Comprehensive Genomic Analysis in NRG Oncology/RTOG 9802: A Phase III Trial of Radiation Versus Radiation Plus Procarbazine, Lomustine (CCNU), and Vincristine in High-Risk Low-Grade Glioma

Abstract

Purpose: NRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802.

Methods: IDH1/2 mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and MGMT promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates.

Results: Of the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were IDH-wild type, 43 (41%) were IDH-mutant/non-codeleted, and 37(35%) were IDH-mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32; P = .003; HR, 0.13; P < .001) and OS (HR, 0.38; P = .013; HR, 0.21; P = .029) in the IDH-mutant/non-codeleted and IDH-mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the IDH-wild-type subgroup.

Conclusion: This study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with IDH-mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.

FIG 1.

Biomarker analysis for NRG oncology/RTOG 9802. (*) Tissue collection was not mandatory for this trial. (†) Patient samples were prioritized for each platform accordingly: (1) IDHR132H IHC, (2) sequencing panel, (3) 1p/19q analysis, (4) MGMT promoter methylation analysis. IHC, immunohistochemistry; PCV, procarbazine, lomustine (CCNU), and vincristine; RT, radiation therapy.

FIG 2.

Mutational landscape in NRG Oncology/RTOG 9802. A summary of the molecular findings in 115 RTOG/NRG 9802 cases along with select clinical data including age, sex, and histology. The top row shows the classification of patients into the 3 newly established molecular subgroups (IDHmutant/codeleted (IDHmut/codel) IDHmutant/non-codeleted (IDHmut/non-codel), and IDHwild-type (IDHwt), along with a fourth group, IDHmut/not determined (ND), because of the lack of available information on 1p19q status within these patients. The second row is a final summary of patients with IDH1/2 mutations acquire by either sequencing or immunohistochemistry (IHC). Below are the individual results of IDH1 IHC and IDH1 and IDH2 sequencing, respectively.

FIG 3.

Molecular subgroup prognostic survival analyses. Kaplan-Meier survival plots show that the 3 WHO-defined molecular subgroups (IDHmut/codel, IDHmut/non-codel, and IDHwt) significantly stratified patients for both (A) overall survival, and (B) progression-free survival.

FIG 4.

Survival by treatment and WHO-defined molecular subgroup. Kaplan-Meier survival plots show that patients with (A, B) IDHmut/codel and (C, D) IDHmut/non-codel demonstrated significantly improved overall survival and progression-free survival rates when treated with radiation therapy (RT) plus PCV (procarbazine, lomustine (CCNU), and vincristine) versus RT alone. (E, F) IDHwt tumors had no significant survival difference by treatment.