Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial

Bernard Escudier, Anna Pluzanska, Piotr Koralewski, Alain Ravaud, Sergio Bracarda, Cezary Szczylik, Christine Chevreau, Marek Filipek, Bohuslav Melichar, Emilio Bajetta, Vera Gorbunova, Jacques Olivier Bay, I. Bodrogi, Agnieszka Jagiello-Gruszfeld, Nicola Moore

Research output: Contribution to journalArticle

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Abstract

Background: Vascular endothelial growth factor (VEGF) inhibition is a valid therapeutic approach in renal cell carcinoma. Therefore, an investigation of the combination treatment of the humanised anti-VEGF monoclonal antibody bevacizumab with interferon alfa was warranted. Methods: In a multicentre, randomised, double-blind, phase III trial, 649 patients with previously untreated metastatic renal cell carcinoma were randomised to receive interferon alfa-2a (9 MIU subcutaneously three times weekly) and bevacizumab (10 mg/kg every 2 weeks; n=327) or placebo and interferon alfa-2a (n=322). The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. An interim analysis of overall survival was prespecified after 250 deaths. On the basis of new second-line therapies that became available while the trial was in progress, which could have confounded analyses of overall survival data, we agreed with regulatory agencies that the pre-planned final analysis of progression-free survival would be acceptable for regulatory submission. The protocol was amended to allow the study to be unblinded at this point. The final analysis of progression-free survival is reported here. Efficacy analyses were done by intention to treat. This trial is registered with centerwatch.com, number BO17705E. Findings: 325 patients in the bevacizumab plus interferon alfa group and 316 in the placebo plus interferon alfa group received at least one dose of study treatment. At the time of unblinding, 230 progression events had occurred in the bevacizumab plus interferon alfa group and 275 in the control group; there were 114 deaths in the bevacizumab plus interferon alfa group and 137 in the control group. Median duration of progression-free survival was significantly longer in the bevacizumab plus interferon alfa group than it was in the control group (10·2 months vs 5·4 months; HR 0·63, 95% CI 0·52-0·75; p=0·0001). Increases in progression-free survival were seen with bevacizumab plus interferon alfa irrespective of risk group or whether reduced-dose interferon alfa was received. Deaths due to adverse events were reported in eight (2%) patients who received one or more doses of bevacizumab and seven (2%) of those who did not receive the drug. Only three deaths in the bevacizumab arm were considered by investigators to be possibly related to bevacizumab. The most commonly reported grade 3 or worse adverse events were fatigue (40 [12%] patients in the bevacizumab group vs 25 [8%] in the control group) and asthenia (34 [10%] vs 20 [7%]). Interpretation: The combination of bevacizumab with interferon alfa as first-line treatment in patients with metastatic renal cell carcinoma results in a significant improvement in progression-free survival, compared with interferon alfa alone.

Original languageEnglish
Pages (from-to)2103-2111
Number of pages9
JournalThe Lancet
Volume370
Issue number9605
DOIs
Publication statusPublished - Dec 22 2007

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Renal Cell Carcinoma
Interferon-alpha
Disease-Free Survival
Therapeutics
Control Groups
Survival Analysis
Vascular Endothelial Growth Factor A
interferon alfa-2a
Bevacizumab
Placebos
Asthenia
Fatigue
Monoclonal Antibodies
Research Personnel
Safety

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Escudier, B., Pluzanska, A., Koralewski, P., Ravaud, A., Bracarda, S., Szczylik, C., ... Moore, N. (2007). Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. The Lancet, 370(9605), 2103-2111. https://doi.org/10.1016/S0140-6736(07)61904-7

Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma : a randomised, double-blind phase III trial. / Escudier, Bernard; Pluzanska, Anna; Koralewski, Piotr; Ravaud, Alain; Bracarda, Sergio; Szczylik, Cezary; Chevreau, Christine; Filipek, Marek; Melichar, Bohuslav; Bajetta, Emilio; Gorbunova, Vera; Bay, Jacques Olivier; Bodrogi, I.; Jagiello-Gruszfeld, Agnieszka; Moore, Nicola.

In: The Lancet, Vol. 370, No. 9605, 22.12.2007, p. 2103-2111.

Research output: Contribution to journalArticle

Escudier, B, Pluzanska, A, Koralewski, P, Ravaud, A, Bracarda, S, Szczylik, C, Chevreau, C, Filipek, M, Melichar, B, Bajetta, E, Gorbunova, V, Bay, JO, Bodrogi, I, Jagiello-Gruszfeld, A & Moore, N 2007, 'Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial', The Lancet, vol. 370, no. 9605, pp. 2103-2111. https://doi.org/10.1016/S0140-6736(07)61904-7
Escudier, Bernard ; Pluzanska, Anna ; Koralewski, Piotr ; Ravaud, Alain ; Bracarda, Sergio ; Szczylik, Cezary ; Chevreau, Christine ; Filipek, Marek ; Melichar, Bohuslav ; Bajetta, Emilio ; Gorbunova, Vera ; Bay, Jacques Olivier ; Bodrogi, I. ; Jagiello-Gruszfeld, Agnieszka ; Moore, Nicola. / Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma : a randomised, double-blind phase III trial. In: The Lancet. 2007 ; Vol. 370, No. 9605. pp. 2103-2111.
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T1 - Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma

T2 - a randomised, double-blind phase III trial

AU - Escudier, Bernard

AU - Pluzanska, Anna

AU - Koralewski, Piotr

AU - Ravaud, Alain

AU - Bracarda, Sergio

AU - Szczylik, Cezary

AU - Chevreau, Christine

AU - Filipek, Marek

AU - Melichar, Bohuslav

AU - Bajetta, Emilio

AU - Gorbunova, Vera

AU - Bay, Jacques Olivier

AU - Bodrogi, I.

AU - Jagiello-Gruszfeld, Agnieszka

AU - Moore, Nicola

PY - 2007/12/22

Y1 - 2007/12/22

N2 - Background: Vascular endothelial growth factor (VEGF) inhibition is a valid therapeutic approach in renal cell carcinoma. Therefore, an investigation of the combination treatment of the humanised anti-VEGF monoclonal antibody bevacizumab with interferon alfa was warranted. Methods: In a multicentre, randomised, double-blind, phase III trial, 649 patients with previously untreated metastatic renal cell carcinoma were randomised to receive interferon alfa-2a (9 MIU subcutaneously three times weekly) and bevacizumab (10 mg/kg every 2 weeks; n=327) or placebo and interferon alfa-2a (n=322). The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. An interim analysis of overall survival was prespecified after 250 deaths. On the basis of new second-line therapies that became available while the trial was in progress, which could have confounded analyses of overall survival data, we agreed with regulatory agencies that the pre-planned final analysis of progression-free survival would be acceptable for regulatory submission. The protocol was amended to allow the study to be unblinded at this point. The final analysis of progression-free survival is reported here. Efficacy analyses were done by intention to treat. This trial is registered with centerwatch.com, number BO17705E. Findings: 325 patients in the bevacizumab plus interferon alfa group and 316 in the placebo plus interferon alfa group received at least one dose of study treatment. At the time of unblinding, 230 progression events had occurred in the bevacizumab plus interferon alfa group and 275 in the control group; there were 114 deaths in the bevacizumab plus interferon alfa group and 137 in the control group. Median duration of progression-free survival was significantly longer in the bevacizumab plus interferon alfa group than it was in the control group (10·2 months vs 5·4 months; HR 0·63, 95% CI 0·52-0·75; p=0·0001). Increases in progression-free survival were seen with bevacizumab plus interferon alfa irrespective of risk group or whether reduced-dose interferon alfa was received. Deaths due to adverse events were reported in eight (2%) patients who received one or more doses of bevacizumab and seven (2%) of those who did not receive the drug. Only three deaths in the bevacizumab arm were considered by investigators to be possibly related to bevacizumab. The most commonly reported grade 3 or worse adverse events were fatigue (40 [12%] patients in the bevacizumab group vs 25 [8%] in the control group) and asthenia (34 [10%] vs 20 [7%]). Interpretation: The combination of bevacizumab with interferon alfa as first-line treatment in patients with metastatic renal cell carcinoma results in a significant improvement in progression-free survival, compared with interferon alfa alone.

AB - Background: Vascular endothelial growth factor (VEGF) inhibition is a valid therapeutic approach in renal cell carcinoma. Therefore, an investigation of the combination treatment of the humanised anti-VEGF monoclonal antibody bevacizumab with interferon alfa was warranted. Methods: In a multicentre, randomised, double-blind, phase III trial, 649 patients with previously untreated metastatic renal cell carcinoma were randomised to receive interferon alfa-2a (9 MIU subcutaneously three times weekly) and bevacizumab (10 mg/kg every 2 weeks; n=327) or placebo and interferon alfa-2a (n=322). The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. An interim analysis of overall survival was prespecified after 250 deaths. On the basis of new second-line therapies that became available while the trial was in progress, which could have confounded analyses of overall survival data, we agreed with regulatory agencies that the pre-planned final analysis of progression-free survival would be acceptable for regulatory submission. The protocol was amended to allow the study to be unblinded at this point. The final analysis of progression-free survival is reported here. Efficacy analyses were done by intention to treat. This trial is registered with centerwatch.com, number BO17705E. Findings: 325 patients in the bevacizumab plus interferon alfa group and 316 in the placebo plus interferon alfa group received at least one dose of study treatment. At the time of unblinding, 230 progression events had occurred in the bevacizumab plus interferon alfa group and 275 in the control group; there were 114 deaths in the bevacizumab plus interferon alfa group and 137 in the control group. Median duration of progression-free survival was significantly longer in the bevacizumab plus interferon alfa group than it was in the control group (10·2 months vs 5·4 months; HR 0·63, 95% CI 0·52-0·75; p=0·0001). Increases in progression-free survival were seen with bevacizumab plus interferon alfa irrespective of risk group or whether reduced-dose interferon alfa was received. Deaths due to adverse events were reported in eight (2%) patients who received one or more doses of bevacizumab and seven (2%) of those who did not receive the drug. Only three deaths in the bevacizumab arm were considered by investigators to be possibly related to bevacizumab. The most commonly reported grade 3 or worse adverse events were fatigue (40 [12%] patients in the bevacizumab group vs 25 [8%] in the control group) and asthenia (34 [10%] vs 20 [7%]). Interpretation: The combination of bevacizumab with interferon alfa as first-line treatment in patients with metastatic renal cell carcinoma results in a significant improvement in progression-free survival, compared with interferon alfa alone.

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