Regorafenib in advanced high-grade glioma: a retrospective bicentric analysis

Abstract

The treatment of progressive high-grade glioma remains a challenge. 1 The phase II REGOMA trial in patients with a first glioblastoma progression revealed a significant improvement in median overall survival (mOS) for regorafenib, with 7.4 (5.8-12.0) versus 5.6 (4.7-7.3) months in the lomustine arm. 2 We present a retrospective bicentric cohort of 24 adult patients (median age 54, range 33-70; Karnofsky performance score [KPS] 80-100% n = 9; 70% n = 9; 50-60% n = 6) with advanced high-grade gliomas (19 glioblastoma isocitrate dehydrogenase (IDH) 1 wildtype, 1 diffuse midline glioma, 1 anaplastic oligodendroglioma, 1 anaplastic astrocytoma, 2 glioblastoma IDH mutation; 6 O 6methylguanine-DNA methyltransferase (MGMT) methylated, 17 MGMT unmethylated, 1 unknown MGMT status). The ethics committees of the Universities of Bonn and Tübingen approved this analysis. All 24 patients were treated with regorafenib (80-160 mg daily, 21 days on, 7 days off), mostly at later stages of the disease (3 first relapse, 9 second relapse, 12 third to seventh relapse). As first-line treatment 23/24 (96%) had alkylating chemotherapy (21/23 with radiation therapy) and 1 patient had radiotherapy only. Further prior systemic treatments for progressive disease included lomustine (21), temozolomide (7), bevacizumab (5), and an experimental IDH inhibitor (1).The first MRI 6-12 weeks after regorafenib initiation, which was obtainable in 18/24 patients (75%), showed a partial response according to RANO in 3 patients (13%) and stable disease in 3 patients (13%). The median progression-free survival (mPFS) was 2.1 months. The mOS after regorafenib onset was 4.1 months in the whole cohort and 4.2 months in the group of 19 patients with IDH wildtype tumors (Fig. 1A). The most common adverse events included dermatological events, mainly hand-foot reaction (HFR) in 8/24 (30%) patients and OS was significantly longer in patients with HFR (mOS 6.7 mo versus mOS 2.6 mo, P = 0.008 log-rank test) (Fig. 1B).Taken together, the mPFS of 2.1 months in our bicentric cohort was similar to REGOMA 2 (2.0 mo). Yet, mOS was longer in REGOMA (7.4 mo) than in our present cohort (4.1 mo). This certainly reflects that our cohort included patients at a later stage of the disease. The population of the present cohort is rather comparable with retrospective data for bevacizumab in patients with third progression of glioblastoma and a KPS <80% leading to mOS of 3.6 months. 3

Regorafenib CSF Penetration, Efficacy, and MRI Patterns in Recurrent Malignant Glioma Patients

“…Based on RANO criteria, all but 2 of 19 patients available for follow-up MRI were classified as PD upon follow-up. This outcome is worse than reported by both the REGOMA trial and Tzaridis et al [14,17] and could be due to the less favorable patient characteristics and short OS in our cohort. Nevertheless, distinct MRI alterations were observed in half of the patients.…”

“…However, these results have been challenged because of the unusually short OS in the lomustine arm [15]. Two small retrospective analyses in late-stage high-grade glioma patients reported poor REG treatment response and significant adverse events (AEs) [16,17]. In a cohort of six glioma patients no impact of REG on MRI findings was observed [16].…”

MGMT promoter methylation analysis for allocating combined CCNU/TMZ chemotherapy: Lessons learned from the CeTeG/NOA‐09 trial

“… Note : Multivariate analysis with strata MGMT ratio determined by qMSP and treatment arm (+ RPA class and study center in analogy to the primary analysis of the trial 5 ) for the entire mITT population (A) and separately for the two treatment arms (B).…”

“… Note : Multivariate analysis with strata treatment arm considering RPA class and study center in analogy to the primary analysis of the trial 5 ) in different subgroups defined by different cutoffs of qMSP MGMT ratio.…”

“…Patients whose tumors exhibit MGMT promoter methylation have a superior overall survival when treated with alkylating chemotherapy due to impaired DNA repair mechanisms. For this subset of glioblastoma patients, the randomized phase III multicenter CeTeG/NOA‐09 trial recently showed a survival benefit when they were treated with a combination of lomustine (CCNU) and TMZ (CCNU/TMZ) instead of TMZ monotherapy 5 …”