Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial

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• 作者：Jaafar Bennouna ; MD^a ; Javier Sastre ; MD^b ; Prof Dirk Arnold ; MD^c ; Pia Ö ; sterlund ; MD^d ; Prof Richard Greil ; MD^e ; Prof Eric Van Cutsem ; MD^f ; Roger von Moos ; MD^g ; Jose Maria Vié ; itez ; MD^h ; Prof Olivier Bouché ; MDⁱ ; Christophe Borg ; MD^j ; Claus-Christoph Steffens ; MD^k ; Vicente Alonso-Orduñ ; a ; MD^l ; Christoph Schlichting ; MD^m ; Irmarie Reyes-Rivera ; MDⁿ ; Belguendouz Bendahmane ; MD^o ; Prof Thierry André ; MD^p ; Prof Stefan Kubicka ; MD^q ; ^{kubicka.stefan@mh-hannover.de} ; on behalf of the ML18147 Study Investigators ^&dagger ;
• 刊名：Lancet Oncology
• 出版年：2013
• 出版时间：January, 2013
• 年：2013
• 卷：14
• 期：1
• 页码：29-37
• 全文大小：281 K

文摘

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Summary

Background

Bevacizumab plus fluoropyrimidine-based chemotherapy is standard treatment for first-line and bevacizumab-naive second-line metastatic colorectal cancer. We assessed continued use of bevacizumab plus standard second-line chemotherapy in patients with metastatic colorectal cancer progressing after standard first-line bevacizumab-based treatment.

Methods

In an open-label, phase 3 study in 220 centres in Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, the Netherlands, Norway, Portugal, Saudi Arabia, Spain, Sweden, and Switzerland, patients (aged ¡Ý18 years) with unresectable, histologically confirmed metastatic colorectal cancer progressing up to 3 months after discontinuing first-line bevacizumab plus chemotherapy were randomly assigned in a 1:1 ratio to second-line chemotherapy with or without bevacizumab 2¡¤5 mg/kg per week equivalent (either 5 mg/kg every 2 weeks or 7¡¤5 mg/kg every 3 weeks, intravenously). The choice between oxaliplatin-based or irinotecan-based second-line chemotherapy depended on the first-line regimen (switch of chemotherapy). A combination of a permuted block design and the Pocock and Simon minimisation algorithm was used for the randomisation. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with , number .

Findings

Between Feb 1, 2006, and June 9, 2010, 409 (50 % ) patients were assigned to bevacizumab plus chemotherapy and 411 (50 % ) to chemotherapy alone. Median follow-up was 11¡¤1 months (IQR 6¡¤4-15¡¤6) in the bevacizumab plus chemotherapy group and 9¡¤6 months (5¡¤4-13¡¤9) in the chemotherapy alone group. Median overall survival was 11¡¤2 months (95 % CI 10¡¤4-12¡¤2) for bevacizumab plus chemotherapy and 9¡¤8 months (8¡¤9-10¡¤7) for chemotherapy alone (hazard ratio 0¡¤81, 95 % CI 0¡¤69-0¡¤94; unstratified log-rank test p=0¡¤0062). Grade 3-5 bleeding or haemorrhage (eight [2 % ] vs one [<1 % ]), gastrointestinal perforation (seven [2 % ] vs three [<1 % ]), and venous thromboembolisms (19 [5 % ] vs 12 [3 % ]) were more common in the bevacizumab plus chemotherapy group than in the chemotherapy alone group. The most frequently reported grade 3-5 adverse events were neutropenia (65 [16 % ] in the bevacizumab and chemotherapy group vs 52 [13 % ] in the chemotherapy alone group), diarrhoea (40 [10 % ] vs 34 [8 % ], respectively), and asthenia (23 [6 % ] vs 17 [4 % ], respectively). Treatment-related deaths were reported for four patients in the bevacizumab plus chemotherapy group and three in the chemotherapy alone group.

Interpretation

Maintenance of VEGF inhibition with bevacizumab plus standard second-line chemotherapy beyond disease progression has clinical benefits in patients with metastatic colorectal cancer. This approach is also being investigated in other tumour types, including metastatic breast and non-small cell lung cancers.

Funding

F Hoffmann-La Roche.