regoma_trial

REGOMA trial


Clinical options for GBM patients remained unaltered for almost two decades until the encouraging results obtained by the phase II REGOMA trial allowed the introduction of the multikinase inhibitor regorafenib as a preferred regimen in relapsed GBM treatment by the National Comprehensive Cancer Network (NCCN) 2020 Guideline. Regorafenib, a sorafenib derivative, targets kinases associated with angiogenesis (VEGFR 1-3), as well as oncogenesis (c-KIT, RET, FGFR) and stromal kinases (FGFR, PDGFR-b). It was already approved for metastatic colorectal cancers and hepatocellular carcinomas 1).


The phase 2 REGOMA trial suggested an encouraging overall survival benefit in glioblastoma patients at first relapse treated with the multikinase inhibitor regorafenib 2)


Despite multimodal treatment with surgery and radiochemotherapy, the prognosis of glioblastoma remains poor, and practically all glioblastomas relapse. To date, no standard treatment exists for recurrent glioblastoma patients and traditional therapies have showed limited efficacy. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor showing encouraging benefits in recurrent Glioblastoma patients enrolled in the REGOMA trial. We performed a large study to investigate clinical outcomes and the safety of regorafenib in a real-life population of recurrent glioblastoma patients. Patients receiving regorafenib outside clinical trials at the Veneto Institute of Oncology were retrospectively reviewed. The major inclusion criteria were: histologically confirmed diagnosis of glioblastoma, prior first line therapy according to “Stupp protocol”, Eastern Cooperative Oncology Group (ECOG) performance status score ≤1. According to the original schedule, patients received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. The primary endpoints of the study were overall survival and safety. A total of 54 consecutive patients were enrolled. The median age was 56, MGMT methylated status was found in 28 out of 53 available patients (52.8%), IDH mutation in 5 (9.3%) and 22 patients were receiving steroids at baseline. The median overall survival was 10.2 months (95% CI, 6.4-13.9), the OS-12 was 43%. Age, MGMT methylation status and steroid use at baseline were not statistically significant on a multivariate analysis for OS. Patients reporting a disease control as best response to regorafenib demonstrated a significant longer survival (24.8 months vs. 6.2 months for patients with progressive disease, p = 0.0001). Grade 3 drug-related adverse events occurred in 10 patients (18%); 1 patient (2%) reported a grade 4 adverse event (rash maculo-papular). No death was considered to be drug-related. This study reported the first large “real-life” experience of regorafenib in recurrent glioblastoma. Overall, our results are close to the ones reported in the previous phase 2 study, despite the fact that we had a longer survival. We showed the encouraging activity and tolerability of this treatment in recurrent glioblastoma patients when used as a second-line treatment 3).


Regorafenib did not negatively affect HRQoL in patients with recurrent glioblastoma. These data combined with the survival benefit shown in the REGOMA trial support the use of regorafenib as a treatment option for these patients 4).


REGOMA trial showed an encouraging overall survival benefit of regorafenib in glioblastoma recurrence. This drug might be a new potential treatment for these patients and should be investigated in an adequately powered phase 3 study 5)


AMPK pathway activation is associated with clinical benefit from treatment with regorafenib in relapsed Glioblastoma 6).


4: Detti B, Scoccianti S, Lucidi S, Maragna V, Teriaca MA, Ganovelli M, Desideri I, Lorenzetti V, Scoccimarro E, Greto D, Livi L. Regorafenib in glioblastoma recurrence: A case report. Cancer Treat Res Commun. 2021;26:100263. doi: 10.1016/j.ctarc.2020.100263. Epub 2020 Dec 10. PMID: 33338858.

5: Santangelo A, Rossato M, Lombardi G, Benfatto S, Lavezzari D, De Salvo GL, Indraccolo S, Dechecchi MC, Prandini P, Gambari R, Scapoli C, Di Gennaro G, Caccese M, Eoli M, Rudà R, Brandes AA, Ibrahim T, Rizzato S, Lolli I, Lippi G, Delledonne M, Zagonel V, Cabrini G. A molecular signature associated with prolonged survival in glioblastoma patients treated with regorafenib. Neuro Oncol. 2021 Feb 25;23(2):264-276. doi: 10.1093/neuonc/noaa156. PMID: 32661549; PMCID: PMC7906066.

6: Indraccolo S, De Salvo GL, Verza M, Caccese M, Esposito G, Piga I, Del Bianco P, Pizzi M, Gardiman MP, Eoli M, Rudà R, Brandes AA, Ibrahim T, Rizzato S, Lolli I, Zagonel V, Lombardi G. Phosphorylated Acetyl-CoA Carboxylase Is Associated with Clinical Benefit with Regorafenib in Relapsed Glioblastoma: REGOMA Trial Biomarker Analysis. Clin Cancer Res. 2020 Sep 1;26(17):4478-4484. doi: 10.1158/1078-0432.CCR-19-4055. Epub 2020 Jun 9. PMID: 32518098.

7: Zeiner PS, Kinzig M, Divé I, Maurer GD, Filipski K, Harter PN, Senft C, Bähr O, Hattingen E, Steinbach JP, Sörgel F, Voss M, Steidl E, Ronellenfitsch MW. Regorafenib CSF Penetration, Efficacy, and MRI Patterns in Recurrent Malignant Glioma Patients. J Clin Med. 2019 Nov 21;8(12):2031. doi: 10.3390/jcm8122031. PMID: 31766326; PMCID: PMC6947028.

8: Lombardi G, De Salvo GL, Brandes AA, Eoli M, Rudà R, Faedi M, Lolli I, Pace A, Daniele B, Pasqualetti F, Rizzato S, Bellu L, Pambuku A, Farina M, Magni G, Indraccolo S, Gardiman MP, Soffietti R, Zagonel V. Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open- label, randomised, controlled, phase 2 trial. Lancet Oncol. 2019 Jan;20(1):110-119. doi: 10.1016/S1470-2045(18)30675-2. Epub 2018 Dec 3. PMID: 30522967.


1)
Mongiardi MP, Pallini R, D'Alessandris QG, Levi A, Falchetti ML. Regorafenib and glioblastoma: a literature review of preclinical studies, molecular mechanisms and clinical effectiveness. Expert Rev Mol Med. 2024 Apr 2;26:e5. doi: 10.1017/erm.2024.8. PMID: 38563164.
2)
Werner JM, Wolf L, Tscherpel C, Bauer EK, Wollring M, Ceccon G, Deckert M, Brunn A, Pappesch R, Goldbrunner R, Fink GR, Galldiks N. Efficacy and tolerability of regorafenib in pretreated patients with progressive CNS grade 3 or 4 gliomas. J Neurooncol. 2022 Jun 18. doi: 10.1007/s11060-022-04066-9. Epub ahead of print. PMID: 35716310.
3)
Lombardi G, Caccese M, Padovan M, Cerretti G, Pintacuda G, Manara R, Di Sarra F, Zagonel V. Regorafenib in Recurrent Glioblastoma Patients: A Large and Monocentric Real-Life Study. Cancers (Basel). 2021 Sep 21;13(18):4731. doi: 10.3390/cancers13184731. PMID: 34572958; PMCID: PMC8471957.
4)
Lombardi G, Del Bianco P, Brandes AA, Eoli M, Rudà R, Ibrahim T, Lolli I, Rizzato S, Daniele B, Pace A, Pasqualetti F, Caccesse M, Bergo E, Magni G, De Salvo GL, Zagonel V. Patient-reported outcomes in a phase II randomised study of regorafenib compared with lomustine in patients with relapsed glioblastoma (the REGOMA trial). Eur J Cancer. 2021 Sep;155:179-190. doi: 10.1016/j.ejca.2021.06.055. Epub 2021 Aug 10. PMID: 34388515.
5)
Lombardi G, De Salvo GL, Brandes AA, Eoli M, Rudà R, Faedi M, Lolli I, Pace A, Daniele B, Pasqualetti F, Rizzato S, Bellu L, Pambuku A, Farina M, Magni G, Indraccolo S, Gardiman MP, Soffietti R, Zagonel V. Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol. 2019 Jan;20(1):110-119. doi: 10.1016/S1470-2045(18)30675-2. Epub 2018 Dec 3. PMID: 30522967.
6)
Indraccolo S, De Salvo GL, Verza M, Caccese M, Esposito G, Piga I, Del Bianco P, Pizzi M, Gardiman MP, Eoli M, Rudà R, Brandes AA, Ibrahim T, Rizzato S, Lolli I, Zagonel V, Lombardi G. Phosphorylated Acetyl-CoA Carboxylase Is Associated with Clinical Benefit with Regorafenib in Relapsed Glioblastoma: REGOMA Trial Biomarker Analysis. Clin Cancer Res. 2020 Sep 1;26(17):4478-4484. doi: 10.1158/1078-0432.CCR-19-4055. Epub 2020 Jun 9. PMID: 32518098.
  • regoma_trial.txt
  • Last modified: 2024/04/02 13:16
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