REGOMA: A randomized, multicenter, controlled open-label phase II clinical trial evaluating regorafenib activity in relapsed glioblastoma patients

Abstract

Background: There is no established treatment regimen for recurrent glioblastoma (GBM). GBMs have high expression of pro-angiogenic factors and activation of multiple signaling pathways in the tumor microenvironment, including the receptor tyrosine kinases, VEGFR, FGFR, and PDGFR. Regorafenib (Reg), an oral multikinase inhibitor, inhibits these angiogenic kinases and the mutant oncogenic kinases KIT, RET, and B-RAF. Methods: The primary aim of this academic trial was to assess Reg activity in prolonging overall survival (OS) in patients (pts) with relapsed GBM after surgery and Stupp regimen (a=0.2, 1-sided; b=0.2). Secondary objectives were disease control rate (DCR), safety, progression free survival (PFS), quality of life (QoL) and analysis of angiogenic and metabolic tissue biomarkers as possible predictors of response to Reg. Eligible pts with histologically confirmed GBM, ECOG PS 0‐1, and documented disease progression were randomized 1:1 to Reg 160 mg/day (3 weeks on, 1 week off) or lomustine (Lom) 110 mg/m2 (every 6 weeks) until disease progression or unacceptable toxicity. Tumor response was evaluated by gadolinium brain MRI every 8 weeks according to the RANO criteria. Results: Between November 2015 and February 2017, 119 pts were enrolled (n = 59 Reg; n = 60 Lom) and stratified for surgery at recurrence; baseline characteristics were balanced. Median age was 57.3 yrs and MGMT was methylated in 47.5% and 44.1% of Reg and Lom pts, respectively. 27 pts (22.7%) had surgery at recurrence. At the time of analysis 73 pts had died. Median OS was 6.5 months(m) (95% CI 5.6–12.0) for REG and 5.5m (95% CI 4.7–8.0) for Lom (HR=0.64; 80% CI 0.47–0.87; p = 0.028, 1-sided log-rank test). DCR (CR+PR+SD) was 44.8% and 21.1% (p = 0.009) for Reg and Lom, respectively. The 6-month PFS rates were 15.5% and 8.3% for Reg and Lom (HR = 0.69; 95% CI 0.47–1.01; p = 0.051). Grade ≥3 adverse events were reported in 56% and 40% of pts who received Reg and Lom. Conclusions: In this randomized, controlled study we report for the first time Reg activity in pts with relapsed GBM. Reg significantly improved OS and DCR in recurrent GBM compared to Lom. Reg administration was feasible and safe. QoL and biomarker analyses are ongoing. Clinical trial identification: EudraCT Number: 2014‐003722‐41. Legal entity responsible for the study: Veneto Institute of Oncology Funding: Veneto Institute of Oncology and Bayer Disclosure: All authors have declared no conflicts of interest.