Observational real-life study on regorafenib in recurrent glioblastoma: does dose reduction reduce toxicity while maintaining the efficacy?

Abstract

Purpose: In the phase 2 REGOMA trial, regorafenib improved overall survival, as compared with lomustine, in glioblastoma (GBM) patients at rst progression after chemoradiation. Recently, some real-life trials showed similar impact on survival but a higher rate of adverse events than in REGOMA, thus raising concerns over tolerability. The aim of this study was to assess the e cacy and tolerability of a lower intensity regorafenib regimen.Patients and Methods: Regorafenib daily dose was gradually increased from 80 to 160 mg across the rst 2 cycles. Progression-free survival (PFS) and overall survival (OS) were de ned as time from regorafenib initiation and disease progression or death. Results: Sixty-six GBM patients were included. Median age was 60.0 years. Median PFS and OS following regorafenib were 2.7 and 7.1 months, respectively. Best RANO response to regorafenib were partial response (PR) in 10 (15.1%), stable disease in 17 (25.8%), and progressive disease in 39 (59.1%) patients. Forty-six (69.7%) patients presented adverse events of any grade, and 21 (31.8%) grade 3-4 toxicity. In a multivariable analysis, higher age and absence of MGMTp methylation were signi cantly associated with poorer disease control after regorafenib.Conclusions: Our study is the largest observational real-life study on the use of regorafenib. Our lower intensity regimen proved as effective as the standard 160 mg daily schedule (mPFS and mOS being 2.7 vs 2.0 months and 7.1 vs 7.4 months in our study vs REGOMA, respectively). Moreover, we observed a higher rate of PRs as compared with REGOMA (15.0% versus 3.0%). Background Glioblastoma (GBM) is the most common primary brain tumour of the adult. 1 To date, the standard treatment of newly diagnosed GBM is maximal surgical resection followed by chemoradiation using temozolomide (TMZ). 2,3 However, disease progression occurs in almost all patients after rst line treatment, and median overall survival (OS) is of the order of 20 months. 4 Since, no highly effective treatment has been found for disease recurrence, the choice of the best second-line therapy remains an open issue. 5 To date, the most employed medical treatments at recurrence consist of nitrosourea-based schedules and / or antiangiogenic therapy. Lomustine, a nitrosourea alkylating agent, has been used as control in several phase 2 and 3 trials, [6][7][8][9][10][11][12][13] with a low objective response rate (around 10%), almost exclusively limited to patients with O6-methylguanine DNA methyltransferase promoter (MGMTp) methylation. 8,10,12 Bevacizumab is a recombinant humanised antibody that blocks angiogenesis by inhibiting the vascular endothelial growth factor receptor A (VEGF-A). As GBM is a highly vascularised tumour with increased endothelial proliferation and VEGFR expression, 14 bevacizumab has been investigated in several trials in both newly diagnosed and recurrent GBM. 15 Overall, it has been shown to increase progression-free survival (PFS), but not OS. 10 Regorafenib is an oral inhibitor of several kinases involve...

Temozolomide, Procarbazine and Nitrosoureas in the Therapy of Malignant Gliomas: Update of Mechanisms, Drug Resistance and Therapeutic Implications

“…These results, as promising as they are, did not remain unchallenged as the REGOMA study referred to a historical cohort of patients treated extensively with O6AA including CCNU. Still, confirmation was found in a recent trial, revealing at the same time that dose reduction was effective in attenuating toxic side effects without reducing the therapeutic benefit [144]. In these studies, the CDK inhibitor was administered after chemotherapy.…”

Antiangiogenic Therapy for Malignant Brain Tumors: Does It Still Matter?

“…Few other studies have shown similar impact on survival [ 74 – 79 ], but a higher rate of adverse events than in REGOMA, thus raising concerns over tolerability. A lower intensity regimen proved as effective as the standard 160 mg daily schedule used in REGOMA trial (median PFS and median OS of 2.0 months and 7.4 months), but with lower adverse events [ 80 ]. The AGILE trial (NCT03970447) will help to clarify the role of regorafenib in patients with newly diagnosed GBM without MGMT promoter methylation.…”

Regorafenib and glioblastoma: a literature review of preclinical studies, molecular mechanisms and clinical effectiveness

“…(Ref. 26 ) evaluated in a real life study the efficacy and tolerability of a lower intensity regimen. Interestingly, authors reported no loss of efficacy in terms of both PFS and OS.…”