Concurrent temozolomide treatment during radiotherapy did not increase overall survival in patients with anaplastic gliomas without 1p/19q co-deletion, according to data from the second interim and first molecular analysis of the EORTC randomized phase III intergroup CATNON trial.1 However, benefit of concurrent temozolomide treatment was observed in patients with IDH-mutant tumors, according to the study investigators. At first interim analysis, the trial demonstrated a significant overall survival benefit from adjuvant temozolomide in patients whose tumors were 1p/19q intact but remained inconclusive about concurrent temozolomide. The current update showed that this benefit is also limited to patients with IDH-mutated tumors.2 The additional benefit of concurrent temozolomide in the patients with IDH-mutated tumors who also receive adjuvant temozolomide requires further study.
Martin J. Van Den Bent, MD, PhD
Howard Colman, MD, PhD
These data were originally presented at the 2019 ASCO Annual Meeting by Martin J. Van Den Bent, MD, PhD, Head of the Neuro-Oncology Unit at Erasmus MC Cancer Center in Rotterdam, the Netherlands, and colleagues.2 The study was later discussed at the Best of ASCO Austin by Howard Colman, MD, PhD, Leader of the Center for Neurologic Cancers at Huntsman Cancer Institute, University of Utah, along with other top selected abstracts in central nervous system tumors.3
“If adjuvant therapy works, and concurrent therapy adds to it slightly, it’s hard—at least in my mind—to argue against using both in the subgroups with bigger benefit, as long as temozolomide is well tolerated in this group,” said Dr. Colman. “Technically, the study wasn’t significant for benefit of concurrent temozolomide overall, but it appears to have at least some trend toward benefit in specific subgroups, and so I do use concurrent temozolomide in these patients.”
IDH Mutation and MGMT-Methylation Status Prognostic
Between December 2007 and September 2015, the trial randomly assigned 751 patients with newly diagnosed, centrally confirmed grade 3 gliomas and no 1p/19q deletion to one of four treatment arms: 59.4 Gy of radiotherapy alone, the same radiotherapy with concurrent temozolomide, radiotherapy with 12 cycles of adjuvant temozolomide, or radiotherapy with both concurrent and adjuvant temozolomide. The trial was powered to determine whether temozolomide improved outcomes, either during or after radiation therapy (Q1 and Q2) but was not formally powered to determine differences between all four treatment groups, Dr. Colman noted.
After a median follow-up of 56 months and 356 events, the hazard ratio for overall survival, adjusted for stratification factors after concurrent temozolomide, was 0.968 (P = .7634). The 5-year overall survival was 50.2% with and 52.7% without concurrent temozolomide (P = .464). The authors concluded that this analysis, “indicates futility in regard to the question of concomitant temozolomide in the overall population,” and the study was stopped at that point.
The negative overall benefit of concurrent temozolomide appeared to be driven by the IDH wild-type subgroup.— Howard Colman, MD, PhD
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However, Dr. Colman pointed out the importance of molecular subtypes in this population and the relevance of IDH-mutated and IDH wild-type tumors, as well as MGMT (O-methylguanine-DNA methyltransferase) promoter methylation status. He noted that the study authors did perform detailed molecular profiling.
“Multivariate analysis showed that if you look at temozolomide as a variable, concurrently, it doesn’t have an effect, whereas other clinically significant variables do,” stated Dr. Colman.
In the entire study population, 70% of patients had an IDH-mutated tumor, and 70% of tumors showed MGMT methylation. Overall, both IDH mutation and MGMT status were highly prognostic across the whole population: median overall survival was 117 months in IDH-mutated patients and 19 months in patients with IDH wild-type tumors (HR = 0.14).
Concurrent Temozolomide Shows Benefit in Some
Subset analysis revealed that concurrent temozolomide did trend toward benefit in IDH-mutant tumors: the 5-year overall survival was 76% and 68% with concurrent and no concurrent temozolomide, respectively (P = .012). This benefit was not seen in wild-type tumors.
Temozolomide also appeared to show a benefit in MGMT-methylated tumors in both the concurrent and adjuvant settings, although this effect was less pronounced compared with the effect of IDH mutational status. “So, molecular phenotype is clearly important in terms of treatment response,” noted Dr. Colman.
For more on concurrent and adjuvant temozolomide treatment in anaplastic glioma without 1p/19 co-deletion from the CATNON trial, see an interview with Martin J. Van Den Bent, MD, PhD, on The ASCO Post Newsreels at www.ascopost.com/videos.
In patients with IDH-mutant tumors who received adjuvant temozolomide, there was a trend toward further improved overall survival when concurrent temozolomide was added (HR = 0.71), although this did not reach statistical significance. The investigators maintain that, although the added value of concurrent temozolomide to adjuvant temozolomide appears small, the limited numbers still prevent firm conclusions.
MGMT Data Still to Come
“The negative overall benefit of concurrent temozolomide appeared to be driven by the IDH wild-type subgroup,” Dr. Colman noted. However, he maintains that the MGMT analysis will be a potentially important predictor in this group, and these data are still to be reported.
Dr. Colman added that many of these tumors are molecularly glioblastoma multiforme, and prior research by Stupp et al4 demonstrated a benefit of temozolomide in MGMT-methylated tumors.
“It’s hard to argue against the use of temozolomide in addition to radiation in the MGMT methylated IDH wild-type tumors,” he said. “But what’s clear, I think, is that the group that derives the least benefit from temozolomide is those with IDH wild-type 1p/19q intact MGMT-unmethylated tumors.”
DISCLOSURE: Dr. Van Den Bent has served as a consultant or advisor to AbbVie, Agios, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Carthera, Celgene, and Daiichi Sankyo; and has received institutional research funding from AbbVie. Dr. Colman has received honoraria from Merck Sharp & Dohme; has served as a consultant or advisor to AbbVie, Bayer, Best Doctors Inc, Deciphera, Foundation Medicine, Innocrin Pharma, Karyopharm Therapeutics, Merck, NewLink Genetics, Orbus Therapeutics, Private Health, and Tactical Therapeutics; and has received institutional research funding from AbbVie, Array BioPharma, BeiGene, DNAtrix, Forma Therapeutics, Kadmon, Merck, NewLink Genetics, Orbus Therapeutics, and Plexxikon.
1. van den Bent MJ, Baumert B, Erridge SC, et al: Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: A phase 3, randomised, open-label intergroup study. Lancet 390:1645-1653, 2017.
2. van den Bent MJ, Erridge S, Vogelbaum MA, et al: Second interim and first molecular analysis of the EORTC randomized phase III intergroup CATNON trial on concurrent and adjuvant temozolomide in anaplastic glioma without 1p/19q codeletion. 2019 ASCO Annual Meeting. Abstract 2000. Presented June 3, 2019.
4. Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005.