Revolumab: A phase II trial of nivolumab in recurrent IDH-mutant high-grade gliomas.

2048 Background: Novel effective treatments are urgently needed for IDH-mutant high-grade gliomas (HGGs) recurring after radiotherapy and chemotherapy. While single-agent immune checkpoint blockade (ICB) showed limited efficacy in IDH-wildtype glioblastoma, results in IDH-mutated HGGs are not yet available. In this multicenter, single-arm, phase II trial (REVOLUMAB, NCT03925246), we assessed the efficacy of the anti-PD1 Nivolumab in recurrent IDH-mutant HGGs. Methods: Main eligibility criteria: adult patients with IDH-mutant HGG recurring after radiotherapy and ≥ one line of alkylating chemotherapy, KPS > 50%, less than 10mg/day prednisone equivalent. The primary endpoint was the 24-weeks progression-free survival (PFS) rate according to the RANO criteria by investigator assessment. Patients received intravenous Nivolumab 240 mg every 2 weeks for 8 cycles, followed by 480 mg every 4 weeks for a maximum duration of one year. 39 patients were planned to be enrolled based on a one-stage A’Hern’s design (p0 = 30%, p1 = 50%, type I error rate = 5%, power = 80%). Results: Between July 2019 and June 2020, 39 patients with recurrent IDH-mutant HGG (n = 21 WHO grade 3, 13 grade 4, and 5 grade 2 tumors with MRI evidence of anaplastic transformation; n = 10 1p/19q- codeleted, 17 non-codeleted tumors) were enrolled. The median follow-up duration was 17.6 months (11.6-24). The median time since diagnosis was 4.05 years (0.39-16.72), the median time since radiotherapy was 4.47 years (0.55-12.66), the median number of previous chemotherapy lines was 2 (1-4). Eight patients completed Nivolumab treatment as planned, thirty patients stopped treatment due to tumor progression and one patient due to adverse event (AE) unrelated to study drug. At 24 weeks, 11/39 patients were alive without disease progression (28.2% CI95% [15%; 44.9%]). According to RANO, one patient (2.6%) achieved complete response (CR), 3 patients (7.7%) partial response (PR), 13 patients (33.3%) stable disease, and 22 (56.4%) had progression as their best response. Median PFS and OS were 1.84 (CI95% [1.81 ; 5.89]) and 14.7 months (CI95% [9.18; NR]), respectively. There was no difference in PFS between 1p/19q-codeleted and non-codeleted tumors. No patient definitively stopped Nivolumab due to side effects; the safety profile was consistent with prior studies of Nivolumab in gliomas and other cancers. Conclusions: To our knowledge, this is the first reported trial of ICB in IDH-mutant gliomas. Nivolumab failed to achieve its primary endpoint. However, Nivolumab was well tolerated and long-lasting responses were observed in a subset of this population, which support further evaluation in combination with other agents such as anti-VEGF or IDH inhibitors. This trial was funded by French Ministry of Health.The sponsor was Assistance Publique – Hôpitaux de Paris. Study drug was supplied by Bristol Myers Squibb (CA209-818). Clinical trial information: NCT03925246.