1136 - Clinical Endpoints Correlation with Molecular Features in the NRG Oncology/RTOG 9802 Low-Grade Glioma, Low-Risk Observation Arm

J. L. Fleming¹, F. Iwamoto², M. Y. Polley³, E. G. Shaw⁴, J. Buckner⁵, G. R. Barger⁶, P. E. Ricci⁷, M. Gilbert⁸, D. E. Bullard⁹, P. D. Brown¹⁰, K. J. Stelzer¹¹, J. McElroy¹, A. Becker¹, L. Rogers¹², G. A. Russo¹³, M. W. Straza Jr¹⁴, J. Huang¹⁵, M. Won¹⁶, M. P. Mehta¹⁷, and A. Chakravarti¹⁸; ¹The Ohio State University, Columbus, OH, ²Columbia University, New York, NY, ³NRG Oncology, Philadelphia, PA, ⁴Department of Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, ⁵Mayo Clinic, Rochester, MN, ⁶Wayne State University School of Medicine, Detroit, MI, ⁷Swedish Medical Center/Radiology Imaging Associates PC, Englewood, CO, ⁸NCI Center for Cancer Research, Bethesda, MD, ⁹Bullard Spine LLC, Raleigh, NC, ¹⁰Department of Radiation Oncology, Mayo Clinic, Rochester, MN, ¹¹Mid-Columbia Medical Center, The Dalles, OR, ¹²Arizona Oncology Services Foundation, Tuscon, AZ, ¹³Dartmouth Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, ¹⁴Department of Radiation Oncology, Froedtert & the Medical College of Wisconsin, Milwaukee, WI, ¹⁵Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, ¹⁶NRG Oncology Statistics and Data Management Center, Philadelphia, PA, ¹⁷Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, ¹⁸Department of Radiation Oncology, The James Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH

Purpose/Objective(s): The phase II portion of the NRG Oncology/RTOG 9802 phase II/III trial of grade 2 glioma enrolled favorable prognosis (age <40) patients on an observation arm after surgeon-reported gross total resection. This post hoc analysis correlates clinical outcomes with molecular features. Materials/

Methods: DNA extraction from formalin fixed paraffin embedded tumor was possible in 61/111 (55%) enrolled patients. IDH1/2 mutation status was captured using a custom IonTorrent targeted sequencing panel, 1p/19q codeletion was determined through the Affymetrix Oncoscan Array, and MGMT promoter methylation was called using the Illumina 450K Array and MGMT-STP27 model. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and tested using the log-rank test.
Results: IDH1/2 mutation and 1p/19q status were available on 58/61 (95%) cases. Of these, 13 (22%) were IDH-wildtype (IDHwt), 29 (50%) IDH-mutant/1p/19q non-codeleted (IDHmut/non-codel), and 16 (28%) IDH-mutant/1p/19q codeleted (IDHmut/codel). MGMT promoter methylation status was determined on 46 cases, 28 (61%) were MGMT methylated and 18 (39%) MGMT unmethylated. MGMT methylation incidence was 1/6 (17%) for patients with IDHwt and 26/39 (67%) IDHmut tumors. At the time of this report, median follow-up was 14.9 years (range: 0.3-19). Median survival time (MST) for IDHmut/non-codel cases was 7.3 years and was not reached for IDHwt and IDHmut/codel cases. Median PFS was 2.8 years for IDHmut/non-codel cases, 8.3 years for IDHmut/codel cases and was not reached for IDHwt cases. Comparisons across the 3 WHO subgroups reached statistical significance for OS and PFS (p < 0.001). No significant differences in OS or PFS were observed between MGMT methylated and MGMT unmethylated cases.
Conclusion: These results have important implications in the management of patients with histologic low-grade glioma. First, IDH mutational status is essential and patients with IDHwt tumors should be evaluated for features of other low-grade tumors (i.e. pilocytic astrocytoma) or molecular glioblastoma, further highlighting the importance of molecular testing. Additionally, this study’s long-term PFS data for IDHmut grade 2 gliomas may have implications for the use of IDH inhibitors. For example, the median PFS of 8.3 years for the IDHmut/codel subgroup with observation makes upfront use of any treatment, including IDH inhibitors, less compelling in those low-risk patients. Finally, notable limitations of this study include small subgroup numbers and possible clinically favorable enrichment in the IDHwt subgroup represented by smaller tumors and lesser burden of residual disease on postoperative MRI. A thorough review of the pathological, clinical, and molecular features of these cases is planned to fully understand these results.