Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA)

a multicentre, open-label, randomised, controlled, phase 2 trial

Giuseppe Lombardi, Gian Luca De Salvo, Alba Ariela Brandes, Marica Eoli, Roberta Rudà, Marina Faedi, Ivan Lolli, Andrea Pace, Bruno Daniele, Francesco Pasqualetti, Simona Rizzato, Luisa Bellu, Ardi Pambuku, Miriam Farina, Giovanna Magni, Stefano Indraccolo, Marina Paola Gardiman, Riccardo Soffietti, Vittorina Zagonel

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Glioblastoma is a highly vascularised tumour and there are few treatment options after disease recurrence. Regorafenib is an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases. We aimed to assess the efficacy and safety of regorafenib in the treatment of recurrent glioblastoma.

METHODS: REGOMA is a randomised, multicentre, open-label phase 2 trial done in ten centres in Italy. Eligible patients (aged ≥18 years) with histologically confirmed glioblastoma, Eastern Cooperative Oncology Group performance status 0 or 1, and documented disease progression after surgery followed by radiotherapy and temozolomide chemoradiotherapy were randomly assigned (1:1) by a web-based system, stratified by centre and surgery at recurrence (yes vs no), to receive regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle or lomustine 110 mg/m2 once every 6 weeks until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02926222, and is currently in follow-up.

FINDINGS: Between Nov 27, 2015, and Feb 23, 2017, 124 patients were screened and 119 eligible patients were randomly assigned to receive regorafenib (n=59) or lomustine (n=60). Median follow-up was 15·4 months (IQR 13·8-18·1). At the analysis cutoff date, 99 (83%) of 119 patients had died: 42 (71%) of 59 in the regorafenib group and 57 (95%) of 60 in the lomustine group. Overall survival was significantly improved in the regorafenib group compared with the lomustine group, with a median overall survival of 7·4 months (95% CI 5·8-12·0) in the regorafenib group and 5·6 months (4·7-7·3) in the lomustine group (hazard ratio 0·50, 95% CI 0·33-0·75; log-rank p=0·0009). Grade 3-4 treatment-related adverse events occurred in 33 (56%) of 59 patients treated with regorafenib and 24 (40%) of 60 with lomustine. The most frequent grade 3 or 4 adverse events related to regorafenib were hand-foot skin reaction, increased lipase, and blood bilirubin increased (in six [10%] of 59 patients each). In the lomustine group, the most common grade 3 or 4 adverse events were decreased platelet count (eight [13%] of 60 patients), decreased lymphocyte count (eight [13%]), and neutropenia (seven [12%]). No death was considered by the investigators to be drug related.

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

FUNDING: Veneto Institute of Oncology and Bayer Italy.

Original languageEnglish
Pages (from-to)110-119
Number of pages10
JournalThe Lancet. Oncology
Volume20
Issue number1
DOIs
Publication statusPublished - Jan 2019

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Lomustine
Glioblastoma
Survival
temozolomide
Italy
Disease Progression
regorafenib
Recurrence
Angiogenesis Inhibitors
Lymphocyte Count
Receptor Protein-Tyrosine Kinases
Chemoradiotherapy
Therapeutics
Neutropenia
Lipase
Platelet Count
Bilirubin
Pharmaceutical Preparations
Foot
Radiotherapy

Cite this

Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA) : a multicentre, open-label, randomised, controlled, phase 2 trial. / Lombardi, Giuseppe; De Salvo, Gian Luca; Brandes, Alba Ariela; Eoli, Marica; Rudà, Roberta; Faedi, Marina; Lolli, Ivan; Pace, Andrea; Daniele, Bruno; Pasqualetti, Francesco; Rizzato, Simona; Bellu, Luisa; Pambuku, Ardi; Farina, Miriam; Magni, Giovanna; Indraccolo, Stefano; Gardiman, Marina Paola; Soffietti, Riccardo; Zagonel, Vittorina.

In: The Lancet. Oncology, Vol. 20, No. 1, 01.2019, p. 110-119.

Research output: Contribution to journalArticle

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abstract = "BACKGROUND: Glioblastoma is a highly vascularised tumour and there are few treatment options after disease recurrence. Regorafenib is an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases. We aimed to assess the efficacy and safety of regorafenib in the treatment of recurrent glioblastoma.METHODS: REGOMA is a randomised, multicentre, open-label phase 2 trial done in ten centres in Italy. Eligible patients (aged ≥18 years) with histologically confirmed glioblastoma, Eastern Cooperative Oncology Group performance status 0 or 1, and documented disease progression after surgery followed by radiotherapy and temozolomide chemoradiotherapy were randomly assigned (1:1) by a web-based system, stratified by centre and surgery at recurrence (yes vs no), to receive regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle or lomustine 110 mg/m2 once every 6 weeks until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02926222, and is currently in follow-up.FINDINGS: Between Nov 27, 2015, and Feb 23, 2017, 124 patients were screened and 119 eligible patients were randomly assigned to receive regorafenib (n=59) or lomustine (n=60). Median follow-up was 15·4 months (IQR 13·8-18·1). At the analysis cutoff date, 99 (83{\%}) of 119 patients had died: 42 (71{\%}) of 59 in the regorafenib group and 57 (95{\%}) of 60 in the lomustine group. Overall survival was significantly improved in the regorafenib group compared with the lomustine group, with a median overall survival of 7·4 months (95{\%} CI 5·8-12·0) in the regorafenib group and 5·6 months (4·7-7·3) in the lomustine group (hazard ratio 0·50, 95{\%} CI 0·33-0·75; log-rank p=0·0009). Grade 3-4 treatment-related adverse events occurred in 33 (56{\%}) of 59 patients treated with regorafenib and 24 (40{\%}) of 60 with lomustine. The most frequent grade 3 or 4 adverse events related to regorafenib were hand-foot skin reaction, increased lipase, and blood bilirubin increased (in six [10{\%}] of 59 patients each). In the lomustine group, the most common grade 3 or 4 adverse events were decreased platelet count (eight [13{\%}] of 60 patients), decreased lymphocyte count (eight [13{\%}]), and neutropenia (seven [12{\%}]). No death was considered by the investigators to be drug related.INTERPRETATION: REGOMA showed an encouraging overall survival benefit of regorafenib in recurrent glioblastoma. This drug might be a new potential treatment for these patients and should be investigated in an adequately powered phase 3 study.FUNDING: Veneto Institute of Oncology and Bayer Italy.",
author = "Giuseppe Lombardi and {De Salvo}, {Gian Luca} and Brandes, {Alba Ariela} and Marica Eoli and Roberta Rud{\`a} and Marina Faedi and Ivan Lolli and Andrea Pace and Bruno Daniele and Francesco Pasqualetti and Simona Rizzato and Luisa Bellu and Ardi Pambuku and Miriam Farina and Giovanna Magni and Stefano Indraccolo and Gardiman, {Marina Paola} and Riccardo Soffietti and Vittorina Zagonel",
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T1 - Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA)

T2 - a multicentre, open-label, randomised, controlled, phase 2 trial

AU - Lombardi, Giuseppe

AU - De Salvo, Gian Luca

AU - Brandes, Alba Ariela

AU - Eoli, Marica

AU - Rudà, Roberta

AU - Faedi, Marina

AU - Lolli, Ivan

AU - Pace, Andrea

AU - Daniele, Bruno

AU - Pasqualetti, Francesco

AU - Rizzato, Simona

AU - Bellu, Luisa

AU - Pambuku, Ardi

AU - Farina, Miriam

AU - Magni, Giovanna

AU - Indraccolo, Stefano

AU - Gardiman, Marina Paola

AU - Soffietti, Riccardo

AU - Zagonel, Vittorina

N1 - Copyright © 2019 Elsevier Ltd. All rights reserved.

PY - 2019/1

Y1 - 2019/1

N2 - BACKGROUND: Glioblastoma is a highly vascularised tumour and there are few treatment options after disease recurrence. Regorafenib is an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases. We aimed to assess the efficacy and safety of regorafenib in the treatment of recurrent glioblastoma.METHODS: REGOMA is a randomised, multicentre, open-label phase 2 trial done in ten centres in Italy. Eligible patients (aged ≥18 years) with histologically confirmed glioblastoma, Eastern Cooperative Oncology Group performance status 0 or 1, and documented disease progression after surgery followed by radiotherapy and temozolomide chemoradiotherapy were randomly assigned (1:1) by a web-based system, stratified by centre and surgery at recurrence (yes vs no), to receive regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle or lomustine 110 mg/m2 once every 6 weeks until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02926222, and is currently in follow-up.FINDINGS: Between Nov 27, 2015, and Feb 23, 2017, 124 patients were screened and 119 eligible patients were randomly assigned to receive regorafenib (n=59) or lomustine (n=60). Median follow-up was 15·4 months (IQR 13·8-18·1). At the analysis cutoff date, 99 (83%) of 119 patients had died: 42 (71%) of 59 in the regorafenib group and 57 (95%) of 60 in the lomustine group. Overall survival was significantly improved in the regorafenib group compared with the lomustine group, with a median overall survival of 7·4 months (95% CI 5·8-12·0) in the regorafenib group and 5·6 months (4·7-7·3) in the lomustine group (hazard ratio 0·50, 95% CI 0·33-0·75; log-rank p=0·0009). Grade 3-4 treatment-related adverse events occurred in 33 (56%) of 59 patients treated with regorafenib and 24 (40%) of 60 with lomustine. The most frequent grade 3 or 4 adverse events related to regorafenib were hand-foot skin reaction, increased lipase, and blood bilirubin increased (in six [10%] of 59 patients each). In the lomustine group, the most common grade 3 or 4 adverse events were decreased platelet count (eight [13%] of 60 patients), decreased lymphocyte count (eight [13%]), and neutropenia (seven [12%]). No death was considered by the investigators to be drug related.INTERPRETATION: REGOMA showed an encouraging overall survival benefit of regorafenib in recurrent glioblastoma. This drug might be a new potential treatment for these patients and should be investigated in an adequately powered phase 3 study.FUNDING: Veneto Institute of Oncology and Bayer Italy.

AB - BACKGROUND: Glioblastoma is a highly vascularised tumour and there are few treatment options after disease recurrence. Regorafenib is an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases. We aimed to assess the efficacy and safety of regorafenib in the treatment of recurrent glioblastoma.METHODS: REGOMA is a randomised, multicentre, open-label phase 2 trial done in ten centres in Italy. Eligible patients (aged ≥18 years) with histologically confirmed glioblastoma, Eastern Cooperative Oncology Group performance status 0 or 1, and documented disease progression after surgery followed by radiotherapy and temozolomide chemoradiotherapy were randomly assigned (1:1) by a web-based system, stratified by centre and surgery at recurrence (yes vs no), to receive regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle or lomustine 110 mg/m2 once every 6 weeks until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02926222, and is currently in follow-up.FINDINGS: Between Nov 27, 2015, and Feb 23, 2017, 124 patients were screened and 119 eligible patients were randomly assigned to receive regorafenib (n=59) or lomustine (n=60). Median follow-up was 15·4 months (IQR 13·8-18·1). At the analysis cutoff date, 99 (83%) of 119 patients had died: 42 (71%) of 59 in the regorafenib group and 57 (95%) of 60 in the lomustine group. Overall survival was significantly improved in the regorafenib group compared with the lomustine group, with a median overall survival of 7·4 months (95% CI 5·8-12·0) in the regorafenib group and 5·6 months (4·7-7·3) in the lomustine group (hazard ratio 0·50, 95% CI 0·33-0·75; log-rank p=0·0009). Grade 3-4 treatment-related adverse events occurred in 33 (56%) of 59 patients treated with regorafenib and 24 (40%) of 60 with lomustine. The most frequent grade 3 or 4 adverse events related to regorafenib were hand-foot skin reaction, increased lipase, and blood bilirubin increased (in six [10%] of 59 patients each). In the lomustine group, the most common grade 3 or 4 adverse events were decreased platelet count (eight [13%] of 60 patients), decreased lymphocyte count (eight [13%]), and neutropenia (seven [12%]). No death was considered by the investigators to be drug related.INTERPRETATION: REGOMA showed an encouraging overall survival benefit of regorafenib in recurrent glioblastoma. This drug might be a new potential treatment for these patients and should be investigated in an adequately powered phase 3 study.FUNDING: Veneto Institute of Oncology and Bayer Italy.

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