TY - JOUR
T1 - Bevacizumab and temozolomide in patients with first recurrence of WHO grade II and III glioma, without 1p/19q co-deletion (TAVAREC)
T2 - a randomised controlled phase 2 EORTC trial
AU - van den Bent, Martin J.
AU - Klein, Martin
AU - Smits, Marion
AU - Reijneveld, Jaap C.
AU - French, Pim J.
AU - Clement, Paul
AU - de Vos, Filip Y.F.
AU - Wick, Antje
AU - Mulholland, Paul J.
AU - Taphoorn, Martin J.B.
AU - Lewis, Joanne
AU - Weller, Michael
AU - Chinot, Olivier L.
AU - Kros, Johan M.
AU - de Heer, Iris
AU - Verschuere, Tina
AU - Coens, Corneel
AU - Golfinopoulos, Vassilis
AU - Gorlia, Thierry
AU - Idbaih, Ahmed
N1 - Funding Information:
MJvdB reports grants and personal fees from Roche during the conduct of the study; personal fees from Celgene, Actelion, Celldex, Bristol-Myers Squibb (BMS), Daiichi Sankyo, and Merck Sharpe & Dohme (MSD); and grants and personal fees from Abbvie outside the submitted work. MS reports financial compensation from Parexel Ltd outside the submitted work. JCR reports fees for travel to congress from Roche Nederland NV outside the submitted work. PC reports personal fees from BMS Belgium NV, Merck NV, Vifor Pharma Belgium NV, AstraZeneca UK Limited, Abbvie, Leo Pharma NV, and MSD Belgium BVBA outside the submitted work. MJBT reports consultancy fees from Hoffmann La Roche outside the submitted work. MW reports grants from Actelion, Acceleron, Piqur, OGD2, and Merck (EMD); grants and personal fees from Roche, Merck (MSD), Tragara, Abbvie, and Novocure; and personal fees from Celldex, Celgene, Orbus, and Tocagen outside the submitted work. OLC reports grants, personal fees, and non-financial support from Roche; personal fees and non-financial support from BMS, Abbvie, and Servier; and personal fees from Immatics, Celdex, and Ipsen outside the submitted work. AI reports grants from Fondation ARC; travel fees and research support from Hoffmann-La Roche and Carthera; and personal fees from BMS, Hoffmann-La Roche, and Cipla (certified continuing education) outside the submitted work. All other authors declare no competing interests.
Funding Information:
We thank all patients and their relatives for their willingness to participate in this clinical trial. We thank the European Organisation for Research and Treatment of Cancer (EORTC) Cancer Research Fund and EORTC staff for their invaluable assistance and support of this trial (Roxana Albu, Pieter Jespers, Jelena Laverty, Sylvie Ledroit, Sara Meloen, Jean-Paul Nzanzu, Christine Olungu, Nabila Sebti, Thibault Smets, Zineb Wadid, and Lorraine Wheeler). We also thank all trial staff at the participating sites and the staff at Roche involved in this study.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/9
Y1 - 2018/9
N2 - BACKGROUND: Bevacizumab is frequently used in the treatment of recurrent WHO grade II and III glioma, but without supporting evidence from randomised trials. Therefore, we assessed the use of bevacizumab in patients with first recurrence of grade II or III glioma who did not have 1p/19q co-deletion.METHODS: The TAVAREC trial was a randomised, open-label phase 2 trial done at 32 centres across Europe in patients with locally diagnosed grade II or III glioma without 1p/19q co-deletion, with a first and contrast-enhancing recurrence after initial radiotherapy or chemotherapy, or both. Previous chemotherapy must have been stopped at least 6 months before enrolment and radiotherapy must have been stopped at least 3 months before enrolment. Random group assignment was done electronically through the European Organisation for Research and Treatment of Cancer web-based system, stratified by a minimisation procedure using institution, initial histology (WHO grade II vs III), WHO performance status (0 or 1 vs 2), and previous treatment (radiotherapy, chemotherapy, or both). Patients were assigned to receive either temozolomide (150-200 mg/m2, orally) monotherapy on days 1-5 every 4 weeks for a maximum of 12 cycles, or the same temozolomide regimen in combination with bevacizumab (10 mg/kg, intravenously) every 2 weeks until progression. The primary endpoint was overall survival at 12 months in the per-protocol population. Safety analyses were done in all patients who started their allocated treatment. The study is registered at EudraCT (2009-017422-39) and ClinicalTrials.gov (NCT01164189), and is complete.FINDINGS: Between Feb 8, 2011, and July 31, 2015, 155 patients were enrolled and randomly assigned to receive either monotherapy (n=77) or combination therapy (n=78). Overall survival in the per-protocol population at 12 months was achieved by 44 (61% [80% CI 53-69]) of 72 patients in the temozolomide group and 38 (55% [47-69]) of 69 in the combination group. The most frequent toxicity was haematological: 17 (23%) of 75 patients in the monotherapy group and 25 (33%) of 76 in the combination group developed grade 3 or 4 haematological toxicity. Other than haematological toxicities, the most common adverse events were nervous system disorders (59 [79%] of 75 patients in the monotherapy group vs 65 [86%] of 76 in the combination group), fatigue (53 [70%] vs 61 [80%]), and nausea (39 [52%] vs 43 [56%]). Infections were more frequently reported in the combination group (29 [38%] of 76 patients) than in the monotherapy group (17 [23%] of 75). One treatment-related death was reported in the combination group (infection after intratumoral haemorrhage during a treatment-related grade 4 thrombocytopenia).INTERPRETATION: We found no evidence of improved overall survival with bevacizumab and temozolomide combination treatment versus temozolomide monotherapy. The findings from this study provide no support for further phase 3 studies on the role of bevacizumab in this disease.FUNDING: Roche Pharmaceuticals.
AB - BACKGROUND: Bevacizumab is frequently used in the treatment of recurrent WHO grade II and III glioma, but without supporting evidence from randomised trials. Therefore, we assessed the use of bevacizumab in patients with first recurrence of grade II or III glioma who did not have 1p/19q co-deletion.METHODS: The TAVAREC trial was a randomised, open-label phase 2 trial done at 32 centres across Europe in patients with locally diagnosed grade II or III glioma without 1p/19q co-deletion, with a first and contrast-enhancing recurrence after initial radiotherapy or chemotherapy, or both. Previous chemotherapy must have been stopped at least 6 months before enrolment and radiotherapy must have been stopped at least 3 months before enrolment. Random group assignment was done electronically through the European Organisation for Research and Treatment of Cancer web-based system, stratified by a minimisation procedure using institution, initial histology (WHO grade II vs III), WHO performance status (0 or 1 vs 2), and previous treatment (radiotherapy, chemotherapy, or both). Patients were assigned to receive either temozolomide (150-200 mg/m2, orally) monotherapy on days 1-5 every 4 weeks for a maximum of 12 cycles, or the same temozolomide regimen in combination with bevacizumab (10 mg/kg, intravenously) every 2 weeks until progression. The primary endpoint was overall survival at 12 months in the per-protocol population. Safety analyses were done in all patients who started their allocated treatment. The study is registered at EudraCT (2009-017422-39) and ClinicalTrials.gov (NCT01164189), and is complete.FINDINGS: Between Feb 8, 2011, and July 31, 2015, 155 patients were enrolled and randomly assigned to receive either monotherapy (n=77) or combination therapy (n=78). Overall survival in the per-protocol population at 12 months was achieved by 44 (61% [80% CI 53-69]) of 72 patients in the temozolomide group and 38 (55% [47-69]) of 69 in the combination group. The most frequent toxicity was haematological: 17 (23%) of 75 patients in the monotherapy group and 25 (33%) of 76 in the combination group developed grade 3 or 4 haematological toxicity. Other than haematological toxicities, the most common adverse events were nervous system disorders (59 [79%] of 75 patients in the monotherapy group vs 65 [86%] of 76 in the combination group), fatigue (53 [70%] vs 61 [80%]), and nausea (39 [52%] vs 43 [56%]). Infections were more frequently reported in the combination group (29 [38%] of 76 patients) than in the monotherapy group (17 [23%] of 75). One treatment-related death was reported in the combination group (infection after intratumoral haemorrhage during a treatment-related grade 4 thrombocytopenia).INTERPRETATION: We found no evidence of improved overall survival with bevacizumab and temozolomide combination treatment versus temozolomide monotherapy. The findings from this study provide no support for further phase 3 studies on the role of bevacizumab in this disease.FUNDING: Roche Pharmaceuticals.
KW - Journal Article
UR - http://www.scopus.com/inward/record.url?scp=85053067573&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(18)30362-0
DO - 10.1016/S1470-2045(18)30362-0
M3 - Article
C2 - 30115593
SN - 1470-2045
VL - 19
SP - 1170
EP - 1179
JO - LANCET ONCOLOGY
JF - LANCET ONCOLOGY
IS - 9
ER -