Bevacizumab (Avastin®) is a recombinant monoclonal antibody that prevents the growth and maintenance of tumour blood vessels. It is indicated in patients with mCRC who have progressed on first-line Avastin®-containing regimen and is administered in combination with fluoropyrimidine-, irinotecan- or fluoropyrimidine-oxaliplatin based chemotherapy. For this indication, both the EMA and the FDA granted marketing authorisation in 2013.
The ML18147 trial, a prospective, randomised, open-label phase III study evaluated the continued use of bevacizumab plus standard second-line chemotherapy in patients with mCRC who had progressed after standard first-line bevacizumab-based treatment. 820 patients were randomly assigned to two treatment arms and received either chemotherapy plus bevacizumab (N=409) or chemotherapy alone (N=411). The median duration of treatment with bevacizumab was 3.9 months. All patients were previously treated with bevacizumab plus standard first-line chemotherapy, including fluoropyrimidine plus either oxaliplatin or irinotecan. Patients in both groups had a median age of 63 years and an ECOG performance status of 0–2.
Analyses showed a gain in median overall survival (OS) of 1.4 months for the bevacizumab plus chemotherapy group compared to the chemotherapy alone group (HR 0.81, 95% CI 0.69–0.94; p=0.0062). For median progression-free survival a risk reduction of 32% was observed, also favouring the combination regimen. Median OS from the start of first-line treatment was prolonged by 1.4 months in the bevacizumab plus chemotherapy arm compared to the chemotherapy alone arm. High rates of adverse events were observed in both treatment arms: 98% (bevacizumab + chemotherapy group) and 99% of patients (chemotherapy alone group) had adverse events. Grade 3–5 adverse events occurred in 64% (bevacizumab plus chemotherapy) and 57% (chemotherapy alone) of patients. From overall 11 grade 5 adverse events resulting in death, 4 deaths in the bevacizumab + chemotherapy group and 3 deaths in the chemotherapy alone group were deemed to be treatment-related. Serious adverse events were reported in 32% of patients in the bevacizumab plus chemotherapy group and in 33% of patients in the chemotherapy alone group.
Patients with mCRC who experienced disease progression after first-line treatment have a poor prognosis and the use of bevacizumab in maintenance therapy adds to the armamentarium of available treatment options. However, modest clinical benefits and high treatment costs have to be weighed against each other. Future research is required to evaluate optimal treatment line(s), dosage, further treatment combinations and side effects associated with long-term therapy, as are investigations into EGFR and various VEGF inhibitors for this indication.