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Clinical Trial
. 2025 Sep 1;123(1):84-92.
doi: 10.1016/j.ijrobp.2025.03.043. Epub 2025 Mar 29.

Comprehensive Molecular Analysis in NRG Oncology/RTOG 9813: A Phase 3 Study of Radiation and Temozolomide Versus Radiation and BCNU/CCNU in Anaplastic Astrocytoma

Jessica L Fleming  1 , Stephanie L Pugh  2 , Susan M Chang  3 , Joseph P McElroy  1 , Aline P Becker  1 , Kenneth D Aldape  4 , Helen A Shih  5 , Lynn Stuart Ashby  6 , Grant K Hunter  7 , Jean-Paul Bahary  8 , Christopher J Schultz  9 , Brian D Kavanagh  10 , Vinay K Puduvalli  11 , H Ian Robins  12 , Maria Werner-Wasik  13 , Minesh Mehta  14 , Arnab Chakravarti  15
Affiliations
Clinical Trial

Comprehensive Molecular Analysis in NRG Oncology/RTOG 9813: A Phase 3 Study of Radiation and Temozolomide Versus Radiation and BCNU/CCNU in Anaplastic Astrocytoma

Jessica L Fleming et al. Int J Radiat Oncol Biol Phys. .

Abstract

Purpose: There is a need to better understand the molecular features that characterize grade 3 astrocytomas and their significance in predicting clinical outcomes. The aim of this study was to determine the significance of the 2021 World Health Organization (WHO)-defined molecular subgroups, along with MGMT promoter methylation, and other alterations in NRG Oncology/RTOG 9813.

Methods and materials: Mutation status was determined by immunohistochemistry and/or next-generation sequencing. Copy number alterations and MGMT methylation were determined by Affymetrix Oncoscan and/or Illumina 450K arrays. Progression-free survival and overall survival were estimated using the Kaplan-Meier method and tested using the log-rank test. Multivariable analyses used Cox proportional hazards models.

Results: Application of the 2021 WHO-defined criteria resulted in the reclassification of 26/79 (33%) patients to grade 4 astrocytoma, IDH-mutant or glioblastoma. When looking at newly assigned molecular grade, grade 3 patients experienced longer survival outcomes compared to grade 4 patients. As individual biomarkers, IDH1/2 mutations, MGMT promoter methylation, and ATRX mutations were each associated with longer survival, whereas TERT promoter mutations, EGFR amplification, and gain of chromosome 7/loss of 10 (Chr+7/-10) were associated with shorter survival. Similar survival outcomes were observed for MGMT methylated patients treated with radiation therapy (RT) and temozolomide (TMZ) or RT and BCNU/CCNU, and MGMT unmethylated patients treated with RT and TMZ. Additionally, IDH-mutant patients seemed to respond well to the addition of TMZ.

Conclusions: This study demonstrated the importance of classifying patients according to the 2021 WHO-defined criteria. The majority of IDH-wildtype anaplastic astrocytomas (grade 3) were reclassified as glioblastoma (grade 4). These analyses also shed light on the efficacy of TMZ in certain molecular subgroups, where the addition of TMZ to RT appeared to benefit patients regardless of MGMT methylation status.

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Conflict of interest statement

Conflicts of Interest

Drs Aldape, Ashby, Becker, Chakravarti, Fleming, Hunter, Kavanagh, McElroy, Pugh, Robins and Schultz have nothing to declare. Dr Bahary declares during the past 36 months NRG Vice Chair for Canadian affairs, NRG membership committee. Dr Chang declares during the past 36 months member of AstraZeneca Scientific Advisory Board. Dr Mehta declares during the past 36 months Consulting fees for Kazia Therapeutics, Novocure, Zap, Xoft, Karyopharm, Sapience, Board of Directors; stock options Oncoceutics, Participation on a Data Safety Monitoring or Advisory Board at Mevion, Brain Committee Chair, salary support to institution at NRG Oncology, Board Member, unpaid at PCG and NAPT, Stock or stock options Chimerix.

Dr Puduvalli declares during the past 36 months Research grant and clinical trial support from Karyopharm, Research grants from Bexion, Consulting fees from Insightec, Servier, Novocure, Orbus Therapeutics, Stock or stock options from Gilead and Amarin. Dr Shih declares during the past 36 months Consulting fees from Servier, Pharmaceuticals, Author/writer, section editor UpToDate, Advisory board Advanced Accelerator Applications, Board member Society of Neuro-Oncology, Institutional financial support for RTOG 3508 from AbbVie. Dr Werner-Wasik declares during the past 36 months Leadership for RTOG Foundation Board, no payments.

Figures

Figure 1.
Figure 1.
Molecular landscape in NRG Oncology/RTOG 9813. A summary of the molecular findings in NRG Oncology/RTOG 9813 patients (n = 113), along with select clinical data including age, sex, and histology. The top row shows the classification of patients into the 2021 WHO-defined molecular subgroups (Oligodendroglioma, grade 3; Astrocytoma, IDH-mutant, grade 3; Astrocytoma, IDH-mutant, grade 4; Astrocytoma, IDH-wildtype, NEC, grade 3, and Glioblastoma). Patients with incomplete molecular data were categorized as Unclassified. Mutation status for IDH1, IDH2, TERT promoter, ATRX, TP53, CIC, and FUBP1 is displayed as mutated (red) or non-mutated (gray). The presence of the following copy number alterations is indicated in blue, 1p/19q co-deletion, CDKN2A/B homozygous deletion, EGFR amplification, and gain of whole chromosome 7 and loss of 10 (Chr+7/−10), whereas absence is in gray. MGMT promoter status is shown as methylated (green) or unmethylated (gray). Not determined (ND) indicates when data was not obtained for a patient (white). Molecular data was not obtained on 3/116 patients and were excluded from the molecular landscape figure. Abbreviations: IHC, immunohistochemistry; NEC, not elsewhere classified.
Figure 2.
Figure 2.
Survival by IDH1/2 mutation status. Kaplan-Meier survival plots show that patients with an IDH1/2-mutant tumor experienced significantly longer overall survival (A) and progression-free survival (B) times compared to patients with IDH1/2-wildtype tumors.
Figure 2.
Figure 2.
Survival by IDH1/2 mutation status. Kaplan-Meier survival plots show that patients with an IDH1/2-mutant tumor experienced significantly longer overall survival (A) and progression-free survival (B) times compared to patients with IDH1/2-wildtype tumors.
Figure 3.
Figure 3.
Survival by MGMT promoter methylation status. Kaplan-Meier survival plots show that patients with MGMT methylated tumors experienced longer overall survival (A) and progression-free survival (B) times compared to patients with MGMT unmethylated tumors.
Figure 3.
Figure 3.
Survival by MGMT promoter methylation status. Kaplan-Meier survival plots show that patients with MGMT methylated tumors experienced longer overall survival (A) and progression-free survival (B) times compared to patients with MGMT unmethylated tumors.
Figure 4.
Figure 4.
Treatment-specific effect of MGMT promoter methylation status and survival. Kaplan-Meier survival plots demonstrate that MGMT methylated patients treated with radiotherapy (RT) plus temozolomide (TMZ) or RT plus BCNU/CCNU experienced similar overall survival (A) and progression-free survival times (B). Patients with MGMT unmethylated tumors treated with RT and BCNU/CCNU had shorter overall survival (C) and progression-free survival (D) times compared to those treated with RT and TMZ.
Figure 4.
Figure 4.
Treatment-specific effect of MGMT promoter methylation status and survival. Kaplan-Meier survival plots demonstrate that MGMT methylated patients treated with radiotherapy (RT) plus temozolomide (TMZ) or RT plus BCNU/CCNU experienced similar overall survival (A) and progression-free survival times (B). Patients with MGMT unmethylated tumors treated with RT and BCNU/CCNU had shorter overall survival (C) and progression-free survival (D) times compared to those treated with RT and TMZ.
Figure 4.
Figure 4.
Treatment-specific effect of MGMT promoter methylation status and survival. Kaplan-Meier survival plots demonstrate that MGMT methylated patients treated with radiotherapy (RT) plus temozolomide (TMZ) or RT plus BCNU/CCNU experienced similar overall survival (A) and progression-free survival times (B). Patients with MGMT unmethylated tumors treated with RT and BCNU/CCNU had shorter overall survival (C) and progression-free survival (D) times compared to those treated with RT and TMZ.
Figure 4.
Figure 4.
Treatment-specific effect of MGMT promoter methylation status and survival. Kaplan-Meier survival plots demonstrate that MGMT methylated patients treated with radiotherapy (RT) plus temozolomide (TMZ) or RT plus BCNU/CCNU experienced similar overall survival (A) and progression-free survival times (B). Patients with MGMT unmethylated tumors treated with RT and BCNU/CCNU had shorter overall survival (C) and progression-free survival (D) times compared to those treated with RT and TMZ.
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References

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