Grade promotion.

Top Line: As promised, the molecular subset analysis of RTOG 0424 is here.

The Study: Remember, this is the phase 2 trial on which we hang our hats to give temozolomide concurrent and adjuvant to radiation for high-risk, low-grade gliomas. We already know from this trial that low-grade meth is telling. Now we have the full post-hoc analysis on 80 enrollees (of 129) with full molecular testing. Again, 76% were MGMT-methylated, and this was a significant predictor of prolonged overall survival on this single arm trial. Now we learn there was a nice divide in terms of the subsets that usually come to mind with low-grade glioma: roughly one-third were each IDH-mutant / 1p19q co-deleted (33%), IDH-mutant / 1p19q non-co-deleted (35%), or IDH-wildtype (33%). On multivariate analysis, the biggest divide in overall survival was per IDH-status: median survival per groups above were 9.4 years, 8.8 years, and 2.3 years, respectively. Importantly, MGMT status didn’t add much beyond this other than the rare case where an IDH-wildtype tumor was MGMT-methylated: median survival here was 3.8 years if methylated (n=5) versus 2.6 years if not (n=11). None of the other mutations evaluated (ATRX, CIC, FUBP1, TERT promoter, and TP53) seemed to have any associations with survival outcomes.

TBL: Among historically grade 2 gliomas treated with modern high-risk treatment strategies, IDH-wildtype tumors do poorly, slightly mitigated by MGMT-methylation, supporting the current paradigm shift to lumping these in with glioblastomas, preferably treated on a clinical trial. | Fleming, JCO Precis Oncol 2021