondary endpoints of the two trials are slightly different. While AVAglio did report improved QOL with preservation of performance status and decreased need for steroids, RTOG 0825 demonstrated decreased neurocognitive function and patient reported outcomes. Although this difference may be due to difference analytic methods, the reasons behind this difference require additional study.
  • Several potential causes for no improvement have been suggested:
    • The tendency for Bevacizumab to decrease enhancement could hide occult disease progression
    • There was a 31% crossover in the AVAglio trial and this rate of crossover was higher in the RTOG trial.
    • Bevacizumab could be ineffective because it is not reaching its target or VEGF may simply be a poor target.
  • Regardless of the reasons, additional follow up is needed with much more research needed for improvements in outcomes for patients with this very serious disease.
  • Despite these disappointing results, Bevacizumab remains a very important drug as it remains one of the few drugs that has shown promise in the setting of recurrent GBM. Future trials are needed to define its role in newly diagnosed patients, and potentially identify a subset of patients that truly benefit from its use.