Updated Analysis of NRG-RTOG 9813 Indicates IDH1/2 Mutation Status is Statistically Associated with Better Overall and Progression-free Survival for Patients with Anaplastic Astrocytoma

October 27 2020

Recent updates were made to reports from NRG-RTOG 9813 to show that IDH1/2 mutation status is a strong, prognostic marker for grade 3 anaplastic astrocytoma patients treated with either radiotherapy (RT) and temozolomide (TMZ) or RT and nitrosourea (NU). MGMT methylation status was also evaluated, however, IDH1/2 mutation status was the greater of the two measures for prognostic value. These findings were presented at the virtual edition of the American Society for Radiation Oncology’s (ASTRO) Annual Meeting in October 2020.

MGMT promoter methylation was significantly associated with better overall survival upon single-marker multivariable analysis; however, significance was lost when IDH1/2 mutation was added to the model, leading us to the conclusion that, in this particular analysis, IDH1/2 mutation was a more valuable prognostic biomarker. Additionally, MGMT promoter methylation appeared to be predictive in the setting of RT and NU with unmethylated patients experiencing substantially shorter survival times; however, these findings need to be further validated prior to coming to any definitive conclusions,” stated Jessica Fleming, PhD, of the Ohio State University Comprehensive Cancer Center and the first author of the NRG-RTOG 9813 abstract.

NRG-RTOG 9813 trial had 116 patients that were eligible for tissue analysis; of which, 111 participants had IDH1/2 mutation status and 67 participants had MGMT methylation status available. The 111 patients who exhibited IDH1/2 mutation status were further stratified into IDH1/2 mutant (IDHmut) and IDH1/2 wild-type (IDHwt): 55% were IDHmut compared to 45% IDHwt. Additionally, the 67 MGMT methylation status participants were stratified by MGMT promoter status: 54% were MGMT methylated and 46% were MGMT unmethylated.

IDHmut patients had significantly longer overall survival (OS) (HR: 0.34 (0.21-0.54); p < 0.001) and progression-free survival (PFS) (HR: 0.41 (0.27-0.63); p < 0.001) when compared to patients with IDHwt tumors. Patients with MGMT methylated tumors trended towards better OS outcomes (HR: 0.56 (0.31-1.02); p = 0.05) and significance was established in the multivariable analysis of MGMT methylated tumor patients (HR: 0.47 (0.25-0.90); p = 0.023). In a multi-marker multivariable model incorporating IDH1/2 mutation and MGMT methylation, IDH1/2 mutation (HR: 0.32 (0.14-0.73); p =0.006), age (HR: 0.34 (0.15-0.75); p = 0.008), and gender (HR: 0.51 (0.26- 1.00); p = 0.049) retained significance for OS and only IDH1/2 was significant for PFS (HR: 0.30 (0.16, 0.58); p < 0.001).

Results indicate that IDHmut patients do well regardless of the treatment used on the trial. The median OS for patients who had IDHmut was 7.9 years for patients treated with RT and NU and was not reached for those treated on RT with TMZ. Additionally, MGMT methylated patients has a median OS of 8 years on the RT and NU treatment arm when compared to 2 years for unmethylated patients.


This project was supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U24CA196067 (NRG Biospecimen Bank) from the National Cancer Institute (NCI), part of the National Institutes of Health. Merck & Co., Also, R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01 (NCI), Brain Tumor Funders Collaborative Grant, and the Ohio State University CCC.

Citation

Fleming JL, Pugh S, Bell EH, Chang SM, McElroy JP, Becker AP, Timmers CD, Shih HA, Ashby LS, Hunter G, Bahary JP, Schultz C, Kavanagh BD, Yung WKA, Robins HI, Werner-Wasik M, Chakravarti A. (2020, October). Prognostic Significance of IDH1/2 Mutation and MGMT Promoter Methylation Status in RTOG 9813. Paper presented at the annual meeting of the American Society for Radiation Oncology. Virtual meeting platform.

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NRG Oncology conducts practice-changing, multi-institutional clinical and translational research to improve the lives of patients with cancer. Founded in 2012, NRG Oncology is a Pennsylvania-based nonprofit corporation that integrates the research of the legacy National Surgical Adjuvant Breast and Bowel Project (NSABP), Radiation Therapy Oncology Group (RTOG), and Gynecologic Oncology Group (GOG) programs. The research network seeks to carry out clinical trials with emphases on gender-specific malignancies, including gynecologic, breast, and prostate cancers, and on localized or locally advanced cancers of all types. NRG Oncology’s extensive research organization comprises multidisciplinary investigators, including medical oncologists, radiation oncologists, surgeons, physicists, pathologists, and statisticians, and encompasses more than 1,300 research sites located world-wide with predominance in the United States and Canada. NRG Oncology is supported primarily through grants from the National Cancer Institute (NCI) and is one of five research groups in the NCI’s National Clinical Trials Network.

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