Adjuvant Temozolomide Improves Outcomes in Anaplastic Glioma More Than Expected in Ongoing Trial

Adjuvant temozolomide improved overall survival in anaplastic glioma without 1p/19q co-deletion, according to a planned interim analysis of a European Organisation for Research and Treatment of Cancer (EORTC)/Radiation Therapy Oncology Group (RTOG) trial.

Interim findings from this randomized phase III trial – the Concurrent and Adjuvant Temozolomide Chemotherapy in Non-1p/19q Deleted Anaplastic Glioma (CATNON) – indicated adjuvant temozolomide after radiotherapy should be the standard of care in treating patients without 1p/19q co-deletion. Based on that result, it was deemed no longer acceptable to withhold adjuvant treatment in any patients in the study.

The role of temozolomide concurrent with radiation, which was also evaluated, remains an open question that is subject to the full analysis of the trial once the final endpoint is reached.

Michael Vogelbaum, MD, PhD, professor of neurosurgery and Associate Director of Cleveland Clinic’s Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, who was the overall study co-chair and North American chair on behalf of RTOG for this trial, says he did not expect to see such an outcome at this stage in the trial. “I think it was everyone’s guess that the concurrent chemotherapy was the more important phase of chemotherapy treatment, and the fact that results for adjuvant therapy were positive this early came as a surprise to us,” he says.

Results from this analysis were accepted for presentation, by Dr. Martin van den Bent, overall study chair, in an oral abstract session at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.

Two separate randomizations to create four study arms

“The CATNON study was designed to ask: what achieves the best balance between efficacy and toxicity in treating non-1p/19q deleted grade III tumors, and which part of the addition of chemotherapy matters the most,” Dr. Vogelbaum says.

He and his team recruited patients ages 18 years and older with newly diagnosed grade III anaplastic glioma without 1p/19q co-deletion and a WHO performance status of 0-2 from December 2007 to August 2015. During this period, 748 patients met eligibility requirements and were randomized to one of four study arms. All patients had initial surgery – for debulking and to evaluate the malignancy. All arms received radiotherapy of 59.4 Gy in 33 factions over about six weeks. Concurrent and adjuvant temozolomide were used as two separate randomizations to create the four arms, and treatments were administered to patient groups as follows:

• Radiotherapy alone
• Radiotherapy with concurrent daily 75 mg/m2 temozolomide
• Radiotherapy followed with 12 cycles of 150-200 mg/m2 adjuvant temozolomide day 1-5/4 weeks (given approximately one month later)
• Radiotherapy with both concurrent and adjuvant temozolomide

The planned interim analysis was conducted in early October 2015, after 221 events occurred. At this time point, the analysis showed a hazard ratio reduction for overall survival of 0.645 (95% CI, 0.450, 0.926; p=0.0014) in patients that received adjuvant temozolomide (arms iii and iv). The five-year overall survival rate was found to be 44.1 percent for arms i and ii, and 55.9 percent for the adjuvant arms.

For progression-free survival (PFS), the risk-adjusted hazard ratio of adjuvant temozolomide was 0.586 (95% CI, 0.472, 0.727; p < 0.0001). The median PFS was 42.8 months with adjuvant temozolomide and 19 months without it.

Adjuvant temozolomide provides clear benefits

“At the time of this planned interim analysis, there was a definitively positive result for adjuvant temozolomide, which shows that it added clear benefits to treatment,” Dr. Vogelbaum says. Although most patients had already concluded their treatment regimen by this point, those who had not yet been randomized were crossed over to assure they would receive adjuvant temozolomide.

To accurately place the results of this analysis in context, however, it’s important to acknowledge that final data points for concurrent temozolomide have not yet been reached.

“For concurrent chemotherapy, it still remains understudied at this point,” Dr. Vogelbaum says. “The actual role of concurrent temozolomide will not be understood until the full analysis of the trial is completed, so it would be wrong to interpret the data that we have on it so far as a negative result.”

Finally, one of the primary stratification factors used in this analysis was O6-methyl-guanine DNA methyltransferase (MGMT) promoter methylation, a known and important prognostic factor. Findings showed that MGMT status could be determined in 74 percent of patients, and was found methylated in 42 percent of them. Although MGMT methylation was validated as a prognostic factor for overall survival (HR 0.54, 95% CI 0.38, 0.77; p=0.001), it did not predict a positive response to adjuvant temozolomide at this stage.

Standard of care established

The current findings of this planned interim analysis offer strong, supportive evidence for the use of adjuvant chemotherapy in this patient population. According to Dr. Vogelbaum, “As a large randomized trial, this is the best evidence we’re going to be able to generate,” he says. “With this, we now consider radiation with adjuvant temozolomide to be the standard of care for patients with non-co-deleted anaplastic glioma, with the question of concurrent temozolomide remaining to be addressed.”

Dr. Vogelbaum is also co-chair of an ongoing Alliance/NRG/EORTC randomized phase III trial on grade II and III anaplastic glioma with 1p/19q co-deletion (“CODEL”). This trial is investigating the role of concurrent and adjuvant temozolomide versus radiotherapy and PCV (procarbazine, CCNU, vincristine), but has not progressed very far due to difficulty in accruing patients. Molecular studies that will address the impact of isocitrate dehydrogenase mutational status and methylation profiling are being conducted as well.