A phase II, open label, single arm study of nivolumab for recurrent or progressive IDH mutant gliomas with prior exposure to alkylating agents.

2056 Background: Somatic mutations in isocitrate dehydrogenase 1 (IDH) are recognized as an important prognostic factor in patients with gliomas and are associated with longer survival. Regardless of initial grade, however, recurrence and transformation into higher grade tumors is almost universal. IDH-mutant gliomas are prone to develop hypermutation after exposure to alkylating agents; in other solid tumors, hypermutation may be a predictive biomarker for PD-1 inhibitor response. In this multicenter phase 2, open label, single arm study, we hypothesize that this specific subgroup of patients would demonstrate a clinically meaningful benefit from nivolumab as measured by overall response rate (ORR), duration of response (DOR), median progression-free survival (PFS), and overall survival (OS). Methods: Eligible patients aged 18 years and older with recurrent or progressive IDH-mutant (WHO Grades 2, 3, or 4) gliomas were included. All had prior exposure to alkylating agents. Nivolumab was given 240 mg q2w for 8 cycles, then 480 mg q4w until disease progression, unacceptable toxicity, withdrawal of consent, or completion of study at 2 years. Efficacy was evaluated by ORR of partial (PR) and complete responses (CR) based on RANO criteria; for patients with non-enhancing disease only, low-grade glioma RANO criteria was used. Secondary endpoints included median PFS and median OS, as well as DOR. Toxicity assessments continued for two safety monitoring follow-up visits off study. Survival follow-up occurred every 3 months until death or until study completion at 2 years. Results: Thirty-five patients were enrolled, with 33 (66.7% male) evaluable at study completion. Histology consisted of oligodendroglioma (N=11; 55% Grade 3) and astrocytoma (N=22; 36% Grade 3, 32% Grade 4). Median number of prior line of systemic therapy was 1 (range 1-6). Median dexamethasone dose at screening was 0 mg (range 0-4) and at end of study was 0 mg (range 0-8). ORR was 9% with two PR and one CR, with median DOR of 33 months. All three patients maintained response at 20+ (Grade 3 oligodendroglioma), 33+ (Grade 3 astrocytoma) and 51+ months (Grade 2 astrocytoma). 11 (33%) patients had stable disease (8 were stable for over 6 months) with median PFS of 2.2 months and median OS of 31 months. Nivolumab was well-tolerated with two treatment-related Grade 3 adverse events (lymphopenia and hypotension). One patient discontinued treatment due to Grade 2 transaminitis. Conclusions: Nivolumab was well-tolerated with no unexpected toxicity in this brain tumor population. Three patients derived a prolonged response and still continue on CR and PR after completing 24 months of planned treatment. This study provides data on single-agent PD-1 inhibition, which will serve as baseline efficacy data for ongoing and future combination immunotherapy trials with PD-1 inhibitors in recurrent IDH-mutant gliomas. Clinical trial information: NCT03557359 .