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

By J. Bennouna, J. Sastre, D. Arnold, P. Österlund, R. Greil, E. Van Cutsem, R. von Moos, J. Viéitez, O. Bouché, C. Borg and 7 more. The Lancet Oncology, 2013

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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 ≥18 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 ClinicalTrials.gov, number NCT00700102. 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.

Subfields: Oncology

View Paper: https://www.semanticscholar.org/paper/03039375aaa590ce1f569accaa9bb5191b757801

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Citations in the corpus

A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). (2015, neutral): “5 mth 0·81 (0·69–0·94) 1 [112]”
Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer (2019, background): “FOLFIRI + BEV [190, 191] CAPIRI + BEV (see comment 5) [192] FOLFIRI + RAM [193] Fig.”
Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. (2014, background): “It has also been shown that continuing bevacizumab while changing the cytotoxic backbone, in second line after progression in first line, improves the outcome (survival and PFS) [21] [I, B].”
VEGF in Signaling and Disease: Beyond Discovery and Development (2019, positive): “…metastatic colorectal cancer, still resulted in a small but significant OS benefit raised the possibility that resistance may be reversible, at least in some circumstances, and suggested that re-treating with the same or an alternate VEGF inhibitor may have clinical benefit (Bennouna et al., 2013).”
Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer (2012, neutral): “• FOLFIRI [62] + Bmab [85] ▪ FOLFIRI + Rmab [86] • IRIS (note 6) [87] + Bmab • IRI [88] + Bmab • FOLFIRI (or IRI) + Cmab/Pmab [88, 89]”
Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions (2014, methodology): “Continuation beyond progression Chemotherapy ± bevacizumab ML18 147 [92] Improvement in OS”
Ten years of anti-vascular endothelial growth factor therapy (2016, background): “80) , involving newly diagnosed GBM patients, PFS, but not OS, were improved with the combination of bevacizumab with radiotherapy and temozolomide compared with radiotherapy and temozolomide alone 87,88 .”
Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. (2014, background): “In colorectal cancer, continuing bevacizumab with second-line chemotherapy significantly improved OS (primary end point) in patients who had received first-line bevacizumab-containing regimens.(19) In AURELIA, only 26 patients (7%) had received prior antiangiogenic therapy; thus, no conclusions coul”
ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. (2016, methodology): “In view of the inclusion criteria of the bevacizumab, aflibercept and ramucirumab trials [283, 287, 289], aflibercept and ramucirumab may be considered for the treatment of patients with RAS mutant or unclassified tumours, and EGFR inhibitors for patients with RAS wild-type disease, especially when ”