Phase II trial evaluating nivolumab in patients with recurrent IDH-mutant gliomas with and without hypermutation phenotype.

Abstract

2064 Background: Tumor mutational burden (TMB) is an emerging biomarker for the prediction of immune therapy success in solid tumors. Response to immune checkpoint inhibitor (ICI) treatment in rare gliomas with biallelic mismatch repair deficiencies has been attributed to their hypermutation phenotype (HMP). This has not been tested in other gliomas. We developed a phase II clinical trial using nivolumab in recurrent IDH-mutant gliomas evaluating response in tumors with HMP (approximately 10% of cases) and in tumors with non-HMP (NHMP). Here we report the results of the analysis of the NHMP cohort. Methods: Adults with recurrent IDH-mutant glioma, KPS ≥ 60, normal organ function, with known somatic TMB (analyzed at NIH) were enrolled in a phase II trial. Nivolumab was given at 480mg IV every 28-day cycle with a maximum of 16 cycles. The primary endpoint is PFS rate at 6 months (PFS6) in both HMP and NHMP cohorts. Responses to treatment were evaluated by MRI every 2 cycles using iRANO criteria. Simon’s two-stage design was used to independently evaluate the HMP/NHMP cohort. For the NHMP cohort, the null and alternative hypotheses for PFS6 are 0.2 and 0.4, respectively. A total of 30 were planned to be accrued across stages I and II. If ≥10 patients are progression-free at 6 months, the null hypothesis will be rejected, indicating that the treatment is promising for patients with NHMP IDH-mutant gliomas. The design controls the type I error at 0.05 and yields a power of 0.8. Tumor samples and peripheral blood were collected for correlative studies. Patient-reported outcomes (PRO) were evaluated by longitudinal symptom burden analysis using Brain Tumor Module of the MD Anderson Symptom Inventory. Results: As of January 2026, thirty patients were enrolled and treated on the NHMP cohort (TMB˂5 mut/Mb). Among 30 evaluable patients, 20 were male, median age 44 and KPS 90. Histological diagnosis included 22 astrocytoma (grade 3, n=10; grade 4, n=12) and 8 oligodendroglioma (grade 2, n=1; grade 3, n=7). Median number of prior recurrences is 2, ranging from 1 to 5. At the time of analysis, all 30 evaluable patients were off study treatment: 7 completed all 16 cycles, 17 had disease progression, 3 withdrew to start other management. Three patients were off treatment due to treatment related grade 3 colitis, pneumonitis and dry mouth. Eleven and 8 out of 30 patients were progression free at 6 and 12 months, respectively. PRO and correlative studies are ongoing. Conclusions: Nivolumab is well tolerated and has shown efficacy in a cohort of patients with recurrent IDH-mutant gliomas with low TMB. Clinical benefit measured by objective response, PFS, OS and PRO, along with longitudinal immune monitoring, will help determine whether tumor TMB correlates with immunologic and clinical response to ICI therapy in IDH-mutant gliomas. Clinical trial information: NCT03718767 .